sirolimus and Proteinuria

Nephrotic-range proteinuria has been known for years to be associated with poor renal outcome. Newer evidence indicates that early (1-3 months after transplantation) low-grade proteinuria and microalbuminuria (1) provide information on the graft in terms of donor characteristics and ischemia/reperfusion injury, (2) may occur before the development of donor-specific antibodies, (3) predict the development of diabetes and cardiovascular events, and (4) are associated with reduced long-term graft and patient survivals. Low-grade proteinuria and microalbuminuria are also predictive of diabetes, cardiovascular morbidity, and death in nontransplanted populations, which may help us to understand the pathophysiology of low-grade proteinuria or microalbuminuria in renal transplantation. The impact of immunosuppressive medications, including mammalian target of rapamycin inhibitors, on graft survival is still discussed, and the effect on proteinuria is crucial to the debate. The fact that chronic allograft rejection may exist as early as 3 months after renal transplantation indicates that optimal management of low-grade proteinuria or microalbuminuria should occur very early after transplantation to improve long-term renal function and the overall outcome of renal transplant recipients. The presence of low-grade proteinuria or microalbuminuria early after transplantation must be taken into account to choose adequate immunosuppressive and antihypertensive medications. Limited information exists regarding the benefit of therapeutic interventions to reduce low-grade proteinuria or microalbuminuria. Whether renin angiotensin blockade results in optimal nephroprotection in patients with low-grade proteinuria or microalbuminuria is not proven, especially in the absence of chronic allograft nephropathy. Observational studies and randomized clinical trials yield conflicting results. Finally, randomized clinical trials are urgently needed.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Prognosis; Proteinuria; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

The role of the mammalian target of rapamycin (mTOR) inhibition in the treatment of autosomal dominant polycystic kidney disease (ADPKD) remains unclear. This meta-analysis included all randomized controlled trials (RCTs) that used mTOR inhibitors (TORIs) to halt the progression of ADPKD.. Databases including MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant trials. RCTs of TORI treatment in patients with ADPKD were included. Effects on the primary outcome [total kidney volume (TKV)] and secondary outcomes [changes in cyst volume (CV) and parenchymal volume (PV), glomerular filtration rate (GFR), proteinuria, and adverse events] were analyzed.. The results of 5 RCTs, which included 619 patients, were analyzed. TORIs did not significantly reduce TKV [mean difference (WMD) -90.01 ml, 95% CI -235.49 to 55.47, p = 0.23; I(2) = 0%; p for heterogeneity = 0.67]. CV decreased after TORI treatment (WMD -15.08 ml, 95% CI -17.82 to -12.34, p < 0.00001), and PV did not change (WMD -0.55 ml, 95% CI -64.55 to 63.45, p = 0.99). There was no significant difference in GFR between the TORI-treated and control groups (WMD 4.94 ml/min, 95% CI -0.81 to 10.68, p = 0.09). Proteinuria was significantly higher in the TORI-treated group than in the control group (standard mean difference 0.27, 95% CI 0.09-0.44, p = 0.002).. Long-term treatment with TORIs does not benefit patients with ADPKD.

Topics: Evidence-Based Medicine; Humans; Immunosuppressive Agents; Longitudinal Studies; Polycystic Kidney, Autosomal Dominant; Proteinuria; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

The use of mammalian target of rapamycin inhibitor (mTOR-I) after kidney transplantation has been associated with a higher incidence of proteinuria compared with calcineurin inhibitors (CNIs). This review will focus on mTOR-I-associated proteinuria in different settings after kidney transplantation: de novo mTOR-I treatment in combination with CNI, de novo mTOR-I-containing and CNI-free treatment, early conversion from a CNI-based regimen to an mTOR-I-based regimen, and late conversion. Some possible mechanisms of mTOR-I-induced proteinuria will also be reviewed.

Topics: Disease Progression; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

SRL, an mTOR inhibitor that inhibits cell cycle progression, represents an important alternative to CNIs, which are still the cornerstones of pediatric solid organ tx. Because there are still limited data on SRL use among pediatric solid organ recipients, further studies are needed to verify the efficacy and safety of SRL. It has unique pharmacokinetic characteristics concerning dosing intervals and reduction of the dose in combination with other immunosuppressants. SRL also has antineoplastic, antiviral, and antiatherogenic advantages over other immunosuppressive agents. The adverse effects of SRL including thrombocytopenia, hyperlipidemia, proteinuria, impaired wound healing, mouth ulcers, edema, male hypogonadism, TMA, and interstitial pneumonitis must be considered carefully in pediatric population. This article reviews the most recent data on SRL application in the field of pediatric renal tx.

Topics: Child; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Pneumonia; Proteinuria; Sirolimus; Thrombocytopenia; Time Factors; TOR Serine-Threonine Kinases; Wound Healing

Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin inhibitors for the prevention of acute rejection in renal transplantation. Despite initial encouraging results, enthusiasm faded with large trials showing an increased risk of acute rejection with this molecule that did not provide superior graft function over cyclosporin or tacrolimus. Recent data showed that SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a paradoxical stimulatory effect on innate immunity, which may explain its incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a concerning safety profile including high risk of delayed graft function and onset of proteinuria. This adds to many other adverse effects, including dyslipidemia, diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, and mouth ulcers, that further limit the use of this molecule. Severe cases of interstitial pneumonia have also been reported with this therapy, raising additional concerns. Incomplete control of immune response, along with a poor tolerability, makes SRL far from being the ideal antirejection drug. Progressive restrictions of SRL indication in renal transplantation have, however, been paralleled by evidence showing mTOR abnormalities involved in many pathogenic conditions, thus opening the avenue to new possible applications of this molecule.

Topics: Animals; Calcineurin Inhibitors; Delayed Graft Function; Graft Survival; Humans; Immunosuppressive Agents; Organ Transplantation; Proteinuria; Risk Assessment; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Proteinuria is common after kidney transplantation and typically urine protein levels are below 500 mg/d. However, even these low levels are associated with reduced graft survival. Most allografts with proteinuria >1500 mg/d have new glomerular pathology. In contrast, lower levels of proteinuria are generally associated with nonglomerular, nonspecific histologic changes. The relationship between proteinuria and graft survival is independent of other variables, including graft function and graft histology. Thus, proteinuria allows stratification of risk in patients with or without glomerular pathology. Proteinuria should be monitored periodically posttransplant and investigation of the cause should be pursued vigorously.

Topics: Calcineurin Inhibitors; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Prognosis; Proteinuria; Sirolimus

Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.

Topics: Biopsy, Needle; Calcineurin Inhibitors; Graft Rejection; Graft Survival; Humans; Immunohistochemistry; Kidney; Kidney Transplantation; Protein Kinases; Proteinuria; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

Topics: Everolimus; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Interdisciplinary Communication; Kidney Function Tests; Male; Patient Selection; Practice Guidelines as Topic; Prognosis; Proteinuria; Randomized Controlled Trials as Topic; Risk Assessment; Sensitivity and Specificity; Sirolimus; Surgical Wound Infection; Transplantation Immunology; Wound Healing

Proteinuria is a common complication occurring after kidney transplantation. It is associated with an increased risk of renal failure and patient death. Treatment with ACE inhibitors or angiotensin receptor antagonists (blockers) has been shown to reduce proteinuria after kidney transplantation, as well as improve both graft and patient survival. An increase in proteinuria has been observed in some patients after initiation of sirolimus therapy. Although the mechanism of this remains unclear, high proteinuria at baseline and poor renal function at baseline have been identified as potential risk factors for the development of proteinuria after conversion to sirolimus. Initiation of sirolimus therapy is not recommended in patients with early histological indicators of glomerular damage; however, in patients with healthy grafts, sirolimus may prevent future glomerulosclerosis. Early treatment with an ACE inhibitor and sirolimus, prior to the appearance of glomerular changes, may result in better outcomes.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Humans; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Risk Factors; Sirolimus

Topics: Calcineurin Inhibitors; Chronic Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sirolimus; Treatment Outcome

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.

Topics: Animals; Humans; Immunosuppressive Agents; Proteinuria; Renal Insufficiency; Sirolimus

The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.. In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.. At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.. Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Topics: Adult; Albuminuria; Disease Progression; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens.. This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL).. Mean TAC concentrations were 6.0 ± 2.4 ng/mL and 5.8 ± 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043-5.267; P = 0.039) were associated with inferior renal function at 24 months.. In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months.

Topics: Adult; Atrophy; Biomarkers; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Drug Substitution; Female; Fibrosis; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Nephritis; Odds Ratio; Proteinuria; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Topics: Antihypertensive Agents; Calcineurin Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Proteinuria; Ramipril; Risk Factors; Sirolimus; Tacrolimus

To explore the efficacy and safety of designed early conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) as major immunosuppressive therapy in renal transplant recipients with stable renal function.. A prospective, open-label and non-randomized control study was performed for 112 renal transplant recipients (3-6 months post-operation) with stable renal function between June 2008 and June 2011. The patients in SRL group (n = 57) switched to sirolimus while those in CNI group (n = 55) continued CNI. The dosing of mycophenolate mofetil and steroids had no change. They were followed up for at least 24 months to evaluate the acute rejection, patient and graft survival, renal function, estimated glomerular filtration rate (eGFR), blood lipids, blood glucose, liver function and urinary protein at 1, 6, 12 and 24 months after inclusion. Adverse events were also recorded.. The serum creatinine of SRL group decreased significantly after conversion ( (89.2 ± 24.7), (87.6 ± 23.8), (86.1 ± 20.4), (86.7 ± 19.7) vs (117.0 ± 16.3) µmol/L, all P < 0.05). CNI group showed no improvement of renal function.SRL group had a significantly higher eGFR than CNI group (P < 0.05). Among 3 cases of acute rejection, there were 2 in SRL group and 1 in CNI group (P > 0.05). Blood lipids in SRL group increased significantly at 1 month after conversion (P < 0.05) and reverted back to average level after intervention (P > 0.05).SRL group had a drop of hemoglobin level within the normal range. Two patients in SRL group developed hypokalemia and another 2 patients had oral ulcer. They all improved after treatment. During follow-ups, 1 case of mild proteinuria was found in SIR group. Three patients were diagnosed with diabetes (1 in SRL group vs 2 in CNI group).. Early conversion from CNI to SRL as major immunosuppressive therapy in renal transplant recipients with stable renal function further improves renal function. There is no higher rate of acute rejection during follow-up.Elevated blood lipids after conversion may be easily controlled. No other adverse events are found.

Topics: Calcineurin Inhibitors; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prospective Studies; Proteinuria; Sirolimus; Treatment Outcome

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.

Topics: Adult; Cyclosporine; Dose-Response Relationship, Drug; Everolimus; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Statistical; Mycophenolic Acid; Proteinuria; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression.. Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF).. A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036).. There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Image Processing, Computer-Assisted; Immunoenzyme Techniques; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Proteinuria; Sirolimus; Vascular Endothelial Growth Factor A

Persistent nephrotic syndrome that does not respond to treatment may cause progression to kidney failure. We designed a therapeutic protocol with sirolimus for this group of patients. We conducted a prospective, interventional, time series, cohort study lasting 20 months. Thirteen patients were enrolled, with a mean age of 10 years (range: 8-18 years old) with steroid-resistant primary nephrotic syndrome and a histological diagnosis of focal and segmental glomerulosclerosis. We administered sirolimus 3.6mg/m2/day. The duration of this regimen was 12 months in responsive patients. The protocol's efficacy was assessed according to reduction of proteinuria (3 response levels: total, partial, or no response). Severity of histological renal damage and mean time from clinical diagnosis to protocol initiation were also assessed. Nine of 13 patients responded to the treatment with sirolimus, and mean progression time and the severity of histological renal damage influenced response to therapy. We believe that sirolimus is a valid treatment option in patients with steroid-resistant nephrotic syndrome, even though this regimen probably requires an earlier treatment.

Topics: Adolescent; Adrenal Cortex Hormones; Child; Cohort Studies; Drug Resistance; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Prospective Studies; Proteinuria; Remission Induction; Sirolimus; Treatment Outcome

Topics: Antilymphocyte Serum; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Sirolimus; Time Factors; Transplantation

Sirolimus has been promoted as an agent to provide immunosuppression for kidney transplant recipients that, in contrast to calcineurin inhibitors, would not be nephrotoxic. However, several reports have observed proteinuria in patients treated with sirolimus, ranging from low grade to nephrotic range. Accordingly, we compared markers of tubular and glomerular damage in an ancillary study of a randomized trial comparing sirolimus and cyclosporine.. Single-center, open-label, randomized, prospective trial.. Patients undergoing cadaveric or living donor kidney transplant at the University Hospital in Basel, Switzerland, between January 2001 and July 2004.. Immunosuppression regimen consisting of cyclosporine, mycophenolate mofetil, and prednisone versus sirolimus, mycophenolate mofetil, and prednisone.. The primary outcome was kidney function, assessed using serum creatinine level. Secondary outcomes included patient and graft survival, number of rejections, and evidence of kidney damage, assessed using glomerular and tubular urine biomarker levels.. Urine and serum were collected at 0, 7, 30, and 90 days. Kidney function was estimated using serum creatinine level. Urinary markers included alpha(1)-microglobulin and retinol-binding protein (tubular), transferrin and albumin (glomerular), and semiquantitative assessment of glucosuria. Protocol kidney biopsies were performed at days 90 and 180.. There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, whereas levels of markers associated with glomerular damage (albumin, 19.5 vs 8.96 mg/mmol creatinine; P < 0.001; transferrin, 13.1 vs 5.7 mg/mmol creatinine; P < 0.001) and those associated with tubular damage (alpha(1)-microglobulin, 11 vs 7.6 mg/mmol creatinine; P = 0.004; retinol-binding protein, 19.6 vs 9.6 mg/mmol creatinine; P = 0.002) were higher beginning at day 7 in patients randomly assigned to sirolimus therapy, with similar findings through day 90. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy beginning by day 30 (65% vs 30% on day 30; P = 0.002; 51% vs 22% on day 90; P < 0.001). On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy.. Small sample size, short-term follow-up likely insufficient to appreciate calcineurin-associated nephropathy.. Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.

Topics: Adolescent; Adult; Aged; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Prospective Studies; Proteinuria; Sirolimus; Young Adult

Results at 1 year of a pilot randomized trial with 87 kidney graft recipients, comparing the maintenance treatment with sirolimus, tacrolimus and steroids (group I) versus tacrolimus withdrawal since the third month onward, followed by maintenance with SRL and steroids (group II) have shown that early elimination of tacrolimus may result in improved renal function and blood pressure control. At 2 years, 26 and 25 patients in groups I and II, respectively, were analyzed in an on-therapy and an ITT analysis. In the on-therapy analysis, group II showed lower serum creatinine (1.3+/-0.2 vs. 1.6+/-0.6 mg/dL) and lower diastolic blood pressure (74+/-9 vs. 80+/-11 mm Hg). No acute rejections occurred during the second year of follow-up. In more than 90% of patients, proteinuria was less than 1 g/d, and in 50% it was negative. In the ITT analysis, differences were found only in diastolic blood pressure (80+/-10 vs. 74+/-8 mm Hg in groups I and II respectively, P=0.009). Tacrolimus withdrawal from a combination of sirolimus and tacrolimus, in selected patients, may be observed at 2 years by an improvement in renal function and blood pressure without a higher incidence of proteinuria.

Topics: Adrenal Cortex Hormones; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Pilot Projects; Proteinuria; Sirolimus; Tacrolimus; Time Factors

Sirolimus (SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after renal transplantation. Nevertheless, the occurrence of proteinuria has recently been recognized among patients on SRL-based therapy. The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii Hook F. (T II) on proteinuria associated with SRL in renal transplant recipients. According to accepting T II, 36 recipients were divided into 2 groups: T II group (n = 21) and valsartan group (n = 15). The T II group was administered 1 mg/kg/d, and the valsartan group, 80 mg twice per day for 12 months. Efficiency was then evaluated. Complete remission: proteinuria decreased by >50%; partial remission: proteinuria decreased by 20% to 50%; ineffective: proteinuria decreased by <20%. Upon 12-month follow-up, the total effective rates in the T II group and the valsartan group were 95.2% and 86.7% (P < .05), respectively. Twenty of 21 patients with proteinuria in the T II group were negative at 3-month follow-up with disappearance of edema. There were some adverse events that had greater incidence rates in the valsartan group compared with the T II group, such as hyperkalemia (26.7% vs 4.8%). We concluded that the application of T II markedly reduced proteinuria associated with SRL in renal transplant patients.

