tacrolimus and Proteinuria

Recurrent glomerulonephritis after renal transplantation is the third most common cause of allograft loss, the most frequent of which is associated with IgA nephropathy (IgAN). This study aims to provide a systematic review of the risk factors associated with recurrent IgAN after renal transplantation. We searched English and Chinese databases, including PubMed, Embase, Web of Science, CNKI, and others, and included all case-control studies involving risk factors for recurrent IgAN after renal transplantation from the databases' establishment to March 2022. Data were analyzed using the Stata 12.0. A total of 20 case-control studies were included in the meta-analysis, with 542 patients with recurrent IgAN and 1385 patients without recurrent IgAN. The results showed that donor age (standardized mean difference [SMD] -0.13 [95% CI -0.26, -0.001]; P = 0.048), patient age at transplantation (SMD -0.41 [95% CI -0.53, -0.29]; P < 0.001), time from diagnosis to end-stage renal disease (SMD -0.42 [95% CI -0.74, -0.10]; P = 0.010), previous transplantation (odds ratio [OR] 1.73 [95% CI 1.06, 2.81]; P = 0.027), living donor (OR 1.86 [95% CI 1.34, 2.58]; P < 0.001), related donor (OR 2.64, [95% CI 1.84, 3.79]; P < 0.001), tacrolimus use (OR 0.71 [95% CI 0.52, 0.98]; P = 0.035), basiliximab use (OR 0.39 [95% CI 0.27, 0.55]; P < 0.001), proteinuria (SMD 0.42 [95% CI 0.13, 0.71]; P = 0.005) and serum IgA level (SMD 0.48 [95% CI 0.27, 0.69]; P < 0.001) were associated with recurrent IgAN after renal transplantation. In general, tacrolimus and basiliximab use were protective factors against recurrent IgAN after renal transplantation, whereas donor age, patient age at transplantation, time from diagnosis to end-stage renal disease, previous transplantation, living donor, related donor, proteinuria, and serum IgA level were risk factors for recurrent IgAN after renal transplantation. Clinical decision making should warrant further consideration of these risk factors.

Topics: Basiliximab; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Kidney Failure, Chronic; Kidney Transplantation; Proteinuria; Risk Factors; Tacrolimus

IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009 and updated in 2015.. To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for (1) the prevention of severe kidney disease in people with IgAV with or without kidney involvement at onset, (2) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in IgAV, and (3) the prevention of recurrent episodes of IgAV-associated kidney disease.. We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in IgAV compared with placebo, no treatment or other agents were included.. Two authors independently determined study eligibility, assessed the risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model, and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Twenty studies (1963 enrolled participants) were identified; one three-arm study has been assessed as two studies. Nine studies were at low risk of bias for sequence generation (selection bias), and nine studies were at low risk of bias for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and outcome assessment (detection bias) was at low risk of bias in four and seven studies, respectively. Nine studies reported complete outcome data (attrition bias), while 10 studies reported expected outcomes, so were at low risk of reporting bias. Five studies were at low risk of other bias. Eleven studies evaluated therapy to prevent persistent kidney disease in IgAV with or without kidney involvement at presentation. There was probably no difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32) or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of IgAV compared with placebo or supportive treatment (moderate certainty evidence). There may be no differences in the risk of any persistent kidney disease with antiplatelet therapy (three studies) or heparin (two studies) in children with or without any kidney disease at study entry, although heparin may reduce the risk of proteinuria by three months compared with placebo or no specific treatment (2 studies, 317 children: RR 0.47, 95% CI 0.31 to 0.73). One study comparing montelukast with placebo found no differences in outcomes as assessed by severity scale scores. Nine studies examined the treatment of severe IgAV-associated kidney disease. In two studies (one involving 56 children and the other involving 54 adults), there may be no differences in efficacy outcomes or adverse effects with cyclophosphamide compared with placebo or supportive treatment. In two studies, there may be no differences in the numbers achieving remission of proteinuria with intravenous (IV) cyclophosphamide compared with mycophenolate mofetil (MMF) (65 children evaluated) or tacrolimus (142 children evaluated). In three small studies comparing cyclosporin with methylprednisolone (15 children), MMF with azathioprine (26 children), or MMF with leflunomide (19 children), it is unclear whether the treatment had any effect on the numbers in remission or the degree of proteinuria between treatment groups because of small numbers of included participants. In one study comparing plas. There are no substantial changes in conclusions from this update compared with the initial review or the previous update despite the addition of five studies. From generally low to moderate certainty evidence, we found that there may be little or no benefit in the use of corticosteroids or antiplatelet agents to prevent persistent kidney disease in children with IgAV in participants with no or minimal kidney involvement at presentation. We did not find any studies which evaluated corticosteroids in children presenting with IgAV and nephritic and/or nephrotic syndrome, although corticosteroids are recommended in such children in guidelines. Though heparin may be effective in reducing proteinuria, this potentially dangerous therapy is not justified to prevent serious kidney disease when few children with IgAV develop severe kidney disease. There may be no benefit of cyclophosphamide compared with no specific treatment or corticosteroids. While there may be no benefit in the efficacy of MMF or tacrolimus compared with IV cyclophosphamide in children or adults with IgAV and severe kidney disease, adverse effects, particularly infections, may be lower in MMF or tacrolimus-treated children. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin, MMF or leflunomide have any role in the treatment of children with IgAV and severe kidney disease. We did not identify any studies which evaluated corticosteroids.

Topics: Adult; Child; Fosinopril; Humans; IgA Vasculitis; Kidney Diseases; Leflunomide; Proteinuria; Tacrolimus; Vasculitis

Numerous studies have demonstrated that the efficacy of drugs differs in idiopathic membranous nephropathy (IMN) patients with moderate or high proteinuria. However, there is no systematic comparison confirming it. This network meta-analysis (NMA) was performed to respectively compare the efficacy of ten IMN treatments in patients with moderate and high proteinuria and compare the risk of adverse events with 10 IMN regimens.. Randomized controlled trials (RCTs) and observational studies analyzing the main therapeutic regimens for IMN were included from some databases. Network comparisons were performed to analyze the rates of total remission (TR), bone marrow suppression, and gastrointestinal symptoms. The surface under the cumulative ranking area (SUCRA) was calculated to rank interventions.. Seventeen RCTs and eight observational studies involving 1778 patients were pooled for comparison of ten interventions. Steroid + tacrolimus (TAC) showed the highest probabilities of TR whether patients had severe proteinuria or not (SUCRA 89.5% and 88.9%, separately). Rituximab (RTX) was more beneficial for TR on patients with proteinuria <8 g/d (SUCRA 66.0%) and was associated with a lower risk of bone marrow suppression and gastrointestinal symptoms (SUCRA 21.7% and 21.4%, separately). TAC + RTX and steroids + cyclophosphamide induced the highest rates of bone marrow suppression (SUCRA 90.6% and 88.3%, separately) and gastrointestinal symptoms (SUCRA 86.0% and 72.1%, separately).. Steroids + TAC showed significant efficacy in patients with all degrees of proteinuria, while RTX was more effective in patients with moderate proteinuria and was safer in bone marrow suppression and gastrointestinal symptoms.

Topics: Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Network Meta-Analysis; Proteinuria; Rituximab; Steroids; Tacrolimus

The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).. The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.. In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.. CsA is an effective and safe agent in the therapy of patients with SRNS.

Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

There is growing interest in the role of tacrolimus as a potential therapeutic agent in SLE. This systematic review and meta-analysis evaluates the evidence for tacrolimus use in the management of lupus nephritis. Thirteen controlled studies were identified (9 suitable for inclusion), using Cochrane database, SCOPUS, Web of Science and OVID (MEDLINE and EMBASE). Data on complete and partial remission rates, proteinuria reduction and adverse events was extracted and analysed using RevMan software. The meta-analysis showed that overall tacrolimus is more effective at inducing complete renal remission than IVCYC (p=0.004), but there is no significant difference compared to MMF (p=0.87). Multi-target TAC+MMF therapy is more effective than IVCYC only when partial remission is included (p=0.0006). Frequency of key adverse effects seems comparable to other agents used in the management of lupus nephritis with fewer gastrointestinal side effects, leukopenia, menstrual disorders, infections and episodes of liver dysfunction reported, but more new onset hypertension and hyperglycaemia. Mortality was lower in the tacrolimus groups, but this was not statistically significant (p=0.15). Tacrolimus may be more effective at reducing proteinuria, but again this was not statistically significant. There are no controlled trials looking at use in pregnancy or juvenile patients, however case reports suggest potential efficacy and safety. In conclusion, in moderately severe lupus nephritis, there is some evidence supporting efficacy of tacrolimus or multi-target TAC+MMF over IVCYC, but no evidence supporting tacrolimus over MMF. Tacrolimus may be more effective at reducing proteinuria, having potential implications for long-term outcome. Key limitations of this study are the lack of long-term outcome data and the lack of high quality, large, blinded controlled trials in multi-ethnic groups.

Topics: Animals; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Remission Induction; Tacrolimus

Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis. One of the patterns of bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS).. We describe a breast cancer patient who developed heavy proteinuria (protein/creatinine ratio 9.1) and nephrotic syndrome following treatment with oral ibandronate for 29 months. CFSGS was proven by biopsy. There was no improvement 1 month after ibandronate was discontinued. Prednisone and tacrolimus were started and she experienced a decreased in proteinuria.. In patient who develops ibandronate-associated CFSGS, proteinuria appears to be at least partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandronate is stopped.

Topics: Administration, Oral; Adult; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Diphosphonates; Female; Glomerulosclerosis, Focal Segmental; Humans; Ibandronic Acid; Prednisone; Proteinuria; Tacrolimus; Treatment Outcome

Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As a standard treatment regimen for remission induction of proliferative LN, intravenous cyclophosphamide (IVCYC) and corticosteroids has been widely accepted. However, cyclophosphamide (CYC) is associated with significant adverse effects. Tacrolimus, a T-cell-specific calcineurin inhibitor, shares similar immunosuppressive actions with cyclosporine. We performed a meta-analysis of randomized controlled trials (RCTs) to compare efficacy and safety between tacrolimus (oral administration and/or IV injection) and IVCYC in the induction treatment for LN. We identified 5 trials, including 225 patients. Meta-analysis showed that tacrolimus could significantly increase complete remission (RR 1.61, 95% CI, 1.17 to 2.23; P = 0.004), response rate (RR 1.25, 95% CI, 1.09 to 1.44; P = 0.001), serum albumin level (SMD 1.11, 95% CI, 0.17 to 2.06; P = 0.02) and anti-dsDNA negative conversion rate (RR 1.34, 95% CI, 1.01 to 1.78; P = 0.04), and decrease urine protein (SMD -0.52, 95% CI, -0.83 to -0.22; P = 0.0008), systemic lupus erythematosus disease activity index (SLE-DAI) (SMD -0.59, 95% CI, -1.00 to -0.19; P = 0.004) compared with that of IVCYC. The rates of gastrointestinal symptoms and irregular menstruation (or amenorrhea) were significantly lower in tacrolimus group than IVCYC group (RR 0.46, 95% CI, 0.22 to 0.93; P = 0.03 and RR 0.14, 95% CI, 0.04 to 0.50; P = 0.003). In conclusion, tacrolimus was found to be more effective and safer than IVCYC as an induction therapy for Chinese LN patients.

Topics: Adult; Complement C3; Cyclophosphamide; Female; Humans; Injections, Intravenous; Lupus Nephritis; Male; Proteinuria; Publication Bias; Randomized Controlled Trials as Topic; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome; Young Adult

The aim of this study was to assess the efficacy and safety of tacrolimus for the treatment of lupus nephritis (LN). A systematic review of clinical trials on tacrolimus in LN was conducted. Seven studies met the review inclusion criteria. Two studies were case-control studies, and five studies were open-label trials. One randomized controlled trial (RCT) found that tacrolimus significantly improved lupus nephritis disease activity index (LNDAI) as compared with a placebo, but no difference was observed between these two groups in terms of treatment-related adverse events. The other case-control study compared tacrolimus with standard protocols of oral cyclophosphamide or azathioprine for the treatment of membranous LN and found that efficacies were similar. All five open-label prospective studies concluded that tacrolimus is safe and effective as an induction and maintenance therapy for LN or for the treatment of LN with persistent proteinuria that failed to respond to prednisolone and immunosuppressants. In conclusion, this systematic review shows that tacrolimus may be effective as an induction and maintenance therapy for LN or as a treatment for LN with persistent proteinuria despite gold standard treatment. However, further RCTs are needed to compare tacrolimus with standard regimens for the treatment of LN.

Topics: Clinical Trials as Topic; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Severity of Illness Index; Tacrolimus; Treatment Outcome

The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN.. Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events.. There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29).. In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy.. ClinicalTrials.gov Identifier NCT03062813.

Topics: Adult; Antiviral Agents; DNA, Viral; Glomerulonephritis; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Prospective Studies; Proteinuria; Serum Albumin; Single-Blind Method; Tacrolimus; Treatment Outcome

The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids.. Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p > .05). Proteinuria (based on 24 h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase.. TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short-term efficiency and patient tolerance are both acceptable.

Topics: Adult; Cyclophosphamide; Diabetes Mellitus; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Glucocorticoids; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome

The immunosuppressive drug tacrolimus has the short-term effect of reducing proteinuria in patients with immunoglobulin A nephropathy (IgAN). Our study investigated the effects on proteinuria and kidney function after discontinuation of tacrolimus.. Patients with biopsy-proven IgAN were included in the study and randomly divided into two treatment groups. There was a corresponding control group for each treatment group. The first group included patients treated with tacrolimus (Tac vs non-Tac group) and the second group included patients with a renin angiotensin system blocker (RASi vs non-RASi group). The Tac group received treatment for up to 16 weeks, with the administration of tacrolimus being ceased at the final visit (trial phase). We tracked the patients at 12, 24, 52, and 240 weeks (observational phase). The primary outcomes examined were the percentage change (from the trial phase to the observational phase) of time-averaged proteinuria (TA-proteinuria; g/g creatinine [cr]) and the estimated glomerular filtration rate (eGFR). Time-averaged proteinuria was defined as the average of urine protein to creatinine ratio (UPCR), measured every 3 months during both the trial and observational phases of the study.. A significant reduction in UPCR was observed in the Tac group compared to non-Tac group at the 4 and 8 week visits during the trial phase (p = 0.023 and p = 0.003, respectively). However, the difference between the Tac group and non-Tac group was not evident in the other review periods, estimated by linear mixed effect model. The percentage change in TA-proteinuria was greater in the Tac group than that in the corresponding control group (116 ± 96% vs. 63 ± 239%, p = 0.004). Therefore, during the observational phase, TA-proteinuria was not significantly different between the Tac group and the non-Tac group (1.150 ± 0.733 g/g cr vs. 1.455 ± 2.017 g/g cr, p = 0.775). The levels of eGFR throughout the observational phase were not significantly different between the two groups. Furthermore, the mean rate of eGFR change throughout both phases of the study was -6.4 ± 5.9 mL/min/1.73 m2/year in the non-Tac group and -5.4 ± 7.9 mL/min/1.73 m2/year in the Tac group (p = 0.988).. The anti-proteinuric effect of tacrolimus was promptly reversed 3 months after discontinuing the drug. The use of tacrolimus for a short period of time for patients with IgAN temporarily reduces proteinuria, but the data showed no long-term efficacy regarding proteinuria reduction and improvement of renal function.