Topics: Adult; Antihypertensive Agents; China; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plant Extracts; Proteinuria; Sirolimus; Tetrazoles; Tripterygium; Valine; Valsartan; Young Adult

This prospective study assesses over a period of 6 months, the variations in glomerular filtration rate (GFR) and safety parameters within a cohort of 44 cadaveric renal-transplant (RT) patients presenting with moderate renal insufficiency. They were progressively switched from calcineurin inhibitors (CNIs) based- to sirolimus (SRL) based-therapies aiming SRL troughs at levels approximately 8 ng/ml (range 6-10). All the patients were receiving in addition mycophenolate mofetil. The intent-to-treat (ITT) patient and graft survivals were 100%. Thirty-four patients, i.e. 77.3% completed the study. Overall, there was a significant improvement in the calculated GFR (Nankivell formula) from day 0 to month 6, i.e. from 45.98 (+/-16.3) to 53.07 (+/-12.68) ml/mn (P=0.03). However, renal function improved in only 20 cases (group I), and deteriorated in the others (group II). Groups I and II did not significantly differ with respect to time between transplantation and drug switch, GFR, serum creatinine, and proteinuria at baseline. There was only one case of steroid-sensitive acute rejection. Overall, there was a significant increase in proteinuria from 0 (0-3.15) to 0.57 (0-4.85) g/day (P=0.002). Finally, the conversion was associated with a significant increase in lipids, and a significant decrease in hemoglobin levels.

Topics: Adult; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Rejection; Hematologic Tests; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy.

Topics: Adult; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; In Vitro Techniques; Kidney Diseases; Male; Middle Aged; Proteinuria; Sirolimus

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.

Topics: Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Recombinant Fusion Proteins; Sirolimus

The contribution of mammalian target of rapamycin (mTOR) inhibitors to proteinuria is controversial. The aim was to analyse proteinuria in suboptimal kidney calcineurin inhibitor-(CNI) free de novo immunosuppression.. All patients from our centre with donors >60 years and CNI-free treatment were included (n = 108). Patients were divided into two groups: (i) SRL group: sirolimus (SRL) + prednisone + mycophenolate mofetil (MMF) + antiCD25; (ii) MMF group: prednisone + MMF w/ or w/o antiCD25 (n = 75). Follow-up was 12 months.. Donors were slightly younger in the SRL group (68 vs 71 years; P < 0.05), receptor age (67 vs 65 years) was not significantly different. Patient survival in the MMF group was 88 vs 94% in the SRL group, however, these differences did not reach statistical significance. One-year graft survival censored for death was 83% in the MMF group and 94% in the SRL group. Acute rejection rate was 45% in the MMF and 15% in the SRL group (P < 0.01). The incidence of CNI introduction was higher in the MMF-group (35 vs 5; P < 0.05). The intention-to-treat analysis revealed significant differences of proteinuria [SRL vs MMF at 12 months: 461 (163-6988) vs 270 (53-3029) mg/day], which did not exist in the on-therapy (OT) analysis [SRL vs MMF at 12 months: 357 (199-1428) vs 279 (53-3029) mg/day]. New onset nephrotic range proteinuria seemed to occur slightly more frequently in SRL patients (3/33 vs 1/75; P = 0.049), however, all four cases occurred in a context of recurrent disease, or previous drug-independent damage or non-adherence. All of these patients were converted to CNI.. SRL-based compared with MMF-based treatment in kidney transplantation with advanced age donors is associated with an acceptable outcome, however, with increased proteinuria in the intention-to-treat analysis. A large subgroup of the patients in the MMF group experienced acute rejection and required conversion to CNI.

Topics: Aged; Calcineurin Inhibitors; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisone; Protein Kinases; Proteinuria; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients.. CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged.. In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group.. Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Lipids; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Proteinuria; Sirolimus; Treatment Outcome; Uric Acid

Proteinuria has been reported in several papers after conversion from calcineurin inhibitors to Sirolimus (SRL), but this complication has not been analyzed in randomized clinical trials using de novo SRL. It is not known whether de novo use of SRL is a risk factor for proteinuria. We analyzed a series of patients included in a big multicenter randomized trial (RMR trial) corresponding to all patients in Spain and Portugal with respect to this issue. We retrospectively evaluated 24-hour proteinuria in all the patients during the study period (5 years postransplant) for comparison between treatment arms group A, continuous cyclosporine (CyA) + SRL and group B SRL with CyA elimination at 3 months postransplant. The elimination of CyA after the third month was not followed by significant changes in proteinuria. Nevertheless, during the last year of follow-up (between 48 and 60 months postransplant) an impressive increase in proteinuria was observed in group A. This surprising finding seemed to be a consequence of a protocol amendment that recommended CyA elimination in patients of group A, due to poorer results in the intermediate analysis of the trial. This fact suggests that the hemodynamic changes induced by elimination of the vasoconstrictor CyA might be responsible for the proteinuria but only in the long term probably when significant pathological lesions are already present. This finding argues for earlier conversion.

Topics: Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Sirolimus

Recent studies have reported a significant increase of proteinuria in kidney transplant recipients who were switched from a calcineurin inhibitor (CI) to sirolimus. This has (partly) been ascribed to the hemodynamic renal effects of CI withdrawal. We have evaluated the evolution of proteinuria in renal transplant recipients who underwent conversion from azathioprine to sirolimus. In a randomized, prospective, multicenter study called RESCUE (Recurrent cutanEous Squamous cell Carcinoma Under RapamunE) the efficacy and safety is investigated of conversion to sirolimus in stable renal transplant recipients with a cutaneus squamous cell carcinoma (SCC). In our center 25 patients have been included in this study of which 13 patients were randomized to continue their current immunosuppressive treatment and 12 to conversion to sirolimus. After a mean follow-up of 360 days mean proteinuria increased from 0.37+/-0.34 to 1.81+/-1.73 g/24 h after conversion to sirolimus (P<0.005). In the control group there was no change in proteinuria. A significant increase of proteinuria was observed in all seven patients with proteinuria before conversion, whereas proteinuria remained absent in all patients without previous proteinuria. Two of the patients with proteinuria were converted from cyclosporine and five were converted from azathioprine to sirolimus. Sirolimus was discontinued in five patients with proteinuria, and in all of them proteinuria declined to baseline values. Our study demonstrates that conversion from azathioprine to sirolimus after kidney transplantation may cause a reversible increase of proteinuria. Sirolimus-induced proteinuria therefore cannot be ascribed to the hemodynamic renal effects of withdrawal of CI.

Topics: Aged; Azathioprine; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Creatinine; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Sirolimus; Skin Neoplasms; Time Factors

Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low-dose CNI therapy. Thirty-nine patients with renal failure on low-dose cyclosporine A (CsA) were studied (62.9 +/- 8.7 years, five female, 8.2 +/- 4.3 years posttransplant, serum creatinine: 1.9 +/- 0.3 mg/dL, calculated GFR (cGFR): 48.2 +/- 18.3 mL/min, CsA C0 level: 64.0 +/- 19.9 ng/mL). All patients had been treated with low-dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7-3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low-dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 +/- 0.15 to 1.67 +/- 0.13 mg/dL, cGFR: 48.5 +/- 21.4 to 61.7 +/- 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantation who are at low risk of rejection, CNI-free rapamycin-based immunosuppression improves cGFR even in those already receiving low-dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.

Topics: Adult; Aged; Blood Pressure; Cholesterol; Cyclosporine; Dose-Response Relationship, Drug; Female; Heart Transplantation; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Platelet Count; Proteinuria; Sirolimus; Triglycerides

A 22-year-old manpresented as a refractory nephrotic syndrome with edema and proteinuria for more than one year. Physical examination revealed facial steatadenomas and periungual fibromas. Images were characterized by hamartomatous lesions in multiple organs, including the central nervous system, heart, lungs, liver, and kidneys. Gene tests verified TSC2 mutation and confirmed the diagnosis of tuberous sclerosis complex. The APOL1 mutation was positive in this patient, which indicated the possibility of steroid-resistant focal segmental glomerulonephritis. Thus, he was treated with sirolimus. Renal angiomyolipoma was shrunk, but proteinuria was not relieved (24h unine protein>10 g) and eventually led into renal insufficiency. Nondialytic therapy was initiated consequently. Losartan 50 mg/d was used to control proteinuria under the close watch of serum creatinine. A recent phone call on October 2018 failed to reachthe patient. Therefore, the follow-up information was not updated.. 患者男性，22岁。因水肿、蛋白尿1年余就诊，考虑为难治性肾病综合征。体检发现患者面部皮脂腺瘤、甲周纤维瘤，影像学显示中枢神经系统、心脏、肺、肝脏、肾脏等多系统受累，基因检查为TSC2基因突变，诊断结节性硬化症。基因检测同时发现APOL1基因突变，提示患者同时存在糖皮质激素抵抗型的局灶节段性肾小球硬化症的可能性。使用西罗莫司治疗，治疗初期肾脏血管平滑肌瘤体积缩小，但尿蛋白始终未缓解（24 h尿蛋白>10 g），最终仍发展为肾功能不全，开始非透析治疗，包括监测血压、血糖和血脂，餐中嚼服碳酸钙500 mg、3次/d，瑞舒伐他汀20 mg/d，补充维生素B(1)（10 mg/d）和叶酸（10 mg/d），使用氯沙坦50 mg/d控制尿蛋白并监测血肌酐变化。2018年10月电话随访未联系到患者，未能获得治疗近况。.

Topics: Angiomyolipoma; Apolipoprotein L1; Creatinine; Female; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Losartan; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Young Adult

Experimental evidence demonstrated that macroautophagy/autophagy exerts a crucial role in maintain renal cellular homeostasis and represents a protective mechanism against renal injuries. Interestingly, it has been demonstrated that in the human proximal tubular renal cell line, HK-2, the MTOR inhibitor rapamycin enhanced autophagy and mitigated the apoptosis damage induced by urinary protein overload. However, the underlying molecular mechanism has not yet been elucidated. In our study we demonstrated, for the first time, that in HK-2 cells, the exposure to low doses of rapamycin transactivated the NGFR promoter, leading to autophagic activation. Indeed, we observed that in HK-2 cells silenced for the NGFR gene, the rapamycin-induced autophagic process was prevented, as the upregulation of the proautophagic markers, BECN1, as well as LC3-II, and the autophagic vacuoles evaluated by transmission electron microscopy, were not found. Concomitantly, using a series of deletion constructs of the NGFR promoter we found that the EGR1 transcription factor was responsible for the rapamycin-mediated transactivation of the NGFR promoter. Finally, our results provided evidence that the cotreatment with rapamycin plus albumin further enhanced autophagy via NGFR activation, reducing the proapoptotic events promoted by albumin alone. This effect was prevented in HK-2 cells silenced for the NGFR gene or pretreated with the MTOR activator, MHY1485. Taken together, our results describe a novel molecular mechanism by which rapamycin-induced autophagy, mitigates the tubular renal damage caused by proteinuria, suggesting that the use of low doses of rapamycin could represent a new therapeutic strategy to counteract the tubule-interstitial injury observed in patients affected by proteinuric nephropathies, avoiding the side effects of high doses of rapamycin.

Topics: Albumins; Apoptosis; Autophagy; Cell Line; Early Growth Response Protein 1; Humans; Kidney Tubules, Proximal; Promoter Regions, Genetic; Protective Agents; Proteinuria; Receptor, Nerve Growth Factor; Sirolimus; TOR Serine-Threonine Kinases; Transcriptional Activation

Previous studies have shown that podocyte autophagy is an important trigger for proteinuria and glomerulosclerosis. The mammalian rapamycin target protein (mTOR) occupies a pivotal position in the autophagy pathway. In this study, we planned to clarify the mechanism of mTOR regulation of podocyte autophagy and the effect of rapamycin (RAPA).. All rats were randomly divided into normal control group (n = 8), DN group (n = 8), and RAPA group (n = 8). Blood and urine samples were collected at the 4th, 8th, and 12th weeks of the experiment. The serum creatinine (Scr), urine volume levels, and the 24 h urine protein (UP) levels were examined. The nephrin, podocin, mTOR, ribosomal S6 kinase 1 (S6K1), and autophagy marker light chain 3 (LC3II) expression levels were evaluated by immunohistochemistry, quantitative PCR, and immunoblotting.. The urine volume, 24 h UP, and Scr of the DN and RAPA groups increased significantly compared with the NC group (p < .05). Nephrin and podocin expression was decreased in the kidney tissues of the DN and RAPA groups compared with the NC group (p < .05). The expression levels of mTOR and S6K1 increased and LC3II expression decreased in the renal tissues of the DN and RAPA groups compared with the NC group (p < .05). After RAPA treatment, all the above indexes were improved compared with the DN group (p < .05), but were significantly abnormal compared with the NC group (p < .05).. The proteinuria and kidney function had improved after RAPA treatment. These results confirmed that RAPA specifically binds to mTOR kinase, and inhibits mTOR activity, thereby regulating the pathological autophagic process.

Topics: Animals; Autophagy; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Podocytes; Proteinuria; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Streptozocin; TOR Serine-Threonine Kinases

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Male; Mice, Inbred C57BL; Mice, Knockout; Podocytes; Proteinuria; Renal Insufficiency, Chronic; Signal Transduction; Sirolimus; Time Factors

Chronic kidney disease is a significant complication after liver transplantation (LT), but the role of pre-existing renal insufficiency and proteinuria remains unclear among LT recipients receiving sirolimus.. We assessed the effects of proteinuria and baseline renal function on long-term renal and survival outcomes among 576 LT recipients who received SRL in a medical center between 2005 and 2014. Renal outcomes were the incidences of >50% reduction in their baseline estimated glomerular filtration rate and end stage kidney disease requiring renal replacement therapy. Proteinuria was identified using morning dipstick results (≥30 mg/dL) at baseline and within the first year after the initiation of SRL therapy. A Kaplan-Meier analysis was performed to estimate time to event. Factors associated with the outcomes were determined using the Cox proportional hazards model with a significance level set at P <0.05.. During the study period, renal function deteriorated in 135 (25.3%) patients and 68 (11.8%) patients died. Persistent and new onset proteinuria contributed to a high rate of mortality and the deterioration of renal function (both log-rank tests, P <0.0001). After adjustments, new onset proteinuria within the first year after the initiation of SRL therapy increased the risk of deteriorating renal function, regardless of baseline estimated glomerular filtration rate. Moreover, pre-existing (hazard ratio = 1.91; P <0.001) and new onset diabetes (hazard ratio = 2.34; P <0.0001) were significantly associated with new onset proteinuria among SRL users.. These findings support the effective monitoring and early management of the predictable risks for proteinuria among new SRL users in order to delay the progression of renal disease.

Topics: Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Sirolimus

Sirolimus (SRL), a mammalian target of rapamycin inhibitor, is widely used in transplantation, but the mechanisms whereby it induces adverse effects, such as proteinuria and edema, remain unclear. To determine whether isolated SRL induces proteinuria or not, the authors intraperitoneally injected C57BL/6 mice with different doses of SRL (0 mg/[kg·d], 3 mg/[kg·d], 10 mg/[kg·d], or 30 mg/[kg·d]) for 24 days. Urinary albumin excretion was then quantified using a double-sandwich enzyme-linked immunosorbent assay, and serum creatinine levels were measured using a single dry-film chemistry auto-analyzer. The mRNA expression levels of various genes were also measured by polymerase chain reaction. Urinary albumin was not detected in the SRL-treated mice, but serum creatinine levels were found to increase dose-dependently and were significantly higher in the animals treated with 30 mg/kg of SRL than in untreated controls. Glomerular mRNA expression profiling showed down-regulations of podocyte-related genes (Wilms tumor 1, synaptopodin, nephrin, CD2-associated protein, and podocin) and of transforming growth factor-beta (a marker of fibrosis) in sirolimus-treated mice. In addition, expressions of the antiapoptotic genes Bcl-2 and Bcl-xL were also down-regulated. Furthermore, the protein levels of these genes in mice kidney were also decreased by sirolimus. Although sirolimus treatment reduced the expressions of slit diaphragm-associated molecules and increased serum creatinine levels, it failed to induce proteinuria. Our findings indicate that proteinuria is not induced by isolated SRL treatment. Further studies are required to identify conditions in which sirolimus induces proteinuria.

Topics: Animals; Immunosuppressive Agents; Kidney; Male; Mice, Inbred C57BL; Proteinuria; Sirolimus

Topics: Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Proteinuria; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Mechanistic Target of Rapamycin Complex 1; Metformin; Multiprotein Complexes; Protein Kinase Inhibitors; Proteinuria; Rats, Zucker; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

IgA nephropathy (IgAN) has been considered to be the most frequent form of primary glomerulonephritis that occurs worldwide with a variety of factors involved in its occurrence and development. The impact of autophagy in IgAN, however, remains partially unclear. This study was designed to investigate the effects of rapamycin in an IgAN model.. After establishing an IgAN rat model, SD rats were divided into 4 groups: control, control + rapamycin, IgAN, IgAN + rapamycin. Proteinuria and the pathological changes and the level of autophagy of kidney were texted. Identify the expression of phosphorylation and total mammalian target of rapamycin (mTOR) and s6k1 as well as cyclin D1 in the kidney of rats through Western blot and immunohistochemistry.. With rapamycin treatment, we observed a significant reduction in the progression of proteinuria as well as alleviation of pathological lesions in IgAN rats. Besides, autophagy was inhibited, while the mTOR/S6k1 pathway was activated and expression of cyclin D1 was increased in IgAN. Rapamycin treatment increased autophagy and decreased the expression of cyclin D1.. These results may suggest that mTOR-mediated autophagy inhibition may result in mesangial cell proliferation in IgAN.

Topics: Animals; Autophagy; Cell Proliferation; Cyclin D1; Disease Models, Animal; Glomerulonephritis, IGA; Humans; Immunohistochemistry; Immunosuppressive Agents; Mesangial Cells; Microscopy, Electron; Proteinuria; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To assess the effectiveness and safety of the conversion therapy from traditional cyclosporine (CsA) triple immunosuppression therapy to sirolimus (SRL) combined with low dose CsA and prednisone (Pred) in renal transplantation recipients in a five-year follow-up period.. A prospective, open-label non-randomized study was performed with 46 renal allograft recipients who visited Tongji Hospital regularly for follow-up visits between January 2007 and May 2011 and were taking CsA+ mycophenolate mofetil (MMF)+ Pred. Conversion therapy to SRL+ low dose CsA+ Pred was initiated after renal transplantation. The recipients were allocated to 2 groups according to their renal function and proteinuria before the conversion: active conversion group [n=27, serum creatinine (SCr) ≤ 140 μmol/L with no or minimal proteinuria] and passive conversion group [n=19, SCr>140 μmol/L with less than moderate proteinuria]. After conversion, dosages of SRL and CsA were adjusted for trough levels of 5-7 μg/L and 20-60 μg/L, respectively. SCr and urine protein were compared before and after the conversion in five-year follow-up. Incidence of acute rejection, renal graft survival and SRL-related adverse effects of the immunosuppressive regimen were also observed.. After conversion, an average 63% dose reduction of CsA was achieved in all the patients. In the active conversion group, the mean SCr level was (110±19) μmol/L at the time of conversion. Eight patients in this group withdrew from the study during the follow-up period for the following reasons: arthralgia (1 case), deteriorated proteinuria (2 cases), chronic diarrhea (2 cases), mild or suspicious acute rejection (2 cases), and recurrent fever (1 case). The rest patients (19/27) with a mean follow-up time of 5 years had a stable SCr level [(103±12) μmol/L] and a 100% 5-year graft survival. In the passive conversion group, the mean SCr level was (205±45) μmol/L at the time of conversion. There were 4 patients quitting the study, 2 for deteriorated proteinuria and 2 for lost to follow-up. Chronic allograft failure developed in 10 patients in this group 1-50 months after conversion, while the remaining 5 patients had a stable SCr during the 5-year follow-up period [(218 ±46) μmol/L before conversion vs (205±73) μmol/L 5 years after conversion]. The overall 5-year graft survival after the conversion therapy in the passive conversion group was 33.3%, significantly lower than that of the active conversion group (P<0.001). Acute rejection was observed in 2 cases in the active conversion group, while not observed in the passive conversion group. None of the patients developed leukopenia, thrombocytopenia, oral ulcer, or pneumonia in the follow-up.. The combination therapy of SRL and low dose of CsA is overall a safe and effective maintenance immunosuppressive regimen, but it is important to initiate at an appropriate stage. More favourable long-term benefits may be obtained from the conversion therapy in patients with normal or only slightly impaired renal graft function. It may offer an option of individualized immunosuppressive therapy after renal transplantation.

Topics: Adult; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Prospective Studies; Proteinuria; Sirolimus; Transplantation, Homologous

The mechanism of podocyte injury observed with the use of rapamycin (RPM) remains unclear. The conversion from calcineurin inhibitors (CNIs) to RPM in kidney transplant recipients has been associated with a higher incidence of proteinuria and renal injury. In this study, we performed proteomic analyses to investigate the alteration of protein expression in mouse podocytes treated with RPM in comparison with CNI/RPM combination.. Immortalized mouse podocytes were treated with 20 nmol/L RPM or 20 nmol/L RPM + 1 μg/mL cyclosporine. Podocyte proteins were separated by 2-dimensional polyacrylamide gel electrophoresis (2DE) and identified by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and peptide fingerprinting. Selected proteins were analyzed by means of Western blot assay.. We identified 36 differently expressed proteins after isolated RPM or CNI/RPM combination treatment in cultured mouse podocytes. There are 3 distinct patterns of protein expression: (1) potentiated down- or upregulation of proteins by CNI/RPM treatment compared with isolated RPM treatment (n = 4); (2) partial offset of down-regulation by CNI/RPM in comparison with RPM treatment (n = 25); (3) no difference in down-regulation between RPM and CNI/RPM treatment (n = 5). We found a significant interplay between RPM and CNI on the expression of the selected proteins in mouse podocytes. This might explain the higher incidence of proteinuria by CNI/RPM combination in clinical settings.. Further study is required to elucidate the target protein associated with RPM-induced podocyte injury.

Topics: Acute Kidney Injury; Animals; Calcineurin Inhibitors; Cells, Cultured; Cyclosporine; Drug Combinations; Immunosuppressive Agents; Kidney; Mice; Podocytes; Proteins; Proteinuria; Proteomics; Sirolimus; TOR Serine-Threonine Kinases

Recently, the mammalian target of rapamycin inhibitor everolimus (EVL) has been introduced as a novel immunosuppressant for heart transplant (HTx) recipients, and is expected to preserve renal function compared to conventional calcineurin inhibitors (CNIs). However, a considerable number of recipients treated with EVL were not free from worsening renal function regardless of CNI reduction. Data were collected retrospectively from 27 HTx recipients who had received EVL (trough concentration, 3.1-9.2 ng/mL) along with reduced CNIs (%decreases in trough concentration, 27.3 ± 13.0%) because of switching from mycophenolate mophetil due to digestive symptoms or neutropenia, progressive coronary artery vasculopathy, or persistent renal dysfunction, and had been followed over 1 year between August 2008 and January 2013. Estimated glomerular filtration rate (eGFR) decreased in 5 recipients (18.5%) during the study period. Univariate logistic regression analysis demonstrated that a higher plasma neutrophil gelatinase-associated lipocalin (P-NGAL) level was the only significant predictor for a decrease in eGFR over a 1-year EVL treatment period among all baseline parameters (P = 0.008). eGFR and proteinuria worsened almost exclusively in patients with baseline P-NGAL ≥ 85 ng/mL, which was the cutoff value calculated by an ROC analysis (area under the curve, 0.955; sensitivity, 1.000; specificity, 0.955). In conclusion, higher P-NGAL may be a novel predictor for the worsening of renal function after EVL treatment that is resistant to CNI reduction in HTx recipients.

Topics: Acute-Phase Proteins; Adult; Dose-Response Relationship, Drug; Drug Monitoring; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Japan; Lipocalin-2; Lipocalins; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Prognosis; Proteinuria; Proto-Oncogene Proteins; Renal Insufficiency; Retrospective Studies; ROC Curve; Sirolimus

Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation.. Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested.. Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected.. Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.

Topics: Analysis of Variance; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glomerular Filtration Rate; Hyaluronic Acid; Male; Proteinuria; Random Allocation; Rats; Reference Values; Risk Factors; Sensitivity and Specificity; Sirolimus; Streptozocin; TOR Serine-Threonine Kinases; Urodynamics

Calcineurin inhibitors (CNI) have failed to improve long-term outcomes in renal transplantation. Anti-proliferative and anti-angiogenic effects of mammalian target of rapamycin inhibitors (m-TOR) without nephrotoxicity could improve long-term survival in selected transplant recipients.. We examined the evolution of 98 low-immunological risk renal transplant recipients on m-TOR monotherapy: 7 patients had induction without CNI and 91 were switched to m-TOR at 12 (p25-p75: 4-36) months after transplant.. Median follow-up time was 46 (p25-p75: 28.5-72.0) months. Fifteen recipients dropped out of the study (15.3%): 8 patients (8.2%) had to change their immunosuppressive treatment because of complications and 7 (7.1%) lost their grafts as a result of chronic rejection (4 cases) or death with a functioning graft (3 cases). At the end of follow-up, 83 of 98 (84.6%) recipients remained on monotherapy. The rates of recipient and graft survivals were 100% and 98.8% at 2 years and 96.9% and 93.5% at 4 years; the percentages of patients on monotherapy after 2 and 4 years were 95.2% and 85.2%, respectively. Renal function improved significantly and proteinuria decreased but not significantly. Those patients switched to m-TOR significantly received more erythropoietin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and hypotensive agents than before starting m-TOR, whereas there were no significant changes related to the use of statins, body weight, or percentage of diabetic patients. No case of non-compliance was reported.. This study supports the safety and efficacy of monotherapy with m-TOR in selected renal transplant recipients.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcineurin Inhibitors; Erythropoietin; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus-containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new-onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151-268 mg/L) at conversion and new-onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new-onset proteinuria (>500 mg/L) post-conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

Topics: Adult; Creatinine; Databases, Factual; Female; Follow-Up Studies; Germany; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Proteinuria; Retrospective Studies; Sirolimus; Survival Rate

Conversion to rapamycin from calcineurin inhibitors may contribute to improvement of graft function in kidney transplant recipients, especially in patients with calcineurin inhibitor-related nephrotoxicity. The conversion from calcineurin inhibitors to rapamycin in kidney transplant recipients has been associated with a higher incidence of proteinuria. It could be explained by possible hemodynamic changes due to withdrawal of calcineurin inhibitors. Podocyte damage occurs commonly in rapamycin-related proteinuria. The vascular endothelial growth factor system has been suggested to be implicated in mammalian target of rapamycin inhibitor-associated proteinuria. However, induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein. In this study, we assessed the role of uPAR in primary cultured podocytes with rapamycin treatment. Our results indicate that 24-hour rapamycin treatment promotes podocyte migration on the wound scratch assay in a dose-dependent manner. Rapamycin treatment for 2 days does not increase the apoptosis of podocytes or affect the podocyte cell viability and morphology. The up-regulation of uPAR in podocytes was confirmed by immunofluorescence staining, real-time polymerase chain reaction (1.8 ± 0.3-fold increase of relative quantification; P < .01) and Western blot analysis. Rapamycin treatment also causes the activation of FAK and ILK in a dose-dependent manner. In summary, rapamycin could promote podocyte migration through the up-regulation of uPAR. This finding provides a new mechanism of rapamycin-associated proteinuria. It also suggests that pharmacologic inhibition of uPAR signaling cascade may have therapeutic potential in the setting of rapamycin-related proteinuria.

Topics: Animals; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation; Focal Adhesion Kinase 1; Immunosuppressive Agents; Podocytes; Primary Cell Culture; Protein Serine-Threonine Kinases; Proteinuria; Rats, Wistar; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Sirolimus; Time Factors; Up-Regulation

A 68-year-old man who underwent living-unrelated kidney transplantation from his spousal donor was immunosuppressed with tacrolimus and mycophenolate mofetil. Despite his uneventful clinical course, protocol biopsy at 2 years post transplant showed de novo CNI tubulotoxicity despite low tacrolimus exposure. Everolimus was added in order to discontinue TACER. However, prominent proteinuria impeded continuation of everolimus since biopsy showed diffuse glomerular endocapillary proliferation without C4d deposition. No donor-specific antibody was detected. Pulse steroids were given and proteinuria returned to normal with histological reversal.

Topics: Aged; Everolimus; Glomerulonephritis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Proteinuria; Sirolimus

The mammalian target of rapamycin inhibitors sirolimus and everolimus are immunosuppressive drugs for kidney transplant patients, but adverse events may include proteinuria. The purpose of this study was to compare the effects of sirolimus and everolimus on creatinine clearance and proteinuria after kidney transplant.. This study was a prospective evaluation period of 50 patients (age, 16-65 y) who had kidney transplant. There were 25 patients who used sirolimus and 25 patients who used everolimus. Evaluation at the beginning mTOR and end of the evaluation period included complete blood count, blood pressure, serum creatinine level, creatinine clearance, and proteinuria level in a 24-hour urine collection.. Mean creatinine clearance at the beginning and end of the evaluation period was significantly less in the everolimus than sirolimus group. There was no significant change in creatinine clearance from the beginning to end of the evaluation period in either the sirolimus or everolimus group. Mean proteinuria at the beginning and end of the evaluation period was similar between the sirolimus and everolimus groups. Both groups had a significant increase in mean proteinuria from beginning to end of the evaluation period, but the increase in proteinuria was similar for the sirolimus and everolimus groups (difference not significant).. In kidney transplant recipients, sirolimus and everolimus are associated with a similar level of increased mean proteinuria.

Topics: Adolescent; Adult; Aged; Biomarkers; Creatinine; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Proteinuria; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

The mammalian target of rapamycin (mTOR), a regulator of cellular protein synthesis and cell growth, plays an important role in the progression of renal hypertrophy and renal dysfunction in experimental chronic kidney disease models. Because the mTOR activity is regulated by nutrients including amino acids, we tested the hypothesis that the renoprotective effect of a low-protein diet (LPD) might be associated with the attenuation of the renal mTOR pathway. In this study, 5/6 nephrectomized rats were fed an LPD or a normal protein diet (NPD), and a number of rats that were fed an NPD received rapamycin (1.0 mg kg⁻¹ d⁻¹), a specific inhibitor of mTOR. After 6 weeks, renal tissue was collected to evaluate the activity of the mTOR pathway and histologic changes. The phosphorylation of p70S6k, a kinase in the downstream of mTOR, was significantly higher in the NPD-fed rats that showed progressive renal dysfunction than in the sham-operated rats (NPD). The LPD attenuated the excessive phosphorylation of p70S6k concomitant with reduced proteinuria and improved renal histologic changes in the 5/6 nephrectomized rats. The effects of the LPD were similar to the effects of rapamycin. The expression of phosphorylated p70S6k was significantly correlated with proteinuria (r² = 0.63, P < .001), the glomerular area (r² = 0.60, P < .001), and the number of phosphorylated Smad2-positive cells in the glomerulus (r² = 0.26, P < .05) of these rats. These results suggest that the preventive effect of an LPD on the progression of renal failure is associated with attenuation of the activated mTOR/p70S6k pathway in the rat remnant kidney model.

Topics: Animals; Cell Proliferation; Cells, Cultured; Diet, Protein-Restricted; Dietary Proteins; Disease Models, Animal; Hypertrophy; Kidney; Male; Phosphorylation; Proteinuria; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rats, Wistar; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Smad2 Protein; TOR Serine-Threonine Kinases

Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN). However, the mechanisms underlying this beneficial effect have not been elucidated.. Passive Heymann Nephritis (PHN) was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague-Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa). The remaining six rats were used as the proteinuric control group (PHN) while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC). All rats were sacrificed at the end of the 7th week.. Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression.. Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Glomerulonephritis, Membranous; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Male; Membrane Proteins; Proteinuria; Rats; Sirolimus

Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI). At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNI-based immunosuppressive protocol to sirolimus (SRL) in recipients with graft in chronic kidney disease (CKD) grade III and proteinuria below 500 mg/day.. In the period 2003-2011 24 patients (6 famale and 18 male), mean age 41 +/- 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF) or azathiopirine (AZA)] and CNI were switched from CNI to SRL and followe-up for 76 +/- 13 months. Nine patients (the group I) had early postransplant conversion after 4 +/- 3 months and 15 patients (the group II) late conversion after 46 +/- 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR), proteinuria, lipidemia and side effects.. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV) infection or disease, and they were successfully treated with standard therapy. After 21 +/- 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients) and double immunosuppressive therapy (3 patients), return to hemodialysis (1 patient) and death (1 patient). Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 +/- 12.7 to 69 +/- 15 mL/min), while the increase in proteinuria (from 265 +/- 239 to 530.6 +/- 416.7 mg/day) and lipidemia (cholesterol from 4.71 +/- 0.98 to 5.61 +/- 1.6 mmol/L and triglycerides from 2.04 +/- 1.18 to 2.1 +/- 0.72 mmol/L) were not significant. They were stable during the whole follow-up period. Ten patients were reconverted from SRL to CNI due to the abrupt increase of proteinuria (from 298 +/- 232 to 1639 +/- 1641/mg day in 7 patients), rapid growth of multiple ovarian cysts (2 patients) and operative treatment of persisted hematoma (1 patient). Thirty days after reconversion they were stable with an insignificant decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/min) and significantly improved proteinuria (from 1639 +/- 1641 to 529 +/- 688 mg/day). By the end of the follow-up these patients showed nonsignificant increase in the serum creatinine (from 172 +/- 88 to 202 +/- 91 mmol/L), decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/day) and increased proteinuria (from 528.9 +/- 688 to 850 +/- 1083 mg/min).. In this small descriptive study, conversion from CNI to SRL was followed by an increased incidence of infections and consecutive 25-50% dose reduction in the second antiproliferative agent (AZA, MMF), with a possible influence on the development of glomerulopathy in some patients, which was the major reason for discontinuation of SRL therapy in the 7 (29%) patients. Nine (37.5%) of the patients experienced the greatest benefit of CIN to SRL conversion without serious post-conversion complications.