Topics: Adult; Antihypertensive Agents; Captopril; Creatinine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Tacrolimus; Treatment Outcome; Valsartan

Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population.. Randomized noninferiority crossover trial (noninferiority margin, -2.8mmHg).. Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m. Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout).. Average daytime (9 am to 9 pm) ambulatory SBP.. Blood pressure and laboratory parameters.. 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, -4.2 [95% CI, -7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, -65 [95% CI, -108 to -35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P<0.05 for both). In contrast, chlorthalidone temporarily reduced kidney function and increased both serum uric acid and glycated hemoglobin levels.. Open-label design, short follow-up, per-protocol analysis.. Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chlorthalidone; Cross-Over Studies; Edema; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus; Treatment Outcome

To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).. This is an open randomised controlled parallel group study.. Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.. 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).. TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.. Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Creatinine; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Recurrence; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Immunosuppressive therapy plays an important role in patients with high-risk idiopathic membranous nephropathy (IMN), but the therapeutic modality is still controversial.. Corticosteroid combined with oral tacrolimus (TAC, target trough blood concentration of 4-8 ng/mL), intravenous cyclophosphamide (CYC, 750 mg/m(2)/mo, or oral mycophenolate mofetil (MMF, 1.5-2.0 g/d) were randomly administered for 9 months to 90 patients with IMN proved with renal biopsy with severe proteinuria (>8 g/d).. Eighty-six of the 90 patients completed the study. The total remission (TR) rates in the TAC group were significantly higher than those in the CYC group at 1 and 2 months (p < 0.01) and the MMF group at 1-4 months (p < 0.01). The TR rates were 83.3%, 73.3%, and 70.0% in the TAC, CYC, and MMF groups at 9 months (p = 0.457), and there were no significant differences between the three groups from 5 to 9 months. Furthermore, TAC reduced proteinuria and ameliorated hypoalbuminemia more quickly and effectively than CYC and MMF. We observed no severe adverse events in the three groups.. Tacrolimus combined with corticosteroid had tolerable adverse effects and induced the remission of IMN more effectively and more rapidly. This is the first prospective randomized cohort study to compare three different therapies in patients at high risk for IMN. It provides strong evidence for choosing optimal treatment for patients with IMN. The long-term efficacy of this treatment strategy should be investigated further in future studies.

Topics: Adrenal Cortex Hormones; Adult; China; Cyclophosphamide; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome

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

Tacrolimus has been used for idiopathic membranous nephropathy (IMN) therapy, but most patients who achieved remission showed a high relapse rate when tacrolimus was withdrawn after 6-12 months of therapy. We proposed that a prolonged therapeutic course should help reduce the relapse rate.. A total of 42 patients with nephrotic syndrome caused by IMN were randomly divided into short-term (n = 20) and long-term (n = 22) groups. All patients received initial treatment with tacrolimus and prednisone for 6 months, and afterward only the long-term patient group was tapered with low-dose tacrolimus until 24 months.. Over 85% of the patients achieved proteinuria reduction, serum albumin improvement and serum lipid recovery; the probability of remission in both groups was over 80% at 6 months. The remission rate was steady at over 80% after 12 and 24 months in the long-term group, but only 50 and 45%, respectively, in the short-term group. Nine patients (45%) relapsed in the short-term group after tacrolimus withdrawal, while not a single patient suffered recurrence in the long-term group. The concentration of tacrolimus remained similar between the two groups at 5-8 ng/ml during the initial 6 months, and was significantly decreased at 12 months compared to 6 months (p < 0.05), along with reduction of oral administration in the long-term group.. Combined therapy of tacrolimus with prednisone can relieve IMN significantly; prolonged tacrolimus treatment at a low blood concentration can alleviate the illness persistently, with a low recurrence rate and gratifying safety.

Topics: Adult; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Proteinuria; Serum Albumin; Tacrolimus; Treatment Outcome

The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS).. Patients with biopsy-proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5-0.75 g/m(2)·month, i.v.) received prednisone at 0.8 mg/kg·day, while patients treated with TAC (0.1 mg/kg·day) received prednisone at 0.5 mg/kg·day. The plasma concentration of TAC was monitored and maintained at 5-10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment.. A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 ± 0.21 versus 2.21 ± 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05).. These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function.

Topics: Adult; Albumins; Cyclophosphamide; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Function Tests; Male; Prospective Studies; Proteinuria; Remission Induction; Secondary Prevention; Tacrolimus; Treatment Outcome

Although the use of aggressive immunosuppression has improved both patient and renal survival of patients with lupus nephritis (LN), the optimal treatment of LN remains challenging. The objective of this study is to assess the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus compared with intravenous cyclophosphamide (IVC) as induction therapies for active lupus nephritis (ALN).. In this open-label, 24-week prospective study, 60 patients with biopsy-proven ALN (Classes III, IV, V or combination) were randomly assigned to receive MMF, tacrolimus or IVC in combination with corticosteroids. The remission of proteinuria, systemic lupus erythematosus disease active index and adverse events were compared.. The response rates at 24 weeks were 70% (14/20) in the MMF group, 75% (15/20) in the tacrolimus group and 60% (12/20) in the IVC group (P>0.05). The complete remission rates were also similar in the three groups (40, 45 and 30%, respectively; P>0.05). There were more cases of infection in the IVC group (8/20) and the MMF group (8/20) than the tacrolimus group (3/20) and more hyperglycemia in the tacrolimus group (5/20) than the other two groups (2 or 3/20), but the results were not statistically significant among the three groups. Proteinuria decreased and serum albumin increased more quickly in the patients treated with tacrolimus (P=0.0051 and P=0.048).. This pilot study suggests that both MMF and tacrolimus are possible alternatives to IVC as induction therapies for ALN in Chinese patients. Tacrolimus possibly results in a faster resolution of proteinuria and hypoalbuminemia. Further studies are necessary to determine the optimal dosage and duration of the therapies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoalbuminemia; Immunosuppressive Agents; Infusions, Intravenous; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult

There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

Topics: Adolescent; Chi-Square Distribution; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; India; Infusions, Intravenous; Kaplan-Meier Estimate; Logistic Models; Male; Nephrotic Syndrome; Odds Ratio; Prednisolone; Proportional Hazards Models; Prospective Studies; Proteinuria; Recurrence; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Intravenous cyclophosphamide with prednisone is an effective treatment for lupus nephritis, but with significant toxicities. We compared the efficacy and safety of tacrolimus versus intravenous cyclophosphamide as induction therapy.. Multicenter noninferiority randomized controlled trial.. 81 patients with biopsy-proven lupus nephritis from 9 nephrology centers in China from 2006-2008.. Prednisone and either tacrolimus (n = 42) or intravenous cyclophosphamide (n = 39) for 6 months. Tacrolimus was started at 0.05 mg/kg/d and titrated to achieve a trough blood concentration of 5-10 ng/mL. Intravenous cyclophosphamide was initiated at 750 mg/m² of body surface area, then adjusted to 500-1,000 mg/m² every 4 weeks for a total of 6 pulse treatments.. The primary outcome was complete remission (proteinuria with protein excretion <0.3 g/24 h, serum albumin ≥3.5 g/dL, normal urinary sediment, and normal or stable serum creatinine level) at 6 months. Response (complete or partial remission), clinical parameters, and adverse effects were secondary end points.. After the 6-month induction therapy, the tacrolimus group achieved higher cumulative probabilities of complete remission and response (52.4% vs 38.5% and 90.5% vs 82.1%, respectively) than the intravenous cyclophosphamide group, but differences were not statistically significant (log-rank test, P = 0.2 and P = 0.7, respectively). Proteinuria [corrected] was significantly decreased in tacrolimus- versus intravenous cyclophosphamide-treated patients after the first month of treatment, even with adjustment for baseline proteinuria (protein excretion, 1.76 vs 2.40 g/d; P = 0.02 for the log-transformed analysis). [corrected] After treatment, serum creatinine levels and estimated glomerular filtration rates were not significantly different between treatment groups. Adverse effects, such as leukopenia and gastrointestinal symptoms, were less frequent in the tacrolimus group.. Nonblinded, small sample size, and short duration of follow-up.. In conjunction with prednisone, induction therapy with tacrolimus is at least as efficacious as intravenous cyclophosphamide and prednisone in producing complete remission of lupus nephritis and has a more favorable safety profile.