Topics: Adult; Azathioprine; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytomegalovirus Infections; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Insufficiency, Chronic; Sirolimus; Time Factors; Treatment Outcome

Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology.. Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed.. Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells.. Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.

Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclosporine; Disease Models, Animal; Immunosuppressive Agents; In Vitro Techniques; Kidney Transplantation; Male; Podocytes; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; Transplantation, Homologous; Vascular Diseases; Vascular Endothelial Growth Factor A

Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.

Topics: Animals; Autophagy; Cells, Cultured; Disease Models, Animal; Humans; Lysosomes; Mice; Mice, Knockout; Mice, Transgenic; Microtubule-Associated Proteins; Mitochondria; Podocytes; Proteinuria; Sirolimus; TOR Serine-Threonine Kinases

We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion.. Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival.. Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion.. Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.

Topics: Adult; Aged; Calcineurin Inhibitors; Cohort Studies; Enzyme Inhibitors; Everolimus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prognosis; Proteinuria; Renal Insufficiency; Retrospective Studies; Risk Factors; Sirolimus; Treatment Outcome

The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear.. Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion.. After a median (interquartile range) of 3.1 (1.6-4.5) years of follow-up, serum creatinine decreased from 1.9 ± 0.8 to 1.8 ± 0.7 mg/dL (P=0.25) and eGFR increased from 40.8 ± 16.7 to 44.3 ± 20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0-155) to 382 (169-999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥ 1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1-9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6-11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2-2.2, P=0.003).. Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥ 1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.

Topics: Aged; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Proteinuria; Retrospective Studies; Sirolimus

The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFβ expression in the 5/6 nephrectomy model in Wistar rats.. This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation.. Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFβ observed in the remnant kidney model.. Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFβ mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin.

Topics: Analysis of Variance; Animals; Blotting, Western; Chromatography, High Pressure Liquid; Creatinine; Everolimus; Immunohistochemistry; Kidney; Nephrectomy; Proteinuria; Rats; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; Spectrophotometry; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

This retrospective single-center study evaluated long-term renal function after conversion from calcineurin inhibitors to sirolimus-based immunosuppression in kidney transplant recipients.. From 2001 to 2009, one hundred fifty kidney transplant recipients were converted from calcineurin inhibitors to sirolimus at least 3 months after transplant.. After a mean follow-up of 171 weeks, 56.7% of converted patients remained on sirolimus. The 5-year survival rate of the patients (including intent-to-treat) and grafts was 85.5% and 83.6%. Patients on sirolimus showed significant improvement in renal function with a creatinine clearance of 50.9 ± 20.7 and 52.9 ± 20.8 mL/minute at month 0 and month 24. Independent predictive factors associated with a stable estimated glomerular filtration rate at the last follow-up of sirolimus patients were (1) having a living donor, (2) absence of anti-HLA alloantibodies at month 0, and (3) cyclosporine versus tacrolimus used before conversion. Adverse effects were reported in 134 patients (89.3%). They included (1) hospitalization for infection (n=52), (2) de novo proteinuria (n=40), and (3) eight patients with biopsy-proven acute rejection. Sirolimus was stopped and replaced by calcineurin inhibitors in 37 patients after a mean of 16 months treatment. After stopping sirolimus, renal-allograft function remained stable at 2 years.. Conversion of calcineurin inhibitors to sirolimus in kidney transplant recipients was associated with improved renal function. The reintroduction of calcineurin inhibitors was safe in patients who were withdrawn from sirolimus owing to adverse effects.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Opportunistic Infections; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tacrolimus

Podocytes are terminally differentiated post-mitotic cells similar to neurons, and their damage leads to nephrotic syndrome, which is characterized by massive proteinuria associated with generalized edema. A recent functional genetic approach has identified the pathological relevance of several mutated proteins in glomerular podocytes to the mechanism of proteinuria in hereditary nephrotic syndrome. In contrast, the pathophysiology of acquired primary nephrotic syndrome, including minimal change disease, is still largely unknown. We recently demonstrated the possible linkage of an energy-consuming process in glomerular podocytes to the mechanism of proteinuria. Puromycin aminonucleoside nephrosis, a rat model of minimal change disease, revealed the activation of the unfolded protein response (UPR) in glomerular podocytes to be a cause of proteinuria. The pretreatment of puromycin aminonucleoside rat podocytes and cultured podocytes with the mammalian target of rapamycin (mTOR) inhibitor everolimus further revealed that mTOR complex 1 consumed energy, which was followed by UPR activation. In this paper, we will review nutritional transporters to summarize the energy uptake process in podocytes and review the involvement of the UPR in the pathogenesis of glomerular diseases. We will also present additional data that reveal how mTOR complex 1 acts upstream of the UPR. Finally, we will discuss the potential significance of targeting the energy metabolism of podocytes to develop new therapeutic interventions for acquired nephrotic syndrome.

Topics: AMP-Activated Protein Kinases; Animals; Energy Metabolism; Everolimus; Glucose Transport Proteins, Facilitative; Immunosuppressive Agents; Membrane Transport Proteins; Nephrotic Syndrome; Podocytes; Proteinuria; Rats; Sirolimus; TOR Serine-Threonine Kinases; Unfolded Protein Response

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation.. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil.. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001).. These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Topics: Adult; Aged; Atrophy; Biopsy; Drug Therapy, Combination; Female; Fibrosis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Linear Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Netherlands; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

We studied efficacy and safety of conversion from CNI- to SRL-based immunosuppression in 92 kidney TX recipients, mainly due to CAN (69%). Median time of conversion was 31 months (r: 0.3-165); median time of follow-up: 36 months (r: 2-102). In the whole group mean eGFR increased from 53 ± 22 to 67 ± 26mL/min/1.73 m(2) at three months (p = 0.02) and did not change subsequently. Patients with grade I CAN had higher eGFR than those with grade II CAN. Patient and graft survival was 96% and 70% 10 yr after conversion. Patients with grade I CAN had better graft survival than those with grade II CAN: 89% vs. 65% at six yr (p = 0.02) post conversion. There were two episodes of BPAR. Baseline proteinuria >20 mg/kg/day (HR: 10) and baseline eGFR <50 mL/min/1.73 m(2) (HR: 8) were independent predictors of graft loss. Sixty-seven of 92 subjects had ≥1 AEs: diarrhea (n = 52), urinary tract infections (n = 35), and lower respiratory tract infections (n = 12) were the most frequent. Patients with >2 AEs had SRL blood levels >9 ng/mL at month 3 (p = 0.01). In conclusion, patients converted from CNI to SRL had good graft survival and tolerable but frequent AEs. Independent predictors of graft loss were baseline proteinuria and eGFR.

Topics: Biopsy; Calcineurin Inhibitors; Child; Cohort Studies; Creatinine; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Pediatrics; Proteinuria; Sirolimus; Treatment Outcome

Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4(+) T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.

Topics: Animals; Gene Expression Regulation; Immunity, Innate; Inflammation Mediators; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Nephritis; Platelet Endothelial Cell Adhesion Molecule-1; Proteinuria; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Conversion to sirolimus (SRL)-based immunosuppression in renal transplant recipients is an alternative for chronic allograft dysfunction (CAD), cancer and viral infections. We sought to analyze the indications for and safety and efficacy of conversion to SRL among renal transplant patients.. We examined a retrospective cohort, using medical records of renal transplant recipients >18 years old who had their immunosuppressive regimen converted to a SRL-based treatment. Data analysis included the indication for conversion, time posttransplant, as well as urine protein and serum creatinine at conversion and 6 months thereafter. The end points included death, graft loss and/or discontinuation of SRL.. We included 112 patients in this series who had indications for conversion: fungal, polyomavirus, or cytomegalovirus infection (n = 32), CAD (n = 30), cancer (n = 21), immunologic (n = 3), and other reasons (n = 26). Changes in immunosuppression were performed at 41 ± 57 months posttransplant or later in cancer patients. SRL was discontinued in 9 patients owing to adverse events such as edema, proteinuria, mucositis, or pneumonitis. Graft loss was observed in 19 patients, and death in 6. In 87 patients with functioning grafts, protein/creatinine ratios increased from 0.28 ± 0.03 (conversion) to 0.63 ± 0.09 (after 6 months; P < .001). Serum creatinine decreased from 2.24 ± 0.13 (conversion) to 1.89 ± 0.75 mg/dL (after 6 months; P < .001). Graft survival was 88% at 1 and 80% at 3 years after conversion.. In, SRL was well tolerated; conversion to SRL improved graft function with a slight increase in proteinuria.

Topics: Biomarkers; Chi-Square Distribution; Creatinine; Drug Substitution; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

Nephrotoxicity is a major complication with immunosuppression regimens used in transplantation. Calcineurin inhibitor-sparing or reduction regimens using sirolimus (SRL) have shown variable success in kidney transplantation. There is limited data on the role of SRL on native kidney function in pancreas transplantation.. All patients undergoing pancreas transplantation from 2003 to 2010 were enrolled in this study (n=65). Patient demographic characteristics were identified and divided into two groups: those receiving tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and those maintained on a regimen of Tac and SRL with or without MMF. The slopes for estimated glomerular filtration rate (eGFR), serum creatinine level (sCr), and proteinuria changes over time were assessed between groups. Urine protein and creatinine ratio (uPr/uCr) was used to assess proteinuria.. There was no difference in baseline demographic characteristics. Patients were followed for a median of 3 years. Baseline sCr and eGFR were similar between groups. Differences in uPr/uCr and rate of change in sCr and eGFR were not significant between the groups overall or for any specific time. There was worsening of sCr, eGFR, and uPr/uCr within the groups over the period of study. There were no significant differences when groups were split by age or gender or when the SRL group was split further based on MMF inclusion.. Our study findings suggest that using a Tac-SRL regimen in patients with pancreas alone transplantation is a safe approach and may not lead to worsening proteinuria and kidney function when compared with regimens using Tac with MMF.

Topics: Adult; Age Factors; Biopsy; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Proteinuria; Retrospective Studies; Sex Factors; Sirolimus; Tacrolimus

The mechanisms underlying the development of proteinuria in renal-transplant recipients converted from calcineurin inhibitors to sirolimus are still unknown.. This is a single-center cohort study. One hundred ten kidney transplant recipients converted from calcineurin inhibitors to sirolimus in the period from September 2000 to December 2005 were included in the study. All patients underwent a graft biopsy before conversion (T0) and a second protocol biopsy 2 years thereafter (T2), according to our standard clinical protocol. On the basis of the changes observed in proteinuria between T0 and T2 (median 70%), the patients were divided into two groups: group I (<70%) and group II (>70%). The authors blinded the sirolimus blood trough levels. We investigated in vivo the effects of sirolimus on nephrin, podocin, CD2ap, and actin protein expression. Slit diaphragm (SD)-associated protein expressions were evaluated in T0 and T2 biopsies. The same analysis was performed in cultured human podocytes treated with different doses of sirolimus (5, 10, 20, and 50 ng/mL).. The SD protein expression in group II T2 biopsies was significantly reduced compared with the T0 biopsies and with T2 group I biopsies. In addition, sirolimus blood trough levels directly and significantly correlated with the SD protein expression at T2 graft biopsies. Group II patients presented significantly higher sirolimus blood levels than group I. In vitro study confirmed that sirolimus effect on podocytes was dose dependent.. Our data suggest that sirolimus-induced proteinuria may be a dose-dependent effect of the drug on key podocyte structures.

Topics: Adaptor Proteins, Signal Transducing; Adult; Cell Line; Cohort Studies; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Transplantation; Membrane Proteins; Microscopy, Electron, Transmission; Middle Aged; Neprilysin; Podocytes; Proteinuria; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Time Factors; WT1 Proteins

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Cell Proliferation; Cytochrome P-450 CYP3A; Everolimus; Haplotypes; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Retrospective Studies; Signal Transduction; Sirolimus; Treatment Outcome

Sirolimus is unlicensed for use in liver transplantation because of concerns over safety, particularly in regard to hepatic artery thrombosis and excess mortality. However, sirolimus offers potential advantages over calcineurin inhibitor-based immunosuppression, relating to its renal sparing and antiproliferative properties.. A review was undertaken of 148 liver transplant patients converted to sirolimus over 10 years at a single center.. The main indications for sirolimus were renal impairment and hepatitis C virus fibrosis. One hundred eleven (75%) patients remained on sirolimus after median follow-up of 1006 days. Mean (+/-standard deviation) glomerular filtration rate improved significantly from 59+/-29 mL/min preconversion to 72+/-39 mL/min at censor point (P<0.05). Improvement in glomerular filtration rate was most marked in patients converted for renal impairment. Liver function tests remained stable or improved, particularly in patients transplanted for hepatitis C virus. Side effects attributed to sirolimus occurred in 101 (68%) patients requiring withdrawal in 20 patients (14%). Moderate increases in serum lipids were observed and controlled effectively with statins. The incidence of proteinuria increased postconversion but had no deleterious impact on renal function. No episodes of hepatic artery thrombosis were observed.. Sirolimus was safe and may improve outcome in selected patients after liver transplantation.

Topics: Adult; Aged; Female; Glomerular Filtration Rate; Hepatitis C; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppression Therapy; Immunosuppressive Agents; Lipids; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Proteinuria; Retrospective Studies; Sirolimus; Treatment Outcome; Young Adult

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.

Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Carrier Proteins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Gene Dosage; Genetic Predisposition to Disease; Humans; Kidney Glomerulus; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Multiprotein Complexes; Nephrosis, Lipoid; Podocytes; Proteins; Proteinuria; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; Sirolimus; TOR Serine-Threonine Kinases; Trans-Activators; Transcription Factors

There is no information on the effects of proteinuria on outcomes following rejection.. We addressed this question in a retrospective study of 925 kidney transplant recipients between January 2003 and December 2007. Selection criteria were based on (i) biopsy proven diagnosis of a first episode of acute rejection, and (ii) available data on urine protein to creatinine (UPC) ratios at baseline (lowest serum creatinine before biopsy), time of biopsy and 1 month after biopsy. We examined the effects of a change in UPC (DeltaUPC = UPC 1 month after biopsy-baseline UPC) on outcomes.. We identified 82 patients with both acute rejection and available data on proteinuria. Mean time (+/-SE) to acute rejection was 19 +/- 2.3 months, and patients were followed up for 38.7 +/- 2.6 months after transplant. Median DeltaUPC was 200 mg/g (95% confidence interval 0.00 to 0.300). Forty-two patients had a DeltaUPC > or =200 (high proteinuria group). Baseline characteristics were similar between high and low proteinuria groups except for more induction therapy with interleukin-2 receptor blockade in the former (71 vs. 47%, P = 0.04). Patient with DeltaUPC > or =200 had higher rates of graft loss (26 vs. 15%, P = 0.01) or combined graft loss or death (38 vs. 20%, P = 0.002 by log-rank). In univariate and multivariate Cox regression analyses, DeltaUPC > or =200 mg/g, sirolimus therapy 1 month after rejection and re-transplant status were significant factors associated with death-censored graft loss (hazard ratio (HR) 4.4, 14.9 and 6.2, P < or = 0.008) or combined graft loss or patient death (HR 3.8, 6.5 and 3.9, P < or = 0.03). Conclusions. An increase in proteinuria > or =200 mg/g after late acute rejection is associated with poor graft and patient outcomes. Clinical trials are needed to determine whether post-rejection anti-proteinuric strategies improve outcomes.

Topics: Adult; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Proteinuria; Retrospective Studies; Sirolimus; Survival Rate

Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African-American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to > or =500 mg/g in 65% of AAs versus 14% of non-AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Risk Factors; Sirolimus; Steroids; Tacrolimus

Topics: Humans; Immunosuppressive Agents; Proteinuria; Sirolimus

Avoidance of calcineurin inhibitor-associated nephrotoxicity has recently gained focus. To assess the impact of the conversion to sirolimus, we performed a retrospective audit on renal transplant patients switched to sirolimus at the Inkosi Albert Luthuli Central Hospital (South Africa) from 2003 until June 2007.. Medical records of transplant recipients were analyzed. Twenty-four-hour urine protein excretion and estimated glomerular filtration rates before initiation of sirolimus (baseline), and at their last clinic visit, were compared. Patients were then subcategorized according to their specific indications for switching to sirolimus.. Thirty patients were included. Average follow-up was 25 months. Indications for use of sirolimus were group 1 (cyclosporine-induced biochemical toxicity, n=6); group 2 (chronic allograft nephropathy, n=6); group 3 (severe gum hypertrophy, n=9); group 4 (posttransplant diabetes, n=4); group 5 (calcineurin-inhibitor-induced histologic nephrotoxicity, n=2); and group 6 (calcineurin inhibitor-associated malignancy, n=3). Average urine protein excretion rate and estimated glomerular filtration rate before starting sirolimus were 0.44 -/+ 0.08 g/24 h and 50.1 -/+ 3.1 mL/min respectively, compared to 0.94 -/+ 0.2 g/24 h and 52.1 -/+ 4.8 mL/min, at an average follow-up of 25 months. On subgroup analysis, estimated glomerular filtration rate was increased/unchanged in groups 1 (47.3 vs 51.16 mL/min) and 4 (60.0 vs 60.0 mL/min) when compared to baseline, but decreased in groups 2 (47 vs 27.6 mL/min), 3 (51.3 vs 42.2 mL/min), 5 (54.0 vs 29.5 mL/min), and 6 (60.0 vs 56.5 mL/min). Combining the latter 2 groups, most patients (80%) received sirolimus within 1 year of transplant, whereas only 2 patients in the former groups (10%) received the drug within 1 year of transplant.. Overall, sirolimus therapy was associated with improved estimated glomerular filtration rate, and also an increase in urine protein excretion rates. Maximum benefit was achieved when patients were switched to sirolimus within the first transplant year.

Topics: Clinical Audit; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Proteinuria; Retrospective Studies; Sirolimus; South Africa; Time Factors; Treatment Outcome

The goal in transplantation is to obtain immunosuppressant combinations that decrease the incidence of acute and chronic rejection but cause fewer side effects. FTY720 is a new immunomodulator that prevents experimental allograft rejection without inhibiting T-cell activation. It is currently under clinical investigation for multiple sclerosis. We investigated whether FTY720 in combination with sirolimus (SRL) could cause renal toxicity in C57BL/6 mice when administered for 21 days. Serum creatinine and 24-hour urinary creatinine concentrations were assessed by enzymatic colorimetric assays. Urinary protein concentration was measured by the Bradford protein assay. Whereas serum creatinine levels were increased in FTY720 + SRL-treated animals, there were no changes in urinary volume, urinary protein levels, serum urea concentration, creatinine clearance, and kidney structure. Our findings suggested that FTY720 monotherapy for multiple sclerosis and other diseases could play an important immunomodulatory role without causing the side effects frequently observed with other transplantation regimens.

Topics: Animals; Creatinine; Diuresis; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mice; Mice, Inbred C57BL; Propylene Glycols; Proteinuria; Sirolimus; Sphingosine

In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation.. We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation.. The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 +/- 0.5, 0.5 +/- 0.3, 0.47 +/- 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 +/- 24 vs 73.04 +/- 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 +/- 29 mL/min).. EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.

Topics: Adult; Cohort Studies; Dose-Response Relationship, Drug; Everolimus; Female; Follow-Up Studies; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prognosis; Proteinuria; Sample Size; Sirolimus

The development of proteinuria has been observed in kidney-transplanted patients on m-TOR inhibitor (m-TORi) treatment. Recent studies suggest that m-TORi(s) may alter the behavior and integrity of glomerular podocytes. We analyzed renal biopsies from kidney-transplanted patients and evaluated the expression of nephrin, a critical component of the glomerular slit-diaphragm. In a group of patients on 'de novo' m-TORi-treatment, the expression of nephrin within glomeruli was significantly reduced in all cases compared to pretransplant donor biopsies. Biopsies from control transplant patients not treated with m-TORi(s) failed to present a loss of nephrin. In a group of patients subsequently converted to m-TORi-treatment, a protocol biopsy performed before introduction of m-TORi was also available. The expression of nephrin in the pre-m-TORi biopsies was similar to that observed in the pretransplant donor biopsies but was significantly reduced after introduction of m-TORi(s). Proteinuria increased after the m-TORi inititiation in this group. However, in some cases proteinuria remained normal despite reduction of nephrin. In vitro, sirolimus downregulated nephrin expression by human podocytes. Our results suggest that m-TORi(s) may affect nephrin expression in kidney-transplanted patients, consistently with the observation in vitro on cultured podocytes.

Topics: Adult; Aged; Cells, Cultured; Humans; Kidney Glomerulus; Kidney Transplantation; Membrane Proteins; Middle Aged; Podocytes; Proteinuria; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases

The present study was designed to investigate the effect of low-dose calcineurin inhibitor (CNI) tacrolimus combined with a mammalian target of rapamycin (mTOR) inhibitor on renal function in transplant recipients without allograft nephropathy.. Twelve patients including seven men (58.3%) of overall mean age of 34.8 ± 14.1 years underwent renal transplantation and were switched to a new second-line treatment of low-dose CNI combined with an mTOR inhibitor, either sirolimus or everolimus.. The underlying cause of renal failure was not clear in half of the cases; for the others it was chronic glomerulonephritis, diabetic nephropathy, polycystic kidney disease, or hypovolemia. After 6 months of the new therapy, there was a significant increase in calculated creatinine clearance levels compared to baseline (75.5 ± 21.9 vs 89.6 ± 19.1 mL/min; P < .001), but no significant change in serum creatinine (1.3 ± 0.4 vs 1.2 ± 0.3 mg/dL) or urinary protein excretion (187.5 ± 142.0 vs 394.0 ± 326.4 mg/g). For almost all patients, proteinuria remained stable, but in two patients, it developed but responded to enalapril treatment. Dose decrement was required for four patients with hyperlipidemia (50%); one patient experienced new-onset hyperlipidemia that responded to treatment. One patient developed a urinary tract infection that responded to antibiotic treatment. None of the patients developed an acute rejection episode.. Low-dose CNI combined with an mTOR inhibitor, as a replacement for mycophenolate mofetil or enteric-coated mycophenolate sodium, seemed to prevent renal dysfunction for at least 6 months among renal transplant patients without allograft nephropathy.

Topics: Adult; Biomarkers; Calcineurin Inhibitors; Creatinine; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Sirolimus; Tacrolimus; Time Factors; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome; Turkey; Urinary Tract Infections; Young Adult

Recent evidence of a high incidence of proteinuria among de novo sirolimus-based regimens has been reported among renal transplant patients at short-term follow-up. We report on long-term evaluation of proteinuria among patients maintained on such regimen.. Between May 2001 and January 2003, 132 patients received a renal allograft from a living donor and were randomized to 2 groups (steroids/sirolimus/tacrolimus, n=65) and (steroids/sirolimus/mycophenolate mofetil, n=67): Both received basiliximab induction. Retrospective review of those patients was performed, 5 years posttransplant with particular emphasis on the incidence of proteinuria.. The 5-year incidence of proteinuria was 29.2% and 38.8% among sirolimus/tacrolimus and sirolimus/mycophenolate mofetil group. Single DR-matched patients (P = .016) and the incidence of acute rejection (P = .039) were associated with significantly higher incidence of proteinuria. Moreover, the presence of mesangial matrix increased (P = .015), and glomerulosclerosis (P = .014), in 1-year protocol biopsies, was found to have a positive predictive value for current and future incidences of proteinuria. Proteinuria was found to be associated with significant inferior graft outcome. Recurrent original kidney disease, de novo glomerulopathy, and acute transplant glomerulopathy were responsible for early cases of nephrotic range proteinuria (first 2 years), while cases presented later were attributed to chronic allograft nephropathy.. Proteinuria has become a recognized, serious event of primarily sirolimus-treated renal transplants patients, which is most probably of glomerular origin. It has been shown that proteinuria exerts a bad prognostic effect upon graft function and subsequent graft survival at 5-year follow-up.

Topics: Adult; Biopsy; Chi-Square Distribution; Drug Therapy, Combination; Egypt; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Proteinuria; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Carcinoma, Squamous Cell; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Everolimus; Humans; Liver Transplantation; Male; Middle Aged; Proteinuria; Sirolimus

Although sirolimus (SRL) use in renal allograft recipients (RTX) is associated with improved renal function, proteinuria develops in a significant proportion. 48 SRL-treated RTX were evaluated for development of proteinuria and stratified by level of proteinuria after SRL therapy. The Proteinuria Group (n = 25, 52.1%) had new-onset proteinuria or >25% increase in proteinuria following SRL conversion; the Nonproteinuria Group had stable proteinuria <0.5 g/day throughout. There was a higher proportion of male RTX and female donors to male recipients in the Proteinuria Group, (24% vs. 10%, P = 0.008). Calcineurin inhibitor- and statin usage were significantly higher in the Nonproteinuria Group (8% vs. 17%, P = 0.046; 28% vs. 83%, P < 0.001 respectively) whereas biopsy-proven acute rejection was higher in the Proteinuria Group (68% vs. 33%, P = 0.037). SDS-PAGE analysis of urine from 23 RTX in the Proteinuria Group demonstrated glomerular proteinuria in 100% and tubular proteinuria in 87%. While male gender and gender mismatch may impact on glomerular proteinuria through inadequate nephron dose and subsequent hyperfiltration, concurrent cyclosporine use may mitigate the development of proteinuria in SRL-treated patients, through afferent arteriolar vasoconstriction. Glomerular injury occurring following acute rejection may further contribute to glomerular proteinuria. Statins, through their anti-inflammatory and anti-fibrotic effects, may protect against development of proteinuria.

Topics: Acute Disease; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Body Mass Index; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Nephrons; Prevalence; Proteinuria; Sex Factors; Sirolimus; Vasoconstriction

Topics: Adult; Antibiotics, Antineoplastic; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteinuria; Sirolimus; Transplantation, Homologous

A 58-year-old man with advanced renal cell carcinoma developed grade 3 proteinuria (8.5 g/24 h) without microscopic hematuria or renal insufficiency five days after temsirolimus infusion. Kidney biopsy revealed ischemic glomeruli and focal segmental glomerulosclerosis lesion. Proteinuria level decreased to 2.80 g per day two weeks after temsirolimus withdrawal. Clinicians should be aware to this complication.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Glomerulosclerosis, Focal Segmental; Humans; Kidney Neoplasms; Male; Middle Aged; Proteinuria; Sirolimus

Sirolimus (SRL) has been shown to improve long-term graft survival in several calcineurin inhibitor avoidance/minimization protocols. Although SRL has been suggested to reduce the progression of chronic renal graft damage and to prevent the development of neoplasia, two of the most prominent challenges in the field of transplantation, its use is significantly limited by an extremely high incidence of side effects. Some of the side effects are directly linked to the antiproliferative action of SRL, whereas the mechanisms underlying most of the undesired effects of the drug are still far from being clarified. Nevertheless, there is an increasing body of evidence linking most these drug-associated events to SRL dose. In addition, it is now possible to identify well-defined risk factors for most of these effects. Thus, to limit SRL-related side effects the two golden rules are (1) accurate selection of patients to be treated and (2) avoidance of high SRL doses.

Topics: Anemia; Diabetes Mellitus; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphocele; Proteinuria; Sirolimus; Wound Healing

Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (

Topics: Cadaver; Cell Division; Creatinine; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Activation; Multicenter Studies as Topic; Patient Selection; Proteinuria; Randomized Controlled Trials as Topic; Sirolimus; T-Lymphocytes; Tissue Donors

Anti-mTOR may induce proteinuria when utilized after renal transplantation. Little is known about the pathogenesis and composition of proteinuria. To clarify this unresolved aspect, we analyzed urinary protein composition utilizing an integrated proteomics approach, including quantitative assays, 2-dimensional electrophoresis, MALDI-TOF, and Western blots among 48 renal transplant recipients treated with everolimus (EVL; n = 31) or enteric-coated mycophenolic acid (EC-MPA; n = 17). High (>3 g/d) or intermediate levels of proteinuria (1-3 g) developed in 12 EVL patients (39%) compared with 4 subjects (23%) in the EC-MPA group. Proteinuria, which started during the first 2 days after EVL, tended to reduce during the follow-up. Quantitative proteomics showed an increase in low molecular proteins beta2 microglobulin (P < .001) and alpha1 microglobulin (P < .025). Qualitative proteomics showed a marked increase among all urinary components in EVL and EC-MPA patients. Major changes involved typical components of glomerular damage: albumin, Zn-alpha1 glycoprotein, alpha2HS glycoprotein, and leucine-rich alpha2 glycoprotein. In addition, we observed specific biomarkers for EVL: clusters of alpha1-antitrypsin fragments and monoclonal lambda chains. In conclusion, EVL induced proteinuria of a mixed glomerular and tubular origin that correlated with the start of treatment and reached nephrotic ranges in few cases. The specific urinary markers may reflect renal alterations related to the transplant or specific alterations associated with the drug.

Topics: Adult; Everolimus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus

Rapamycin is an immunosuppressive drug used to prevent acute allograft rejection in solid organ transplantation. It shows less nephrotoxicity than calcineurin inhibitors. We evaluated the effect of rapamycin in rats undergoing 5/6 nephrectomy, a model of proteinuric and progressive renal failure. Fourteen days after surgery rats were randomized either to receive rapamycin or to remain untreated (control). Rats were humanely killed on day 91; serum creatinine, creatinine clearance, and proteinuria were assessed. Renal sections were stained with periodic acid-Schiff to evaluate glomerular volume (Gv), glomerulosclerosis (GS) and tubulointerstitial damage (TIS); we evaluated GS and TIS by Sirius red staining (SR). Epithelial-to-mesenchymal transition (EMT) was assessed by immunohistochemistry. Rapamycin affected neither serum creatinine nor creatinine clearance; it reduced Gv (controls, 5.9 +/- 3.1 x 10(6); rapamycin, 1.3 +/- 0.7 x 10(6) microm(3)) and proteinuria (control, 349 +/- 146; rapamycin, 56 +/- 27 mg/24 h; P < .05); rapamycin ameliorated GS (control, 78 +/- 7; rapamycin, 36 +/- 7%; P < .05; SR: control, 13.2 +/- 3.5; rapamycin, 3.8 +/- 1.0%; P < .05), and TIS (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05; SR: control, 29 +/- 3; rapamycin, 11 +/- 3%; P < .05). Rapamycin reduced alphaSMA (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05), VIM (control, 3.5 +/- 0.6; rapamycin, 1.0 +/- 1.4; P < .05), and CD68(+) cells infiltration (control, 110 +/- 43; rapamycin, 24 +/- 1 cells; P < .05). Rapamycin slows the progression of renal damage in the rat remnant kidney and may represent a novel approach to the treatment of chronic kidney disease.

Topics: Animals; Immunosuppressive Agents; Proteinuria; Rats; Sirolimus

Improvement in renal function has been noted in some lung allograft recipients with chronic kidney disease (CKD) converted from a calcineurin inhibitor (CNI)- to a sirolimus (SRL)-based immunosuppressive regimen. However, not all patients have such a positive response. We sought to investigate independent predictors of a favorable renal response in a cohort of lung transplant recipients.. We retrospectively studied 56 lung transplant recipients with CKD, defined as a pre-conversion estimated glomerular filtration rate (eGFR) < or =60 ml/min/1.73 m(2), who had been converted to CNI-sparing regimens using SRL (CNI-free: n = 10; CNI dose reduction + SRL: n = 46). Proteinuria prior to conversion, defined as > or =1(+) on urine dipstick, was determined when available (n = 51). Changes in mean eGFR post-conversion and independent predictors of a favorable renal response, defined as a rise in eGFR > or =20% within 1 month, were investigated.. Mean eGFR at conversion was 35 +/- 14 ml/min/1.73 m(2), increasing by 8 +/- 14 ml/min/1.73 m(2) (p < 0.01) by 1 month post-conversion, a trend that remained significant out to 18 months. A total of 43% (n = 24) of patients had a rise in eGFR > or =20%. Forced expiratory volume in 1 second (FEV(1)) remained stable in survivors maintained on SRL and only 1 rejection episode occurred. When controlling for gender, age, pre-conversion eGFR and CNI-free vs CNI-dose reduction, the only variable that remained independently predictive of a favorable renal response was absence of proteinuria, with an odds ratio = 3.3 (95% confidence interval 1.0 to 12.5, p = 0.05).. Non-proteinuric lung transplant survivors with CKD are more likely to respond favorably from a renal standpoint after conversion to SRL with CNI-dose reduction or elimination.

Topics: Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Cohort Studies; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Lung Transplantation; Male; Middle Aged; Predictive Value of Tests; Proteinuria; Retrospective Studies; Sirolimus; Treatment Outcome

In participants of the CONVERT trial, which enrolled recipients of kidney transplants, conversion of immunosuppressive therapy from calcineurin inhibitors to sirolimus did not improve renal function. More importantly, the intervention was detrimental among patients with impaired kidney function and/or proteinuria. Sirolimus conversion resulted, however, in lower rates of malignancy.