Topics: Adult; Anti-Inflammatory Agents; China; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

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

Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. Its treatment is still under debate.. We report our experience in a pilot study using initially low doses of steroids and tacrolimus (Tac). After 3 months of treatment, mycophenolate mofetil (MMF) was added if the proteinuria was higher than 1 g/day.. In accordance with this standard, 21 patients entered the study. A proteinuria level lower than 1 g/day was reached at month 3 of therapy with steroids and Tac in 11 patients. These patients continued this treatment for 12 months. MMF was added in nine cases after the third month and triple therapy was maintained for 12 more months. Two patients were withdrawn because of side effects. At the end of the treatment, remission of the NS was present in 15 out of all the patients (71.4%). Remission of the NS was complete in eight (53.3%) patients and partial in seven (46.7%) others. The remaining four patients did not respond. There were no significant changes in renal function. At a mean time of 23.1 months after treatment was discontinued, 11 (73.3%) patients had relapsed.. In this trial, treatment with tacrolimus showed a good efficacy but a high relapse rate when it was discontinued.

Topics: Adrenal Cortex Hormones; Adult; Aged; Albuminuria; Biopsy; Cholesterol; Creatinine; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Tacrolimus

Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown.. This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups.. A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57+/-12, 65.2+/-20, 73.5+/-27 ml/min, P=0.044), the Jelliffe-2 (51.5+/-16, 56+/-19, 59.4+/-19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53+/-17, 58.5+/-20, 61.6+/-22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008).. Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.

Topics: Adult; Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Proteinuria; Survival Analysis; Tacrolimus

Steroid resistance and steroid dependence constitute a major problem in the treatment of minimal-change disease and focal segmental glomerulosclerosis (FSGS). Cyclophosphamide and cyclosporine are well-established alternative immunomodulating agents, whereas data on FK 506 (tacrolimus) are rare.. The present work provides data from 10 patients of an open, monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid-dependence, prednisolone was tapered off in presence oftacrolimus within one month.. Within 6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients (40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroid-refractory minimal-change), another patient became secondarily resistant to tacrolimus after an initial remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/- 1.4 - 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 - 64.6 +/- 1.9 g/l (p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 - 5.1 +/- 0.2 mmol/l), systolic blood pressure (131.4 +/- 7.1 - 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 103.2 +/- 15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4 of them (80%). Relapse occurred at tacrolimus levels between 2.6 and 6.9 ng/ml.. Our data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.

Topics: Adult; Blood Glucose; Blood Pressure; Blood Proteins; Creatinine; Drug Resistance; Drug Therapy, Combination; Female; Glomerulosclerosis, Focal Segmental; Humans; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Proteinuria; Steroids; Tacrolimus

Tacrolimus is a calcineurin inhibitor that has been increasingly used in transplant medicine. However, the efficacy and safety of combined therapy of low-dose tacrolimus and prednisone in the treatment of nephrotic syndrome (NS) with slight mesangial proliferation has not been reported.. Sixty patients with NS with slight mesangial proliferation were randomly divided into a prednisone therapy group (control), a combined low-dose tacrolimus (2 mg/day) and a prednisone therapy group (tacrolimus group). The efficacy and safety of tacrolimus was analysed. The initial dose of prednisone was 1 mg/kg per day and 30 mg/day in the control group and tacrolimus group, respectively. The duration of treatment was 6 months.. After a 6-month trial of combined low-dose tacrolimus and prednisone, complete remission was achieved in 29 patients (96.66%) and partial remission in one patient (3.33%). In the control group, complete remission was achieved in 27 patients (90%) and partial remission in three patients (10%). A significant improvement in proteinuria levels was observed in the tacrolimus group compared with the control group, starting at the second week and remaining throughout the study period. Furthermore, a significant improvement in serum albumin levels was observed in the tacrolimus group compared with the control group, starting at the first month and remaining until the third month. The main side-effect was obesity (100%) and acne (46.66%) in the control group. However, these adverse events were not observed in the tacrolimus group.. The results demonstrated that combined therapy of low-dose tacrolimus and prednisone is an effective and safe therapeutic method for NS with slight mesangial proliferation.

Topics: Adult; Cell Division; Cholesterol; Drug Therapy, Combination; Female; Glomerular Mesangium; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Proteinuria; Serum Albumin; Tacrolimus; Treatment Outcome; Triglycerides

Topics: Adrenal Cortex Hormones; Creatinine; Drug Administration Schedule; Europe; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Prednisone; Proteinuria; Tacrolimus

With tacrolimus-based immunosuppression, it appears safe to withdraw steroids 3 to 6 months after renal transplantation. We hypothesized whether steroids could also be safely withdrawn early after transplantation.. Sixty-two patients (first or second transplant, with no previous immunological failure, and current panel reactive human leucocyte antigen [HLA] antibodies [PRA]<50%), treated with tacrolimus, were prospectively randomized to stop steroids (10 mg prednisolone) after day 7 posttransplantation (stop group [STOP], n=28) or to gradually wean off steroids in 3 to 6 months (tapering group [TAP], n=34). Analyses were performed on an intention-to-treat basis.. After a median follow-up of 2.7 years, patient and graft survival were 97 and 90% and comparable between both groups (P =0.11 and P=0.13, respectively). The incidence of acute rejection was 29 (STOP) versus 33% (TAP) ( P=0.30). The time to the first rejection was a median of 35 days (STOP) versus 11 days (TAP) ( =0.19). The severity of the rejections (1997 Banff classification) was comparable (P =0.57). Creatinine clearance and proteinuria were similar (P >0.70). The incidence of infections was comparable ( P>0.10). The incidence of new-onset diabetes mellitus, defined as the use of antidiabetic medication, was 8.0 (STOP) versus 30.3% (TAP) (P =0.04). All cases occurred in the STOP group after 1 year, while all cases occurred in TAP in the first 4 months ( P<0.001).. Compared with tapering in 3 to 6 months, stopping steroids 1 week posttransplantation results in comparable patient and graft survival and in a similar incidence of acute rejections. The incidence of new-onset diabetes may be reduced. The immunosuppressive benefit of adding 10 mg prednisolone to tacrolimus seems to be limited.