Topics: Calcineurin Inhibitors; Delayed Graft Function; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Neoplasms; Kidney Transplantation; Proteinuria; Sirolimus

In clinical renal transplantation, an increase in proteinuria after conversion from calcineurin inhibitors to rapamycin has been reported. In contrast, there are studies showing a nephro-protective effect of rapamycin in proteinuric diseases characterized by progressive interstitial inflammatory fibrosis.. Because of the contradictory reports concerning rapamycin on proteinuria, we examined proteinuria and podocyte damage markers on two renal disease models, with clearly different pathophysiological mechanisms: a glomerular toxico-immunological model induced by puromycin aminonucleoside, and a chronic hyperfiltration and inflammatory model by mass reduction, both treated with a fixed high rapamycin dose.. In puromycin groups, rapamycin provoked significant increases in proteinuria, together with a significant fall in podocin immunofluorescence, as well as clear additional damage to podocyte foot processes. Conversely, after mass reduction, rapamycin produced lower levels of proteinuria and amelioration of inflammatory and pro-fibrotic damage. In contrast to the puromycin model, higher glomerular podocin and nephrin expression and amelioration of glomerular ultrastructural damage were found.. We conclude that rapamycin has dual opposing effects on subjacent renal lesion, with proteinuria and podocyte damage aggravation in the glomerular model and a nephro-protective effect in the chronic inflammatory tubulointerstitial model. Rapamycin produces slight alterations in podocyte structure when acting on healthy podocytes, but it clearly worsens those podocytes damaged by other concomitant injury.

Topics: Animals; Disease Models, Animal; Immunosuppressive Agents; Male; Nephrosis, Lipoid; Podocytes; Proteinuria; Rats; Rats, Sprague-Dawley; Sirolimus

Sirolimus (SRL) is a potent and specific immunosuppressive drug used in organ transplantation, as basic therapy or in combination with calcineurin inhibitors. Although SRL is a nonnephrotoxic drug, many reports have related its use with the development of proteinuria, especially after conversion. Therefore, the aim of this study was to elucidate the interrelation between early and late SRL administration on the development of glomerular hypertrophy and proteinuria in a model of renal mass reduction (RMR).. Rats underwent 2/3 cryoablation of the left kidney and subsequent right nephrectomy (n=42) or sham operations (n=29). Two weeks before (early study) or 12 weeks after (late study) surgery, SRL or vehicle was administered three times weekly. Creatinine clearance and proteinuria were determined throughout the study, and a complete histologic analysis was performed at the end of the study.. Treatment with SRL had no effect on creatinine clearance, independently of the administration time. Four weeks after RMR, a significant increase in proteinuria was observed. Proteinuria was stabilized after early and late SRL administration, whereas vehicle-treated animals showed a further increase in proteinuria. Glomerular hypertrophy was strongly associated with proteinuria, and early SRL introduction prevented glomerular enlargement. The histologic analysis showed less structural damage in the two groups of animals treated with SRL than in the control group.. Although early SRL introduction blocked glomerular hypertrophy, SRL treatment revealed the potential to halt progression of proteinuria and histologic damage at any time of administration in a model of RMR.

Topics: Animals; Creatinine; Disease Models, Animal; Disease Progression; Hypertrophy; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Protein Kinases; Proteinuria; Rats; Rats, Wistar; Sirolimus; TOR Serine-Threonine Kinases

We studied early sirolimus (SRL) therapy in renal transplant recipients at high risk after administration of antithymocyte globulin or interleukin-2 receptor blockade induction.. In 45 patients, SRL therapy was started within 1 month after transplantation. The primary indications for conversion of treatment from calcineurin inhibitors (CNIs)-mycophenolate mofetil (MMF)-steroid to SRL-MMF-steroid were biopsy-proved rejection (after treatment), CNI toxicity, CNI elimination, and acute tubular necrosis. Pediatric, geriatric, and other patients with medical comorbidities were not excluded.. Post-SRL rejection episodes were reported in 22.2% of recipients including 15.6% who were resistant to steroid therapy. Mean (SD) follow-up after SRL therapy was 59.9 (8.1) months. Proteinuria greater than 2 g/d (P = .001), leukopenia (P < .001), hyperlipidemia (P < .001), and transaminases values (P = .02) increased significantly after SRL therapy. Graft survival was 88.8%, and patient survival was 93.3%. There was significant improvement in serum creatinine concentration and estimated creatinine clearance by the end of the study (P < .001). A high incidence of adverse effects and infections was noted post-SRL therapy, and the drug was discontinued in 31% of patients because of multiple adverse effects. At multivariate analysis, age, hypertension, nutritional status, bone marrow suppression, hyperlipidemia, and graft dysfunction were identified as risk factors for worse graft and patient outcome.. Early treatment with combined SRL-MMF-steroid may be effective as a CNI-free immunosuppression regimen in patients at high risk; however, there is a high rate of adverse effects during long-term follow-up.

Topics: Adult; Biopsy; Cadaver; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Patient Selection; Proteinuria; Risk Factors; Sirolimus; Tissue Donors; Treatment Failure; Treatment Outcome

The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.

Topics: Administration, Oral; Animals; Drug Administration Schedule; Emulsions; Everolimus; Hypertrophy; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Male; Polycystic Kidney Diseases; Protein Kinases; Proteinuria; Pulse Therapy, Drug; Rats; Sirolimus; TOR Serine-Threonine Kinases

Replacing a calcineurin inhibitor (CNI) with sirolimus (SRL) may preserve kidney graft function. However, at the present time, only short follow-up after conversion is available. The aim of this study was to assess whether conversion from a CNI-based to an SRL-based maintenance regimen was safe and effective.. We performed a retrospective cohort study among kidney graft patients whose CNI was withdrawn to be replaced by SRL. Two-tailed paired t tests were used to compare glomerular filtration rates (GFRs) and proteinuria levels before and up to 2 years after conversion. We used linear regression to determine the factors associated with changes in renal function after conversion.. The 193 study subjects had a mean GFR at conversion of 41 +/- 16 mL/min/1.73 m(2) a median proteinuria level of 0 g/L (interquartile range = 0-0.15). After conversion, the GFR was stable: at 1 year, the change was -0.34 mL/min/1.73 m(2) (95% confidence interval [CI] = -2.71, 2.03) and at 2 years, -0.96 mL/min/1.73 m(2) (95% CI = 4.26, 2.34). There was a small but significant increase in dipstick proteinuria at 1 year of +0.5 g/L, (95% CI = 0.20, 0.75). On multivariate analysis, proteinuria > or = 1 g/L at the time of conversion was the only predictor of deteriorating GFR at 1 year (beta: -7.91 mL/min/1.73 m(2); 95% CI = -14.10, -1.70). SRL had to be discontinued in 31% of patients.. Conversion from CNI to SRL resulted in stable graft function at 2 years and in a slight increase in proteinuria. Despite the relatively high reconversion rate, this strategy offers a reasonable alternative to CNIs for most patients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Calcineurin; Calcineurin Inhibitors; Cohort Studies; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Proteinuria; Regression Analysis; Retrospective Studies; Sirolimus; T-Lymphocytes; Treatment Failure; Treatment Outcome

Chronic renal dysfunction is a multifactorial and frequent event after organ transplantation. The measurement or the estimation of glomerular filtration rate is essential to detect early progressive renal dysfunction. Proliferation signal inhibitors are nonnephrotoxic immunosuppressive drugs which may be useful to minimize calcineurin inhibitors-related side effects through a conversion strategy. Most studies in the setting of kidney transplantation showed improvement in glomerular filtration rate as high than conversion was early. Proliferation signal inhibitors may be included quickly in new immunosuppressive regimen for liver transplanted patients with chronic renal dysfunction.

Topics: Calcineurin Inhibitors; Cyclosporine; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Postoperative Complications; Protein Serine-Threonine Kinases; Proteinuria; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 +/- 22 to 59.38 +/- 28.6 mL/min/1.73 m(2) (p = 0.04) at six months and 57.46 +/- 31.1 mL/min/1.73 m(2) (p = 0.02) at 12 months post-withdrawal. Forty-one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 +/- 1.0 to 1.71 +/- 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI-based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.

Topics: Adolescent; Biopsy; Calcineurin; Calcineurin Inhibitors; Child; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Patient Selection; Pediatrics; Proteinuria; Retrospective Studies; Sirolimus

We retrospectively reviewed our experience with 45 kidney transplant recipients (KTR) that were switched from CNI to SRL, mainly for chronic allograft dysfunction (CAD) (41/45). The mean serum creatinine at switch was 2.5 +/- 0.8 mg/dl. At 1 year, patient survival was 93%. Death-censored graft survival was 67% at 1 year and 54% at 2 years. SRL was stopped because of severe side effects in 15 patients. Among these, eight patients developed 'de novo' high-grade proteinuria. Univariate analysis revealed that (1) a higher SRL level at 1 month was a predictor of SRL withdrawal due to severe side effects (P = 0.006), and (2) predictors of graft failure after SRL conversion were low SRL loading dose (P = 0.03) and a higher creatinine level at conversion (P = 0.003). In conclusion, the therapeutic index of SRL in patients suffering from CAD is narrow, with high exposure triggering serious adverse events that may mandate SRL discontinuation, while too low exposure may expose patients to under-immunosuppression and graft loss.

Topics: Adult; Creatinine; Dose-Response Relationship, Drug; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Retrospective Studies; Risk Factors; Sirolimus; Transplantation, Homologous

Topics: Adult; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Lymphoma, Large-Cell, Anaplastic; Male; Proteinuria; Sirolimus; Transplantation, Homologous

One major cause of graft loss is chronic allograft nephropathy (CAN), which may relate to calcineurin inhibitors (CNIs). We converted CAN cases from CNIs to sirolimus and observed the outcomes.. From January 2004 to August 2007, there were 28 kidney recipients in our center with creeping creatinine levels compatible with CAN. We started sirolimus at 2 mg/d and reduced the CNIs gradually. Sirolimus trough levels were kept between 5 and 8 ng/mL. Mycophenolic acid was cut in half; there was no adjustment on prednisolone dose.. The mean switch time was 47.3 months after transplantation. One case discontinued sirolimus due to severe drug-induced pneumonitis. Twelve of the 27 (45%) patients showed improvements in graft function. The most frequent complications were anemia (13/28), hyperlipidemia (13/28), and pneumonitis (4/28). A baseline serum creatinine level less than 2.2 mg/dL seemed to forecast a response to sirolimus conversion. Most of the graft functional improvement occurred within 6 months after the switch. No graft or patient loss was encountered.. Our experience suggested that 45% of patients with sirolimus conversion showed improved graft function. Among patients within 1 year after transplantation, those with a creatinine level less than 2.2 mg/dL, no proteinuria, and no hyperlipidemia seemed to be better candidates for Sirolimus conversion.

Topics: Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Retrospective Studies; Sirolimus; Time Factors

The aim was to evaluate long-term graft survival and function after conversion to sirolimus (SRL) for chronic calcineurin inhibitor (CNI) toxicity and the predictive value of baseline proteinuria. This is a follow-up conversion study of 59 renal transplant patients with deteriorating graft function and histologic signs of CNI toxicity. Previously, baseline proteinuria <800 mg/day was identified as a short-term predictor for successful conversion. Follow-up was 5.3 +/- 0.8 (3.7-6.8) years. Patient survival was 88%, graft survival 38%. Creatinine clearance at the last follow-up was 33.7 +/- 14 ml/min, proteinuria 826 +/- 860mg/day. Baseline proteinuria <800 mg/day was associated with better graft survival. In a cox analysis including proteinuria >800 mg, glomerular filtration rate, age at conversion, chronic Banff score at conversion and time after transplantation at conversion, higher proteinuria was associated with a relative risk of graft loss of 3.98. Prognosis of chronic allograft dysfunction is poor. However, conversion to SRL remains an option for patients with low baseline proteinuria, which can slow down deterioration of graft function during a follow-up period of up to 5 years.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Sirolimus

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

Topics: Adrenal Cortex Hormones; Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Environmental Monitoring; Female; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Male; Mycophenolic Acid; Patient Selection; Prospective Studies; Proteinuria; Sirolimus; Survival Analysis

Sirolimus is the latest immunosuppressive agent used to prevent rejection, and may have less nephrotoxicity than calcineurin inhibitor (CNI)-based regimens. To date there has been little documentation of clinically significant proteinuria linked with the use of sirolimus. We have encountered several patients who developed substantial proteinuria associated with sirolimus use. In each patient, the close temporal association between the commencement of sirolimus therapy and proteinuria implicated sirolimus as the most likely etiology of the proteinuria.. We analyzed the clinical and laboratory information available for all 119 patients transplanted at the Washington Hospital Center between 1999-2003 for whom sirolimus was a component of their immunosuppressant regimen. In these patients, the magnitude of proteinuria was assessed on morning urine samples by turbidometric measurement or random urine protein:creatinine ratios, an estimate of grams of proteinuria/day. Laboratory results were compared between prior, during and following sirolimus use.. Twenty-eight patients (24%) developed increased proteinuria from baseline during their post-transplantation course. In 21 patients an alternative cause of proteinuria was either obvious or insufficient data was available to be conclusive. In 7 of the 28 patients there was a striking temporal association between the initiation of sirolimus and the development of nephrotic-range proteinuria. Proteinuria correlated most strongly with sirolimus therapy when compared to other demographic and clinical variables. In most patients, discontinuation of sirolimus resulted in a decrease, but not resolution, of proteinuria.. Sirolimus induces or aggravates pre-existing proteinuria in an unpredictable subset of renal allograft recipients. Proteinuria may improve, but does not resolve, when sirolimus is withdrawn.

Topics: Adult; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nephelometry and Turbidimetry; Proteinuria; Retrospective Studies; Sirolimus

Topics: Animals; Biological Transport; Cells, Cultured; Endocytosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules, Proximal; Models, Animal; Opossums; Postoperative Complications; Proteinuria; Serum Albumin; Sirolimus; Transplantation, Homologous

Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Although treatment with corticosteroids and cytotoxic drugs may be useful in many cases, morbidity associated with these drugs and the relapsing nature of the disease make it necessary to develop new treatment strategies. Five-month old female NZB/W F1 mice were divided into the following groups: CYP group (n = 10), cyclophosphamide (CYP) 50 mg/kg intraperitoneally every 10 days; RAPA 1 group (n = 10) oral daily sirolimus (SRL), 1 mg/kg; RAPA 12 group (n = 13), oral daily SRL, 12mg/kg; FTY group (n = 10), oral fingolimod (FTY720), 2 mg/kg three times per week. An additional group of 13 non-treated mice were used as a control (control group). Follow-up was performed over four months. Animal survival, body weight, anti-DNA antibodies and proteinuria were determined. Kidneys were processed for conventional histology and immunofluorescence for IgG and complement. Total histological score (HS) was the sum of mesangial expansion, endocapillary proliferation glomerular deposits, extracapillary proliferation, interstitial infiltrates, tubular atrophy and interstitial fibrosis. All treated groups had lower proteinuria at the end of the follow-up with respect to the control group (P < 0.0001). Serum anti-DNA antibodies were appropriately controlled in RAPA 1 and CYP groups, but not in FTY or RAPA 12 groups. SRL and CYP arrested, and perhaps reversed almost all histological lesions. FTY720 ameliorated histological lesions but did not control mesangial expansion or interstitial infiltrates. SRL produces great improvement in murine lupus nephritis, while FTY720 seems a promising alternative if used in appropriate doses.

Topics: Administration, Oral; Animals; Antibodies, Antinuclear; Apoptosis; Autoantigens; Cell Movement; Chromatin; Complement C3; Complement C3 Nephritic Factor; Cyclophosphamide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Fingolimod Hydrochloride; Glomerular Mesangium; Immunoglobulin G; Immunosuppressive Agents; Injections, Intraperitoneal; Kidney Glomerulus; Lupus Nephritis; Lymphocytes; Mice; Mice, Inbred NZB; Nucleosomes; Propylene Glycols; Proteinuria; Receptors, Lysosphingolipid; Sirolimus; Sphingosine

Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 +/- 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 +/- 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Proteinuria; Sirolimus

An eight-yr-old combined liver and kidney transplant recipient for hyperoxaluria type I developed significant proteinuria and hypertension after conversion of a Tacrolimus, MMF, and corticosteroids-based immunosuppression to Sirolimus, low-dose Tacrolimus, and corticosteroids six and a half yr after the transplant for chronic allograft nephropathy. There was only one class I HLA match and the recipient had multiple blood exposures prior to transplantation. The patient was treated with combined hemodialysis and peritoneal dialysis while awaiting transplantation to reduce the oxalate load. A renal biopsy revealed a de novo transplant glomerulopathy that was associated with specific HLA antibodies unrelated to the donor (HLA DR 17 and 18). After reintroduction of MMF, these antibodies became undetectable and the proteinuria completely resolved. We hypothesize that HLA antibodies may cause transplant glomerulopathy even if they are not donor-specific. Their production appears more susceptible to MMF therapy. A thorough work-up of new-onset proteinuria after conversion to Sirolimus should be performed, including an immunological work-up and a renal biopsy.