Topics: Acute Disease; Adult; Aged; Anti-Inflammatory Agents; Creatinine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Incidence; Infections; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prednisolone; Prospective Studies; Proteinuria; Risk Factors; Tacrolimus

Topics: Azathioprine; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Triglycerides

Topics: Acetylglucosaminidase; Administration, Oral; Adult; Biomarkers; Cyclosporine; Female; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Proteinuria; Tacrolimus

There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients.. In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion≥2.0g/24h and estimated glomerular filtration rate≥50mL/min/1.73m. After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P=0.7). However, the serum creatinine level from baseline was an increase of 13±13.5μmol/L in the tacrolimus group and a decrease of 8.2±20μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group.. Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

Topics: Glomerular Filtration Rate; Glomerulonephritis, IGA; Glucocorticoids; Humans; Immunosuppressive Agents; Prospective Studies; Proteinuria; Tacrolimus; Treatment Outcome

Children with severe Henoch-Schönlein purpura nephritis (HSPN) may progress to end-stage renal disease without appropriate treatment.. This study aimed to investigate the efficacy and safety of tacrolimus combined with glucocorticoids in the treatment of pediatric HSPN.. A total of 87 HSPN patients with urinary protein ≥ 0.75 g/24 h received standard of care, including angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and glucocorticoids. Patients were divided into three groups and additionally received tacrolimus (n = 30), cyclophosphamide (n = 31), or mycophenolate mofetil (MMF) (n = 26). We monitored outcome measures, including proteinuria, hematuria, and renal function and analyzed the efficacy and side effects in each group.. At 2-month follow-up, the overall efficacy was 93.3%, 83.9%, and 61.5% for tacrolimus, cyclophosphamide, and MMF, respectively (P < 0.05). Urinary protein significantly decreased for all groups. Urinary red blood cell counts significantly decreased for patients treated with tacrolimus (P < 0.001) and cyclophosphamide (P < 0.05), whereas no significant decrease was seen for those receiving MMF (P = 0.09). Although urine β2-microglobulin significantly decreased following 2 months of treatment with all medications, efficacy was greater with tacrolimus than with cyclophosphamide and MMF (P < 0.001). Major adverse events were respiratory and urinary infections, with MMF having the highest infection rate. The cyclophosphamide group also experienced additional adverse events, including arrhythmia, hemorrhagic cystitis, leukocytosis, thrombocytopenia, and hyperglycemia.. These results indicate that tacrolimus is more effective at reducing proteinuria and hematuria and improving renal function, with relatively milder side effects, in the treatment of pediatric HSPN.. ChiCTR2200055323, retrospectively registered on January 7, 2022.

Topics: Child; Cyclophosphamide; Glucocorticoids; Hematuria; Humans; IgA Vasculitis; Immunosuppressive Agents; Mycophenolic Acid; Nephritis; Proteinuria; Tacrolimus

Topics: Acute Kidney Injury; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Nephrology; Proteinuria; Tacrolimus

BACKGROUND After renal transplantation, immunosuppressants should be administered to prevent organ rejection and prolong graft survival. One of them is tacrolimus, which is metabolized by the CYP3A enzyme family. The variability of the CYP3A5 gene in renal transplant recipients has been previously studied for its correlation with acute rejection and allogeneic kidney function. CYP3A5 enzyme is also present in the renal tissue, and its relevance has not yet been extensively investigated. This study aimed to evaluate the effect of donor and recipient CYP3A5 expression status on early and long-term transplant outcomes. MATERIAL AND METHODS Single-nucleotide polymorphism in CYP3A5 (rs776746) was analyzed in 95 kidney transplant recipients and their grafts. The effect of donor and recipient genotypes on the primary endpoint, which was the loss of the renal graft over 5-year follow-up, was assessed. The secondary endpoints were biopsy-proven acute rejection, proteinuria, delayed graft function, and renal function. RESULTS Patients who received a CYP3A5*1 allele-carrying kidney (n=16) were at greater risk of graft loss (adjusted hazard ratio, 95% CI: 10.61, 2.28-49.42, P=.003) than those with the CYP3A5*3/*3 genotype (n=79). Renal CYP3A5 expression was also a predictor of acute rejection between the 2nd and 12th post-transplant months (adjusted odds ratio, 95% CI: 4.36; 1.08-17.6, P=.038) and proteinuria at different time intervals. No effect of the recipient CYP3A5 genotype was observed. CONCLUSIONS The donor CYP3A5 genotype is associated with inferior transplantation outcomes. Local renal tacrolimus metabolism is a potential target for improving long-term transplantation outcomes.

Topics: Cytochrome P-450 CYP3A; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Polymorphism, Single Nucleotide; Proteinuria; Tacrolimus; Transplant Recipients

Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we report, for the first time, a case of GS overlapping nephrotic syndrome (NS) related to PLA2R-associated membranous nephropathy (MN).. We described a male patient had a 4-year history of recurrent fatigue. Serum biochemistry revealed hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hyperreninemia, hypocalciuria, as well as nephrotic-range proteinuria, hypoalbuminemia, and elevated serum anti-phospholipase A2 receptor (PLA2R) antibody. Gene sequencing identified compound heterozygous mutations in SLC12A3 [c.536T > A(p.V179D) and c.1456G > A(p.D486N)]. The unusual association of SLTs and nephrotic-range glomerular proteinuria prompted us to perform a renal biopsy. Renal biopsy showed idiopathic MN. Due to the potential to activate the sodium-chloride co-transporter (NCC) and cause hyperkalemia, tacrolimus was selected to treat NS. Following treatment with potassium chloride, magnesium oxide, low-dose glucocorticoid combined with tacrolimus, the fatigue significantly improved, and concurrently hypokalemia, hypomagnesemia were corrected and NS was remitted.. Renal biopsy should be warranted for GS patients with moderate to nephrotic-range proteinuria. Tacrolimus was preferred to the management of GS patients with NS.

Topics: Fatigue; Gitelman Syndrome; Glomerulonephritis, Membranous; Humans; Hypokalemia; Magnesium; Male; Potassium; Proteinuria; Solute Carrier Family 12, Member 3; Tacrolimus

To assess the clinical profile and primary treatment response and outcomes in idiopathic membranous nephropathy (IMN) patients.. This study was carried out between December 2013 and January 2019 in a tertiary care hospital in North India on 2 years retrospective and 3 years prospective renal biopsy proven patients with IMN presenting with nephrotic syndrome. Basic baseline investigations carried out were urinary proteins, serum albumin, serum creatinine, other special tests wherever necessary or possible (including phospholipase A2 receptor antibodies), and different treatment regimens were offered for treatment. The patients were followed up for a minimum period of 6 months after administration of treatment.. The study was carried out in 120 patients with mean age of 43±14.6 years and male female ratio of 1.65:1. Hypertension was noted in 36%, microscopic hematuria in 13%, and mean 24 hours urinary proteinuria 10.5±3.1 gm. Complete or partial response at 6 months was observed in 57% and 34% cases to cyclophosphamide, 60% and 40% to modified Ponticelli treatment, 81% and 19% to tacrolimus, and 40% and 36% cases to rituximab. Relapse was observed in 6% of cyclophosphamide and 13% in tacrolimus groups.. Our results show a good and comparable response to cyclophosphamide, tacrolimus, and rituximab at 6 months of follow up. The cases which achieved complete remission had significantly lower baseline proteinuria compared to those who did not respond.

Topics: Adult; Cyclophosphamide; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Proteinuria; Retrospective Studies; Rituximab; Tacrolimus; Treatment Outcome

BACKGROUND The interaction of viral infection may be associated with increased morbidity after renal transplantation. This study aimed to identify the incidence and risk factors of viruria infections in renal transplant recipients. MATERIAL AND METHODS In this longitudinal study, 502 episodes recorded in 81 kidney transplant patients from 1/2019 to 12/2021 in a hospital in Vietnam were included. BK, JC polyomaviruses, CMV, EBV, and HSV were detected. Multivariable Cox regression analysis was performed to evaluate risk factors for the viruria infection. RESULTS Fifty-six patients (69.1%) had viruria co-infection. The incidence of JC, CMV, and BK infection was the most common viruria, with 67.9%, 61.7%, and 56.8%, respectively. Cox regression revealed that the risk factors for JC were single infection, dose of MMF (HR 1.002), corticoid (HR 1.02), hypertension (HR 1.65), and hematuria (HR 2.03); risk factors for CMV infection were male sex (HR 1.92) and eGFR (HR 0.98); risk factors for BK single infection were hypertension (HR 1.67), proteinuria (HR 3.80), higher tacrolimus trough level (HR 1.17), and dose of MMF (HR 1.002). Hypertension (HR 1.68), fasting plasma glucose (HR 1.13), proteinuria (HR 6.01), tacrolimus trough level (HR 1.12), and dose of MMF (HR 1.004) were independent risk factors for the viruria co-infection. CONCLUSIONS Kidney function was associated with the incidence of viruria. Higher tacrolimus trough level and dose of MMF were associated with higher risk of BK, JC, and co-infection.