Topics: Biopsy; Child; Chronic Disease; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Mycophenolic Acid; Proteinuria; Sirolimus

The effects of rapamycin (RAPA) were examined in active Heymann nephritis (HN), an experimental model of human membranous nephropathy (MN). Current opinion on the therapy of MN is controversial, and medications used for its treatment have not yielded the expected results.. In a two-part study, we examined the effects of RAPA (1.5 mg/kg/day) during the induction phase of HN and on the evolving disease. In both parts, control groups of immunized rats not treated with RAPA and control groups of unimmunized rats were observed and sacrificed concurrently with the treated groups.. During the induction phase no significant changes in proteinuria were observed in the group treated with RAPA, in comparison to those in the untreated group (p < 0.001). During the evolving disease RAPA significantly lowered proteinuria (p < 0.001). The characteristic pathohistologic changes and IgG depositions along the glomerular basement membrane were considerably diminished, and infiltration of CD8+ cells completely prevented.. RAPA demonstrated beneficial effects on disease progression, given either in the induction phase or during evolving HN. It would be desirable to investigate the effect of RAPA on patients with MN.

Topics: Animals; CD8-Positive T-Lymphocytes; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Immunosuppressive Agents; Male; Proteinuria; Rats; Rats, Wistar; Sirolimus

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.

Topics: Animals; Immunosuppressive Agents; Kidney; Male; Protein Kinases; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Sirolimus is a new immunosuppressive drug used to avoid allograft rejection. The immunosuppressive effect of sirolimus is due to inhibition of the mammalian target of rapamycin, necessary for the proliferation and clonal expansion of activated T-cells. Because T-cells play a central role in the pathogenesis of autoimmune disease developed in (NZBxNZW)F1 mice, we evaluated the therapeutic use of sirolimus in such mice. (NZBxNZW)F1 female mice received 1mg/kg/day of sirolimus from 12 to 37 weeks of age. The development of autoimmune disease was evaluated by measuring the serum levels of auto-antibodies (autoAbs) and their immunoglobulin isotypes, prevalence of glomerulonephritis and mortality rates. Sirolimus directly inhibited production of autoAbs, glomerular deposits of immunoglobulins and development of proteinuria; also the survival of these mice was prolonged. Our results demonstrate the beneficial effects of sirolimus in preventing the development of lupus disease in (NZBxNZW)F1 female mice.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Female; Immunoglobulin Isotypes; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred NZB; Proteinuria; Sirolimus; Survival Rate; Treatment Outcome

CAN is a common cause of late graft loss. Nephrotoxicity due to CNIs is known to contribute to CAN. We retrospectively evaluated the efficacy and safety of SRL in pediatric renal Tx recipients showing CAN in their allograft biopsy. Twenty-one patients aged 10.4 +/- 4.6 yr at Tx time receiving CNIs as primary immunosuppression were converted to SRL at 58.9 +/- 49.1 months after Tx, due to progressive decline of renal function and biopsy proven CAN. Mean follow-up after switch was 19.7 +/- 9.5 months. All patients received CsA as part of the immunosuppressive regimen, at a mean dose 4.4 +/- 1.2 mg/kg/day. Mean daily dose of SRL three month after conversion was 2.6 +/- 0.8 mg/body surface area/day and the mean through levels where 6.9 +/- 2.5 ng/mL. Graft biopsies showed Grade I CAN in 12 children and Grade II CAN in nine. After SRL introduction, there were neither acute rejection episodes nor graft losses. GFR improved at three months and was sustained thereafter only in children with Grade I CAN. Post-Tx time at conversion was the only significant variable between patients who had Grade I CAN and Grade II CAN (33.6 +/- 33.3 vs. 92.7 +/- 47.5 months, p = 0.003). Nine patients had no AEs, six patients had nine SAE: five diarrhea, one herpes zoster, one pancreatic pseudo cyst, one pneumonia, and one Influenza A infection; 11 patients had 13 AEs: six oral aphthous ulcers, three urinary tract infections, two herpes simplex, one lymphedema, and one nephrotic proteinuria. Significant improvement of GFR occurred in Grade I CAN group at three months from conversion and was sustained during follow-up. Those who had Grade II CAN experienced no change in GFR. The incidence of AEs and SAE is of concern and further studies are necessary to assess their relevance.

Topics: Biopsy; Child; Cholesterol; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Platelet Count; Postoperative Complications; Proteinuria; Retrospective Studies; Safety; Sirolimus; Transplantation, Homologous; Triglycerides

Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria >150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In >84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria >1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p < 0.0001) and higher protein excretion (378 + 997 vs. 955 + 1986 mg/day, p < 0.0001). Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria >500. Thus, proteinuria, usually at low levels (<500 mg/day), is present in 45% of recipients at 1 year. However, and even low levels of proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.

Topics: Adult; Biopsy; Cohort Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proteinuria; Retrospective Studies; Risk Factors; Sirolimus; Transplantation, Homologous

Under certain circumstances the nonnephrotoxic, antiproliferative, immunosuppressive mammalian target of rapamycin (mTOR) inhibitors can cause renal deterioration and proteinuria after conversion from calcineurin inhibitors, especially in long-term renal transplant patients with low glomerular filtration rates. The mTOR inhibitors also show an impaired glomerular healing reaction during acute renal injury in experimental mesangial proliferative glomerulonephritis. In this study, everolimus treatment was investigated in a low nephron number model, the remnant kidney model in rats.. The remnant kidney model was induced by uninephrectomy and infarction of 2/3 of the remaining kidney in 31 male Sprague-Dawley rats. Three days after disease induction, rats were randomly treated either with everolimus or vehicle. Changes in progression of renal disease were investigated by immunohistochemistry on days 22 and 38 after disease induction.. In the remnant kidney model, everolimus treatment worsened chronic disease progression as assessed by increased proteinuria, glomerulosclerosis, interstitial fibrosis, glomerular inflammation as well as decreased creatinine-clearance. This result was due to a markedly increased fraction of glomeruli with a defective glomerular architecture in the everolimus group. Everolimus apparently inhibited the chronic glomerular repair reaction via inhibition of the proliferative but not apoptotic activity of the glomerular endothelial and mesangial cells, which was associated with reduced glomerular vascular endothelial growth factor mRNA and protein. In contrast, the fraction of glomeruli with an intact glomerular architecture within the everolimus group showed clearly less glomerular enlargement compared to vehicle-treated nephrectomy rats.. This study demonstrates potential mechanisms of mTOR inhibitor induced renal deterioration and proteinuria in the low nephron number remnant kidney model.

Topics: Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Endothelium; Everolimus; Glomerular Mesangium; Kidney Diseases; Male; Protein Kinases; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sirolimus; Thrombosis; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Wound Healing

The study was conducted in order to describe possible intraglomerular haemodynamic changes inducing proteinuria after 14 patients with chronic allograft dysfunction were converted from calcineurin inhibitors (CIs) to sirolimus without changing concomitant immunosuppression or antihypertensive treatment.. Creatinine, glomerular filtration rate (GFR), proteinuria, renal functional reserve (RFR) and effective renal plasma flow (ERPF) were determined before and 8 months after conversion. Intraglomerular pressure (P(G)), afferent arteriolar resistance (AAR) and efferent arteriolar resistance (EAR) were calculated using Gomez's formula.. Creatinine (1.97 vs 2.075 mg/dl; P = 0.270) and GFR (40 vs 43 ml/min; P = 0.505) remained unchanged, proteinuria increased (338 vs 1146 mg/24 h; P = 0.006), RFR decreased (34.84 vs 13.47%; P = 0.019), ERPF (248 vs 310.6 ml/min; P = 0.0625) and P(G) (42.72 vs 46.17 mmHg; P = 0.0625) tendentially increased and AAR tendentially decreased (14.12 vs 10.28 dyne/s/cm(5); P = 0.0625).. After conversion, P(G) shows a tendency to increase and RFR decreases significantly-characteristics of hyperfiltration, which could possibly partially explain the increase of proteinuria. Therefore, the application of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers seems promising. To avoid hyperfiltration, conversion should be performed early when renal insufficiency is still moderate.

Topics: Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Female; Hemodynamics; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Proteinuria; Sirolimus

Sirolimus is a new and potent immunosuppressive agent. Recently, increased proteinuria has been recognized as an important complication. However, the mechanism thereof has remained unclear. We describe a patient who received sirolimus as standard therapy after living donor kidney transplantation. Within 10 days the patient developed a severe proteinuria that disappeared completely after substituting tacrolimus for sirolimus. Renal biopsy disclosed normal glomeruli even without effacement of the podocytic foot processes. Using FITC labeled anti-albumin antibodies we noted complete absence of albumin in the proximal tubules, whereas an abundant albumin staining was observed in a control patient with a comparable level of proteinuria due to a recurrence of focal segmental glomerulosclerosis after transplantation. Our data suggest that sirolimus can induce severe proteinuria, and that reduced tubular protein reabsorption contributes to the protein loss.

Topics: Biopsy; Creatinine; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Proteinuria; Sirolimus

Mutations in the NPHS2 gene, which encodes podocin, are associated with steroid-resistant nephrotic syndrome in childhood. Renal histology frequently presents focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria in patients affected by homozygous or compound heterozygous NPHS2 mutation is encountered rarely (1-2%) compared to 30% recurrence in nonhereditary FSGS. We report on a pediatric kidney transplant recipient with NPHS2-associated nephrotic syndrome and FSGS, who developed biopsy-proven recurrence of FSGS 10 years post-transplant in temporal association with conversion from cyclosporin A (CsA)- to sirolimus (SRL)-based immunosuppression, due to histological evidence of severe CsA-induced nephrotoxicity. Reswitch of the immunosuppressive regimen from SRL to CsA led to a noticeable decrease of proteinuria and to stabilization of graft function. We conclude that patients with hereditary FSGS are not entirely protected from post-transplant recurrence of proteinuria, even in the long term. The close temporal relationship of FSGS recurrence with CsA withdrawal and conversion to SRL suggests that caution should be exercised in the use of CsA-free immunosuppression also in patients with NPHS2-associated FSGS.

Topics: Adolescent; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Transplantation; Living Donors; Membrane Proteins; Mutation; Nephrotic Syndrome; Proteinuria; Recurrence; Renal Insufficiency; Risk Factors; Sirolimus; Time Factors

Everolimus is a potent immunosuppressant used in renal transplant therapy, but its effects on renal endothelial cell regeneration after injury are unknown. The effects of an everolimus therapy were investigated in a model of renal thrombotic microangiopathy (TMA) with specific endothelial cell (EC) injury in the rat in vivo as well as in glomerular ECs in vitro.. During the early regenerative phase (day 3) of the renal microvascular injury model in vivo, everolimus inhibited glomerular EC proliferation by up to 60% compared with vehicle-treated rats, whereas apoptosis was not different in these groups. This decreased EC proliferation was associated with an enhanced deposition of fibrin in everolimus treated animals on day 3. In cultured glomerular endothelial cells, everolimus effectively and dose dependently inhibited cellular proliferation. This anti-proliferative effect was associated with a reduced phosphorylation of the p70S6 kinase and reduction of the pro-angiogenic factor VEGF in glomeruli in vivo and in cultured podocytes in vitro.. Despite the prolonged EC repair and in contrast to the anti-Thy1 nephritis model, everolimus therapy did not disturb the long-term repair reaction in this thrombotic microangiopathy model.. Everolimus is anti-proliferative for glomerular EC in vitro and in vivo and does not seem to have detrimental long-term effects in experimental renal TMA, when only the glomerular endothelium, but not the mesangium is severely injured.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Everolimus; Glomerular Mesangium; Glomerulonephritis; Immunohistochemistry; Immunosuppressive Agents; Kidney Glomerulus; Male; Mice; Phosphorylation; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Thrombosis; Vascular Endothelial Growth Factor A

Calcineurin inhibitor(CNI)-free protocols using sirolimus (SRL) in kidney transplantation have proven effective, although reports have linked SRL to proteinuria. We sought to investigate this link and its impact on graft function.. We retrospectively analyzed 184 live donor kidney transplant recipients who exclusively received de novo CNI-based (n = 106) or SRL-based (n = 78) regimens. Estimated glomerular filtration rate (GFR) and semi-quantitative dipstick proteinuria measurements were obtained at one, six, 12, and 24 months and six and 12 months, respectively.. SRL-treated patients had higher frequencies of proteinuria (> or =1+) at 6 months (40.8% vs. 21.4%, P = 0.006) and 12 months (37.8% vs. 18.4%, P = 0.004) than those treated with CNI. Independent predictors of proteinuria at 12 months were GFR at one month (OR 0.62 per 10 ml/min/1.73 m, P<0.001), delayed graft function (OR 11.5, P = 0.02), and a SRL-based regimen (OR 4.18, P=0.002). By univariable analysis, SRL vs. CNI patients had higher GFR at each point. SRL-treated patients without proteinuria had higher GFR at 12 months compared to CNI-treated patients with and without proteinuria (66 vs. 50 or 56 ml/min/1.73 m, P < 0.05). No difference in GFR was seen between SRL-treated patients with proteinuria vs. CNI-treated patients without proteinuria (57 vs. 56 ml/min/1.73 m, P > 0.05). Absence of proteinuria and a SRL-based regimen remained independently associated FS with higher GFR at 12 months by multivariable analyses.. De novo SRL-based immunosuppression is associated with a higher frequency of semi-quantitative proteinuria, however, estimated graft function at 1 year posttransplant remains superior to that of CNI-treated patients. Nevertheless, the long-term implications of these findings need to be determined.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Living Donors; Male; Middle Aged; Proteinuria; Sirolimus

Conversion from calcineurin inhibitor to sirolimus, rapamycin has become an option in patients with chronic allograft dysfunction (CAD). However, in many cases an increase of proteinuria has been observed. The aim was to characterize the course of this so far unexplained proteinuria after conversion.. In 149 renal transplant patients from various Spanish centres, proteinuria and renal function were analysed 6 months before until 6 months after conversion. Patients were divided into three groups according to mean proteinuria before conversion (1:300-3500 mg/day; 3:>3.5 g/day).. Generally patients showed an increase of proteinuria from 864+/-1441 (0-12125) to 1541+/-1878 (0-10976) mg/day after conversion; P<0.001. Group 1: 145+/-92 vs 669+/-868 mg/day, P<0.001; group 2: 1041+/-799 vs 1995+/-2021 mg/day, P<0.001; group 3: 6205+/-3184 vs 4859+/-2122 mg/day, P=NS. Patients with an increase of proteinuria of >500 mg/day (n=60; 40%) had a higher serum creatinine before conversion compared with patients with no or moderate increase (2.5+/-0.8 vs 2.15+/-0.72 mg/dl; P=0.002). The group that experienced an increase>500 mg/day had a higher serum creatinine after conversion compared with the patients with no or moderate increase (2.8+/-1.0 vs 2.1+/-1.2; P<0.001). Of 64 patients, 19 in group 1 showed an increase>500 mg/day.. Conversion for CAD can be associated with an increase of proteinuria in patients with pre-existing renal damage; however, it preserves renal function in patients with better creatinine and proteinuria before conversion, and might not be of benefit if advanced loss of renal function and high proteinuria are already present before conversion.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Proteinuria; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation, Homologous

Sirolimus (SRL) is a new, potent immunosuppressive agent. More recently, proteinuria has been reported as a consequence of sirolimus therapy, although the mechanism has remained unclear. We retrospectively examined the records of 25 renal transplant patients, who developed or displayed increased proteinuria after SRL conversion. The patient cohort (14 men, 11 women) was treated with SRL as conversion therapy, due to chronic allograft nephropathy (CAN) (n = 15) neoplasia (n = 8); Kaposi's sarcoma, Four skin cancers, One intestinal tumors, One renal cell carsinom) or BK virus nephropathy (n = 2). SRL was started at a mean of 78 +/- 42 (15 to 163) months after transplantation. Mean follow-up on SRL therapy was 20 +/- 12 (6 to 43) months. Proteinuria increased from 0.445 (0 to 1.5) g/d before conversion to 3.2 g/dL (0.2 to 12) after conversion (P = 0.001). Before conversion 8 (32%) patients had no proteinuria, whereas afterwards all patients had proteinuria. In 28% of patients proteinuria remained unchanged, whereas it increased in 68% of patients. In 40% it increased by more than 100%. Twenty-eight percent of patients showed increased proteinuria to the nephrotic range. Biopsies performed in five patients revealed new pathological changes: One membranoproliferative glomerulopathy and interstitial nephritis. These patients showed persistently good graft function. Serum creatinine values did not change significantly: 1.98 +/- 0.8 mg/dL before SRL therapy and 2.53 +/- 1.9 mg/dL at last follow-up (P = .14). Five grafts were lost and the patients returned to dialysis. Five patients displayed CAN and Kaposi's sarcoma. Mean urinary protein of patients who returned to dialysis was 1.26 (0.5 to 3.5) g/d before and 4.7 (3 to 12) g/d after conversion (P = .01). Mean serum creatinine level before conversion was 2.21 mg/dL and thereafter, 4.93 mg/dL (P = .02). Heavy proteinuria was common after the use of SRL as rescue therapy for renal transplantation. Therefore, conversion should be considered for patients who have not developed advanced CAN and proteinuria. The possibility of de novo glomerular pathology under SRL treatment requires further investigation by renal biopsy.