Topics: BK Virus; Blood Glucose; Coinfection; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Humans; Hypertension; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Polyomavirus; Polyomavirus Infections; Proteinuria; Risk Factors; Tacrolimus

BACKGROUND Nephrotic syndrome caused by minimal mesangial lupus nephritis is considered rare. Nephrotic syndrome can be caused by minimal mesangial lupus nephritis with diffuse epithelial foot-process effacement and lupus podocytopathy. CASE REPORT A 23-year-old Japanese woman diagnosed with mixed connective tissue disease was admitted because of weight gain and generalized edema for 2 weeks prior to admission. She had butterfly-shaped erythema on her cheeks, proteinuria, leukocytopenia with lymphocytopenia, and hypoalbuminemia. She was positive for antinuclear antibodies, and specific autoantibodies were only positive for the ribonucleoprotein (RNP) antigen. She was diagnosed with systemic lupus erythematosus. Renal biopsy showed minor glomerular abnormalities, and immunofluorescence revealed peripheral deposits of IgM and complement C3c. Electron microscopy revealed diffuse podocyte foot-process effacement of >80% of the capillary loop surfaces, with only a few subendothelial deposits. Consequently, we diagnosed minimal mesangial lupus nephritis with lupus podocytopathy. On hospital day 4, we administered 1000 mg/day of methylprednisolone for 3 days, followed by prednisolone 50 mg/day, but proteinuria persisted. On day 12, we administered tacrolimus (3 mg/day). Proteinuria improved and then disappeared on day 17. Prednisolone was gradually tapered and stopped after 3 years, although tacrolimus 3 mg/day was continued. No flare-up was observed 4 years after admission. CONCLUSIONS Tacrolimus showed good efficacy in this case of minimal mesangial lupus nephritis with lupus podocytopathy. Prospective and randomized controlled trials should be conducted to demonstrate the efficacy of tacrolimus for this indication.

Topics: Adult; Female; Humans; Induction Chemotherapy; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Prospective Studies; Proteinuria; Tacrolimus; Young Adult

The index case is a 45-year old male with unknown cause for native kidney disease, who received a kidney from his wife. Antithymocyte globulin (ATG) was used for induction, and tacrolimus, mycophenolate mofetil and prednisolone were prescribed for maintenance. His baseline serum creatinine was 0.9 mg/dl. Two years after the transplant, the patient developed 3+ proteinuria on routine urinalysis with stable graft function. His 24-hour urinary protein was 2.3 grams, serum albumin was 3.0 g/dl, and the total cholesterol was 251 mg/dl. The tacrolimus C0 levels were maintained between 6 and 8 ng/ml range. Allograft biopsy revealed diffuse thickening of glomerular basement membranes, with the immunofluorescence showing 2+ granular positivity along the loops for IgG and C3. Further, tissue staining for PLA2R and THD7A were both negative. Also, no donor-specific antibodies (DSA) were detected, and serum PLA2R antibody assay was also negative. The patient was managed conservatively with losartan 50 mg and atorvastatin 20 mg, with subsequent reports of proteinuria of 1.5-2.0 grams/day. After 52 months of renal transplant, the patient presented with a serum creatinine of 2.06 mg/dl and proteinuria of 6.8 grams/day. A repeat allograft biopsy revealed thickened glomerular basement membranes with spikes on silver staining. (Figure 1a) Further, immunofluorescence studies showed 2+-3+ granular positivity for IgG, C3, with the added findings of C4d positivity on the peritubular capillaries and tissue PLA2R positivity on the basement membranes by immunohistochemistry. (Figures 1b-d) The biopsy also revealed peritubular capillaritis and acute tubular injury. Antibodies to donor Class II (HLA DR) were positive with a mean fluorescence intensity (MFI) of 6885, but serum PLA2R antibodies remained negative. Based on these findings, the patient was treated with pulse methylprednisolone, 5 sessions of plasma exchange at 40 ml/kg with 5% human albumin and fresh frozen plasma replacement, intravenous immunoglobulin (at 100 mg/kg × 5) and rituximab (two doses of 1 g 2 weeks apart). Subsequently, the serum creatinine settled to 1.6 mg/dl, and DSA reduced to < 500 MFI. Three months after discharge, the serum creatinine is 1.5 mg/dl, 24-hour urine protein is 982 mg/day and follow-up DSA remains negative.

Topics: Antilymphocyte Serum; Biopsy; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus

FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F-actin). FKBP12 interacted with the actin-associated proteins 14-3-3 and synaptopodin. RNA silencing for FKBP12 reduced 14-3-3 expression, F-actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F-actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.

Topics: Actin Cytoskeleton; Animals; Female; HEK293 Cells; Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Rats; Rats, Wistar; Tacrolimus; TOR Serine-Threonine Kinases

Acute kidney injury (AKI) is a major cause of patient mortality and a major risk multiplier for the progression to chronic kidney disease (CKD). The mechanism of the AKI to CKD transition is complex but is likely mediated by the extent and length of the inflammatory response following the initial injury. Lymphatic vessels help to maintain tissue homeostasis through fluid, macromolecule, and immune modulation. Increased lymphatic growth, or lymphangiogenesis, often occurs during inflammation and plays a role in acute and chronic disease processes. What roles renal lymphatics and lymphangiogenesis play in AKI recovery and CKD progression remains largely unknown. To determine if the increased lymphatic density is protective in the response to kidney injury, we utilized a transgenic mouse model with inducible, kidney-specific overexpression of the lymphangiogenic protein vascular endothelial growth factor-D to expand renal lymphatics. "KidVD" mouse kidneys were injured using inducible podocyte apoptosis and proteinuria (POD-ATTAC) or bilateral ischemia reperfusion. In the acute injury phase of both models, KidVD mice demonstrated a similar loss of function measured by serum creatinine and glomerular filtration rate compared to their littermates. While the initial inflammatory response was similar, KidVD mice demonstrated a shift toward more CD4+ and fewer CD8+ T cells in the kidney. Reduced collagen deposition and improved functional recovery over time was also identified in KidVD mice. In KidVD-POD-ATTAC mice, an increased number of podocytes were counted at 28 days post-injury. These data demonstrate that increased lymphatic density prior to injury alters the injury recovery response and affords protection from CKD progression.