Topics: Adult; Cadaver; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Neoplasms; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tissue Donors

We performed a retrospective study to evaluate the safety, incidence, and management of proteinuria in 31 renal transplant recipients converted to Rapamycin (RAPA). All patients received RAPA immediately after the cessation of the calcineurin inhibitor or the antiproliferative drug. No acute rejection episodes were seen after this regimen. Chronic allograft nephropathy (58.1%) and calcineurin inhibitor toxicity (51.6%), both biopsy-proven, were the major reasons to introduce RAPA. Post-RAPA proteinuria was defined as the appearance of urine protein excretion >300 mg/d or any further increase in protein among those who showed previously elevated levels. We observed an elevated incidence of proteinuria of 48.4%. It started at 5.3 +/- 2.5 months after the conversion and 60% occurred within 6 months. The proteinuria increased from a median of 200 mg/d to 1466 mg/d (P < .001). Age, gender, race, HLA mismatches, time to onset of RAPA, level of previous proteinuria, glomerular filtration rate, use of renin-angiotensin blockers, and etiology of chronic kidney disease were similar between the groups with or without proteinuria. Once it appeared, we suspended the drug in only 4 patients (26.7%), initiated or augmented the dosage of renin-angiotensin blockers in 26.7%, adjusted the RAPA dose in 20.1%, and did not perform a specific measure in 40% (6 of 15). At 15.6 +/- 12.7 months, 91% showed no further increase or reduction in proteinuria. We observed a high prevalence of proteinuria among renal transplant recipients converted to RAPA (48.4%). In addition, RAPA was suspended in only 4 patients and the proteinuria showed a tendency to stabilize or reduce over time.

Topics: Adult; Biopsy; Female; Glomerular Filtration Rate; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prevalence; Proteinuria; Retrospective Studies; Sirolimus

Topics: Creatinine; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Proteinuria; Sirolimus; Treatment Failure

Both antigen-dependent and -independent factors influence long-term organ allograft function and survival. Brain death (BD), a significant antigen-independent, donor-related injury upregulates a variety of inflammatory mediators in peripheral organs. One of the earliest responses to such an insult is the expression of selectins by endothelial cells of the transplanted tissues; these in turn trigger a cascade of nonspecific events, that enhance host alloresponses and which may be worsened by toxic effects of long-term immunosuppression. Using a rat model in which donor BD accentuates subsequent renal allograft injury, we have tested the effects of therapy with recombinant P-selectin glycoprotein ligand (rPSGL-Ig) alone, or in combination with sirolimus (SRL) and cyclosporin A. We found that in contrast to the effects of standard doses of SRL or cyclosporine, rPSGL-Ig decreased inflammation in the early posttransplant period such that lower doses of maintenance immunosuppression were sufficient to maintain long-term graft function.

Topics: Animals; Brain Death; Creatinine; Cyclosporine; Cytokines; Immunohistochemistry; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Rats; Rats, Inbred F344; Renal Insufficiency; Selectins; Sirolimus; Time Factors

Proteinuria is a risk factor for progression of chronic renal failure. A model of proteinuria-associated tubulointerstitial injury was developed and was used to examine the therapeutic effect of rapamycin. Two studies were performed. In study A, proteinuric rats were given sheep anti-Fx1A to induce experimental membranous nephropathy; control rats received normal sheep serum. Four weeks later, groups were subdivided and underwent laparotomy alone (two kidneys), nephrectomy alone (one kidney), or nephrectomy with polectomy (0.6 kidney). Renal function and morphology were evaluated 4 wk later. Whereas control rats never developed proteinuria, anti-Fx1A induced severe proteinuria. Proteinuria was unaffected by renal mass reduction. Proteinuric rats developed tubulointerstitial disease that was most severe in rats with 0.6 kidneys. Renal function (GFR) was reduced by loss of renal mass and was reduced further in proteinuric rats with 0.6 kidneys. In study B, the effect of rapamycin on the expression of candidate proinflammatory and profibrotic genes and the progression of proteinuria-associated renal disease were examined. All rats received an injection of anti-Fx1A and were nephrectomized and then divided into groups to receive rapamycin or vehicle. Gene expression, renal morphology, and GFR were evaluated after 4, 8, and 12 wk. Rapamycin reduced expression of the proinflammatory and profibrotic genes (monocyte chemotactic protein-1, vascular endothelial growth factor, PDGF, TGF-beta(1), and type 1 collagen). Tubulointerstitial inflammation and progression of interstitial fibrosis that were present in vehicle-treated rats were ameliorated by rapamycin. Rapamycin also completely inhibited compensatory renal hypertrophy. In summary, rapamycin ameliorates the tubulointerstitial disease associated with chronic proteinuria and loss of renal mass.

Topics: Animals; Cytokines; Disease Models, Animal; Fibrosis; Glomerulonephritis, Membranous; Immunosuppressive Agents; Kidney; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Sirolimus

Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Proteinuria; Sirolimus

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerulonephritis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Aged; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Liver Transplantation; Male; Podocytes; Proteinuria; Sarcoma, Kaposi; Sirolimus; Vascular Endothelial Growth Factor A

Sirolimus is an alternative option for kidney transplant patients treated with calcineurin inhibitors (CNI) when renal function is deteriorating. However, the incidence of proteinuria following a switch from CNI to sirolimus has caused concern, and was therefore investigated here.. In a retrospective study, 68 renal transplant recipients were switched from CNI to sirolimus. Proteinuria was measured using 24-hour urine collection before the switch and collections 3, 6, 12, and 24 months thereafter. In addition, proteinuria was measured in patients who had to be switched back to CNI due to side effects. Survival analyses were performed.. Baseline proteinuria was 0.39+/-0.69 g/day in all 68 patients. It increased to a mean 1.44+/-1.90 g/day at 3 months (P<0.001) and remained elevated at 6, 12 and 24 months. When sirolimus was withdrawn after the CNI-sirolimus switch for 19 patients, proteinuria decreased from 1.95+/-2.06 g/day to 0.9+/-1.4 g/day (P<0.05). Proteinuria above 0.3 g/day before the CNI-sirolimus switch correlated significantly with the decrease of renal function thereafter.. CNI-treated kidney transplant recipients may develop reversible proteinuria when switched to sirolimus.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Retreatment; Retrospective Studies; Sirolimus; Tacrolimus

Chronic allograft nephropathy (CAN), cardiovascular mortality, and posttransplant malignancy are complications of conventional immunosuppression after kidney transplantation. The aim was to study feasibility of sirolimus (SRL) maintenance monotherapy in a pilot experience. All patients with SRL monotherapy of at least 6 months follow-up were included. In 19 patients, age 58 (34-74) years, SRL monotherapy was introduced 98.1 (49-193) months after transplantation by withdrawing concomitant immunosuppressants from protocols already including SRL or introducing SRL and withdrawing other immunosuppressants. Follow-up is 20.0 (6-41) months. One patient died from hepatocellular carcinoma, diagnosed before SRL monotherapy, with functioning graft. No rejections occurred. SRL trough concentration was 10.7 (4.6-16.1) microg/L. Creatinine (1.77 [1.0-2.9] mg/dL vs. 1.68 [0.8-3.3] mg/dL after 6 months, 1.97 [0.8-4.6] mg/dL at last follow-up; P=NS). Proteinuria increased tendentially (333 [67-893] vs. 890 [46-4011] mg/day). No significant changes of hemoglobin, triglycerides, or cholesterol occurred. SRL monotherapy late after kidney transplantation is feasible in selected patients.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Drug Administration Schedule; Dyslipidemias; Feasibility Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Proteinuria; Sirolimus

Rapamycin (sirolimus) is associated with functional nephrotoxicity in some patients with nephrotic glomerular diseases but the pathophysiologic mechanisms are not known. This study investigated the effects of rapamycin on renal function and structure in protein overload nephropathy.. Rats with protein overload nephropathy [induced by bovine serum albumin (BSA), 2.1 g by daily intraperitoneal injection, day 0 to day 3] received daily intraperitoneal injections of either vehicle [dimethyl sulfoxide (DMSO)], rapamycin (0.2 mg/kg, an inhibitor of mammalian target of rapamycin), or roscovitine (3.5 mg/kg, a small molecule cyclin-dependent kinase inhibitor) (N= 9 each) from day -3 to day 3.. In protein overload nephropathy, rapamycin caused severe acute renal failure and mild hypercholesterolemia (both P < 0.05). Rapamycin dramatically increased intratubular cast formation, and proximal tubular epithelial cells were swollen and engorged with increased cytoplasmic protein droplets. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive tubular epithelial cells increased by more than 20-fold on day 3 in protein overload nephropathy, and this was attenuated by 65% with rapamycin (P < 0.05), whereas roscovitine was ineffective. Rapamycin increased the protein expression of p27(kip1) in tubular epithelial cells, but did not alter D-type cyclin expression or apoptosis.. Rapamycin caused a specific pattern of acute renal injury characterized by increased intratubular cast formation in protein overload nephropathy. This could be due to disruption of a potentially important compensatory mechanism in nephrotic glomerular diseases involving tubular epithelial cell protein endocytosis and proliferation.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cell Division; Cyclin D1; Cyclin D3; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Cytoplasm; Epithelial Cells; Female; Growth Inhibitors; Immunosuppressive Agents; Kidney Cortex; Kidney Tubules; Monocytes; Proteinuria; Purines; Rats; Rats, Wistar; Roscovitine; Serum Albumin, Bovine; Sirolimus

Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) has become an option in patients with chronic allograft nephropathy or other conditions. However, in some cases an increase of proteinuria has been reported after such therapeutic intervention. The aim of this study was to characterize the clinical course of this so far unexplained proteinuria after conversion. We performed a retrospective analysis evaluating 94 renal transplant patients from various Spanish centers. Proteinuria (629 determinations) and clinical developments were analyzed between 6 months before and 6 months after conversion. Patients were divided into three groups according to mean proteinuria before conversion (group A: <300 mg/d; group B: 300 to 2000 mg/d; and group C: >2 g/d). The mean proteinuria level was 1.69 g/24 h (n = 312 determinations) before and 2.36 g/24 h after conversion (n = 317 determinations; P = .006), which corresponds to an overall increase of 25% (1.55 to 1.69 g/24 h considering only determinations of 1 month before and 1 month after conversion; P = NS). We could not detect any clear correlation between proteinuria and serum creatinine nor between changes of proteinuria and changes of serum creatinine. A variance analysis for repeated measures showed an increase in proteinuria compared to the preconversion values (P = .003), and when the three groups of preconversion proteinuria were evaluated separately it could be observed that this change in the evolution of proteinuria was almost completely dependent of an increase in the group C (preconversion proteinuria greater than 2 g/d; P = .03), whereas in the other two groups changes were almost irrelevant. Finally, the switch to SRL in renal transplant recipients is followed by an increase in the level of proteinuria predominantly dependent of an increase in patients with high levels of preconversion proteinuria, whereas it seems to be irrelevant in patients without or with light or moderate proteinuria. These results suggest that this might not be a direct effect of SRL.

Topics: Calcineurin Inhibitors; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sirolimus; Spain; Time Factors

Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, non-nephrotoxic immunosuppression. We report, however, on four kidney-transplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2-9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Creatine; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Proteinuria; Sirolimus; Time Factors; Treatment Outcome

Little is known about the incidence and evolution of proteinuria as a complication of sirolimus rescue in children. This study describes pediatric renal transplant (Tx) recipients who were treated with sirolimus and who developed heavy proteinuria. Risk factors for the development of proteinuria and its time course are explored.. Data at various time points after sirolimus introduction were abstracted from the records of children treated at the author's center. The repeated measures general linear model and the Student's paired t test were used to analyze changes in laboratory values over time.. Of the 13 children on sirolimus, 12 developed heavy proteinuria after a mean interval of 1 month. The mean urine protein (Up)-to-creatinine (c) ratio increased from 1.1 to a peak value of 3.9 (P=0.003) at 4.6 months after the start of sirolimus. Although not statistically significant, children on no calcineurin inhibitor (CNI) had a greater increase in the Up/c than those on low-dose CNI. At last follow-up, with the use of angiotensin receptor blockers (ARB), the Up/c declined to 2.2. No predictors could be identified for the development of proteinuria.. Heavy proteinuria is common after the use of sirolimus as rescue therapy in children with renal Tx. Whether this is attributable to a toxic effect of the sirolimus itself or to lower CNI exposure is uncertain. Early detection of proteinuria is important to enable prompt intervention. Most children have a reduction in their Up/c with the use of ARB and can therefore be continued on sirolimus.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Proteinuria; Sirolimus

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; France; Humans; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Retrospective Studies; Sirolimus

Topics: Animals; Animals, Genetically Modified; Hypertension, Renal; Kidney; Proteinuria; Rats; Renal Artery; Renal Veins; Reperfusion Injury; Sirolimus; Time Factors; Transforming Growth Factor beta

Topics: Animals; Body Weight; Cyclosporine; Disease Models, Animal; Everolimus; Glomerulosclerosis, Focal Segmental; Graft Rejection; Hypertrophy; Immunosuppressive Agents; Kidney Transplantation; Organ Size; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Losartan; Myocardial Infarction; Proteinuria; Risk Factors; Sirolimus

The induction of transplantation tolerance is one of the primary goals following solid organ transplantation. The combination of a single dose of rapamycin (RAPA) with a short course of cyclosporine (CsA) has been shown to induce transplantation tolerance in the nonfunctional rat heterotopic cardiac transplant model. The purpose of this study was to assess this effective induction protocol in a functional renal transplant model. Male ACI (RTl(a)) and Lewis (RT1(1)) rats were used as donor and recipients respectively. Allografts received a single RAPA dose of (1.5 mg/kg) combined with CsA (10 mg/kg) 12-14 hr prior to transplantation. CsA (5 mg/kg) was given daily on days +1 - +7. Untreated Lewis to Lewis isografts served as histological controls. Chimerism, assessed in recipient skin, and intragraft interleukin (IL) 10 expression was determined utilizing PCR and RT-PCR techniques respectively. Treated animals and isografts were sacrificed 120-130 days posttransplant for functional and histological evaluation. Allografts (n=9) were functionally tolerant with serum creatinine (0.77+/-0.1 vs. 0.88+/-0.1; P=0.275), blood urea nitrogen (37.6+/-4.6 vs. 23.3+/-1.9; P=0.123), and 24 hr protein excretion (27.0+/-4.4 vs. 17.9+/-5.2; P=0.131) similar to single kidney ACI controls. Histologically, 45% (4/9) allografts were indistinguishable from isografts with no evidence of rejection, and were considered immunologically tolerant. Donor/recipient chimerism was not detected. All immunologically tolerant allografts had evidence of intragraft IL-10 expression. Rejecting allografts and isografts did not express intragraft IL-10. This study confirms the efficacy of pre-engraftment single-dose RAPA combined with CsA in inducing true immunologic tolerance in this stringent functional renal transplant model. The expression of intragraft IL-10 in tolerant recipients suggests a Th-2 shift as the mechanism of tolerance in this model.

Topics: Actins; Animals; Blood Urea Nitrogen; Creatinine; Cyclosporine; DNA Primers; Drug Therapy, Combination; Graft Rejection; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-10; Kidney Transplantation; Male; Polyenes; Polymerase Chain Reaction; Proteinuria; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Sirolimus; Transplantation Chimera; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Animals; Autoimmune Diseases; Cyclosporine; Drug Evaluation, Preclinical; Female; Glomerulonephritis; Immunosuppressive Agents; Mercuric Chloride; Polyenes; Proteinuria; Rats; Rats, Inbred BN; Sirolimus; Splenomegaly; Weight Loss