Topics: Acute Kidney Injury; Animals; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Collagen; Disease Models, Animal; Kidney; Lymphangiogenesis; Lymphatic Vessels; Mice; Mice, Transgenic; Podocytes; Proteinuria; Recovery of Function; Reperfusion Injury; Tacrolimus; Vascular Endothelial Growth Factor D

The index case is a 45-year old male with unknown cause for native kidney disease, who received a kidney from his wife. Antithymocyte globulin (ATG) was used for induction, and tacrolimus, mycophenolate mofetil and prednisolone were prescribed for maintenance. His baseline serum creatinine was 0.9 mg/dl. Two years after the transplant, the patient developed 3+ proteinuria on routine urinalysis with stable graft function. His 24-hour urinary protein was 2.3 grams, serum albumin was 3.0 g/dl, and the total cholesterol was 251 mg/dl. The tacrolimus C0 levels were maintained between 6 and 8 ng/ml range. Allograft biopsy revealed diffuse thickening of glomerular basement membranes, with the immunofluorescence showing 2+ granular positivity along the loops for IgG and C3. Further, tissue staining for PLA2R and THD7A were both negative. Also, no donor-specific antibodies (DSA) were detected, and serum PLA2R antibody assay was also negative. The patient was managed conservatively with losartan 50 mg and atorvastatin 20 mg, with subsequent reports of proteinuria of 1.5-2.0 grams/day. After 52 months of renal transplant, the patient presented with a serum creatinine of 2.06 mg/dl and proteinuria of 6.8 grams/day. A repeat allograft biopsy revealed thickened glomerular basement membranes with spikes on silver staining. (Figure 1a) Further, immunofluorescence studies showed 2+-3+ granular positivity for IgG, C3, with the added findings of C4d positivity on the peritubular capillaries and tissue PLA2R positivity on the basement membranes by immunohistochemistry. (Figures 1b-d) The biopsy also revealed peritubular capillaritis and acute tubular injury. Antibodies to donor Class II (HLA DR) were positive with a mean fluorescence intensity (MFI) of 6885, but serum PLA2R antibodies remained negative. Based on these findings, the patient was treated with pulse methylprednisolone, 5 sessions of plasma exchange at 40 ml/kg with 5% human albumin and fresh frozen plasma replacement, intravenous immunoglobulin (at 100 mg/kg × 5) and rituximab (two doses of 1 g 2 weeks apart). Subsequently, the serum creatinine settled to 1.6 mg/dl, and DSA reduced to < 500 MFI. Three months after discharge, the serum creatinine is 1.5 mg/dl, 24-hour urine protein is 982 mg/day and follow-up DSA remains negative.

Topics: Antilymphocyte Serum; Biopsy; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus

The purpose of this study was to investigate the potential impact of CYP3A4, CYP3A5, and CYP3A7 polymorphisms on the concentration and efficacy of tacrolimus in a cohort of pediatric patients with nephrotic range proteinuria.. Genetic variants including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), rs4646437, and CYP3A7 rs2257401 and rs10211 were detected in 70 pediatric patients with nephrotic range proteinuria. The relationships of dose-adjusted trough concentration (C. Our study demonstrated the associations between CYP3A5*3, CYP3A7 rs2257401 and rs10211, and tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Children with CYP3A5*3 A, CYP3A7 rs2257401 C, and rs10211 G alleles might need a higher dose of tacrolimus.

Topics: Adolescent; Child; Child, Preschool; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Male; Nephrosis; Polymorphism, Single Nucleotide; Proteinuria; Tacrolimus

Topics: Animals; Animals, Genetically Modified; Cyclosporine; Disease Models, Animal; Disease Progression; Drug Resistance; Gene Knockout Techniques; Glucocorticoids; Humans; Immunosuppressive Agents; Membrane Proteins; Monomeric GTP-Binding Proteins; Nephrotic Syndrome; Podocytes; Proteinuria; Signal Transduction; Tacrolimus; Treatment Outcome; Zebrafish; Zebrafish Proteins

Membranous nephropathy (MN) caused by disease-modifying antirheumatic drugs is relatively common in patients with rheumatoid arthritis (RA). However, MN rarely occurs due to RA itself. We describe a 61-year-old woman with RA who showed nephrotic syndrome. She was admitted because of systemic edema and severe arthritis. She had a long history of RA successfully treated with methotrexate (MTX), but discontinued all treatments 4 years before hospitalization. She had never been treated with bucillamine or gold. Laboratory test results were positive for anti-cyclic citrullinated peptide antibody and negative for anti-nuclear antibody. Renal pathologic findings were compatible with MN. Immunofluorescence microscopy showed IgG, IgA, κ, λ, and C3 along the glomerular capillary wall, whereas deposition of IgM or C1q was not detected. In terms of the IgG subclasses, only IgG2 findings were positive. Results for glomerular antigen and serum antibody for M-type phospholipase A2 receptor and thrombospondin type 1 domain-containing 7A were negative. HLA type did not include the HLA-DQA1 gene that is a concern in primary MN (PMN). She responded to intensive immunosuppressive therapy consisting of prednisolone, tacrolimus, and MTX with a parallel reduction of proteinuria. Based on assessments for differentiating PMN from secondary MN (SMN), the diagnosis of the present case was incompatible with PMN. Taken together, we consider that SMN in the present case was due to RA itself rather than drug-induced MN.

Topics: Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Methotrexate; Middle Aged; Nephrotic Syndrome; Prednisolone; Proteinuria; Tacrolimus; Treatment Outcome

In China, the prevalence of idiopathic membranous nephropathy (IMN) is increasing with a younger age of onset. From January 2012 to October 2018, biopsy-proven nephrotic IMN patients aged between 15 and 40 in Taian City Central Hospital treated with tacrolimus (TAC) were retrospectively analyzed. Twelve-month follow-up data were collected. A total of 86 patients were enrolled in this study. Forty patients in the TAC group received TAC monotherapy with an initial dose of 0.05 to 0.1 mg/kg/day. Forty-six patients in the TAC + Pred group received TAC combined with oral prednisone (0.5 mg/kg/day initially). Remission rate, relapse rate, and adverse events in the two groups were assessed. Total remission (TR) rates at the end of the 3rd, 6th, and 12th month were 15%, 35%, and 77.5% (TAC group) and 28.3%, 56.5%, and 80.4% (TAC + Pred group), respectively. Compared with the TAC group, the TAC + Pred group had higher complete remission rates at the end of the 6th and 12th month, and TR rate at the 6th month was significantly higher. Twenty-four-hour urinary protein excretion, serum albumin and estimated glomerular filtration rate between the two groups were comparable during the follow-up. Decrease in proteinuria was significantly greater in the TAC + Pred group. No significant difference of relapse rate was found between the two groups. Adverse effects in the two groups were mild and controllable. Both TAC monotherapy and TAC combined with medium-dose prednisone are effective and safe for young adults with nephrotic IMN, while TAC + Pred regimen brings more benefits.

Topics: Adolescent; Adult; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Proteinuria; Retrospective Studies; Tacrolimus; Young Adult

HLA antibodies have been shown to be associated with late graft loss. In this study, we defined the incidence and profiles of anti-HLA antibodies and their impact on graft outcome in long-term kidney recipients.. The sera of 118 kidney transplant recipients were screened for anti-HLA antibody presence. The antigen specificity of the detected HLA class I and class II antibodies was identified using a Luminex assay (Luminex Corp, Austin, TX, United States). Presence of donor specific antibodies (DSA) was examined in individuals with anti-HLA antibodies using the Luminex method.. Anti-HLA class I and/or class II antibodies were detected in serum of 16.1% of the kidney transplant patients. The antibodies were directed against HLA class I antigens in 4 patients (21.1%), HLA class II antigens in 9 patients (47.4%), and both class I and class II antigens in 6 patients (31.6%). The overall prevalence of DSA was 10.2%. Anti-HLA antibodies were significantly associated with higher rate of cyclosporine use. Presence of DSA was associated with a lower rate of tacrolimus use, a higher rate of cyclosporine use, and lower donor age. Presence of anti-HLA antibodies was associated with higher acute cellular rejection and higher chronic active humoral rejection rates. Presence of DSA was associated with chronic active humoral rejection.. The presence of either HLA antibodies or DSA significantly correlated with lower graft survival, poor transplant function, and proteinuria.

Topics: Adult; Antibody Specificity; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Living Donors; Male; Middle Aged; Proteinuria; Tacrolimus; Transplants; Treatment Outcome

In clinical practice, some IgA nephropathy (IgAN) patients show resistance to or are unable to achieve complete remission using steroids and/or immunosuppressants. The current study aimed to assess the efficacy and safety of tacrolimus in the treatment of cases of refractory IgAN.In this retrospective observational study, 34 primary IgAN patients with refractory proteinuria received tacrolimus for at least 12 months. Complete remission, partial remission, and other clinical data were measured at 1, 3, 6, and 12 months after the initiation of treatment.After 12 months, complete remission was achieved in 20 (58.8%) patients and partial remission in 5 (14.7%) patients, yielding a total response rate of 73.5%. The mean time for response to tacrolimus for those who achieved complete remission and partial remission was 7.0 ± 4.7 weeks. Serum creatinine (Scr), uric acid, estimated glomerular filtration rate, alanine aminotransferase, aspartate transaminase, white blood cell count, blood pressure, blood glucose, total cholesterol, and total triglyceride were stable over time. Three patients demonstrated a loss of eGFR >15 mL/min·1.73 m from baseline. Three cases of upper respiratory infection and 2 cases of urinary tract infection were observed during the study. Patients who achieved complete remission had better renal function and lower baseline proteinuria than partial remission and nonresponder patients. Crescent formation in biopsy specimens was seen more often in nonresponder patients.Tacrolimus was safe and effective at lowering proteinuria in refractory IgAN patients. Lower baseline proteinuria and better renal function were associated with a higher probability of complete remission, while crescent formation was associated with a worse prognosis.

Topics: Adult; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Male; Middle Aged; Proteinuria; Remission Induction; Respiratory Tract Infections; Retrospective Studies; Tacrolimus; Urinary Tract Infections; Young Adult

Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197-37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997-0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001-1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996-0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.

Topics: Adult; Creatinine; Cyclophosphamide; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Logistic Models; Lupus Nephritis; Male; Methylprednisolone; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Podocytes; Prednisolone; Prognosis; Proteinuria; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus

We evaluated the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in treating patients with idiopathic membranous nephropathy (IMN). One hundred seventy-seven biopsy-proven IMN patients were recruited in this retrospective clinical study. Sixty patients received TAC (target blood concentration of 4-8 ng/mL) and 117 patients received daily cyclophosphamide (CYC, 100 mg) combined with prednisone. Remission rates at the end of the first, second and third month in the TAC group were significantly higher than that in the CYC group (1st: 35.0 vs 19.7%, P<0.05; 2nd: 56.7 vs 38.5%, P<0.05; 3rd: 76.7 vs 59.0%, P<0.05). In the first 3 months, daily urinary protein and serum albumin in the TAC group obtained a better improvement than that in the CYC group (P<0.05). At the end of the sixth and the twelfth month, the remission rates, daily urinary protein and serum albumin were all comparable between the two groups (P>0.05). No significant difference of relapse rate between the groups was found (16.3 vs 12.0%, P>0.05). Patients were more likely to develop glucose intolerance in the TAC group. The TAC regimen obtained more benefits in treating IMN patients, especially in the first 3 months, than the CYC regimen.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Proteinuria; Reproducibility of Results; Retrospective Studies; Serum Albumin; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Calcineurin inhibitor (CNI)-induced nephrotoxicity and chronic graft dysfunction with deteriorating glomerular filtration rate (GFR) are common problems of kidney transplant recipients. The aim of this study was to analyze the role of belatacept as a rescue therapy in these patients.. In this retrospective, observational study we investigated 20 patients (10 females, 10 males) who were switched from a CNI (tacrolimus) to a belatacept-based immunosuppression because of CNI intolerance or marginal transplant function. Patient follow-up was 12 months.. Patients were converted to belatacept in mean 28.8 months after transplantation. Reasons for conversion were CNI intolerance (14 patients) or marginal transplant function (6 patients). Mean estimated GFR (eGFR) before conversion was 22.2 ± 9.4 ml/min at baseline and improved significantly to 28.3 ± 10.1 ml/min at 4 weeks and to 32.1 ± 12.6 ml/min at 12 months after conversion. Serum bicarbonate significantly increased from 24.4 ± 3.2 mmol/l at baseline to 28.7 ± 2.6 mmol/l after 12 months. Conversion to belatacept decreased parathyroid hormone and phosphate concentrations significantly, whereas albumin levels significantly increased. In 6 cases an acute rejection preceded clinically relevant CNI toxicity; only two patients suffered from an acute rejection after conversion. Belatacept was well tolerated and there was no increase in infectious or malignant side effects.. A late conversion from a tacrolimus-based immunosuppression to belatacept is safe, effective and significantly improves renal function in kidney transplant recipients. Additionally, the conversion to belatacept has a beneficial impact on acid-base balance, mineral-bone and protein metabolism, independently of eGFR.

Topics: Abatacept; Acid-Base Equilibrium; Adult; Aged; Biomarkers; Bone and Bones; Bone Remodeling; Calcineurin Inhibitors; Drug Substitution; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Recovery of Function; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

BACKGROUND To explore the effects and the mechanism of vitamin D (VD) and tacrolimus (TAC) combinatorial therapy in the treatment of IgA nephropathy (IgAN) in a rat model. MATERIAL AND METHODS IgAN rat models constructed by oral immunization with bovine serum albumin (BSA) and lipopolysaccharide (LPS) (n=30) and were treated with: saline (model group), TAC (TAC group), or TAC+VD therapy (TAC+VD group) through gavage daily for 14 days. Serum creatinine (Scr), albumin (ALB), blood urea nitrogen (BUN), and urinary protein (UAE) levels were determined. Histopathology of renal tissues was examined after hematoxylin and eosin (H&E) staining. The levels of cytokines TGF-β1, IL-5, IFN-γ, and IL-4 in serum were detected by enzyme-linked immunosorbent assay (ELISA). Changes in TLR4/NF-κB pathway were evaluated by western blot. RESULTS Both TAC and TAC+VD treatment significantly restored the dysregulated Scr, ALB, BUN, and UAE levels in IgAN rats. TAC+VD therapy more prominently restored Scr and UAE levels (p<0.05). TAC+VD therapy demonstrated superior efficacy in reducing glomerular mesangial cells hyperplasia, reducing thickening of the glomerular basement membrane and glomerular infiltration of inflammatory cells. Thymus and spleen indexes were also increased (p<0.05). The levels of TGF-β1, IL-5, and IL-4 of the TAC+VD group were also lower than those of the TAC group (p<0.05). The TAC+VD group also demonstrated increased IFN-γ, and decreased p-P65/P65 and TLR4 compared to the TAC group. CONCLUSIONS TAC+VD combinatorial therapy can effectively alleviate renal tissue damage in IgAN rats by regulating immune response and the NF-κB/TLR4 pathway.

Topics: Albumins; Animals; Blood Urea Nitrogen; Creatinine; Drug Therapy, Combination; Glomerulonephritis, IGA; Interferon-gamma; Interleukin-4; Interleukin-5; Kidney; NF-kappa B; Proteinuria; Rats, Sprague-Dawley; Spleen; Tacrolimus; Thymus Gland; Toll-Like Receptor 4; Transforming Growth Factor beta1; Vitamin D

FK506 is an immunosuppressive drug and a calcineurin inhibitor that has been widely used in kidney disease in recent years. FK506 shows a wide range of biological and pharmaceutical effects; however, the mechanism of its anti- proliferative effect has not been well elucidated. An IgA nephropathy (IgAN) model was used to generate a mesangial cell proliferation model. This study aims to examine the effect of FK506 on IgAN rats and the underlying mechanisms.. Hematuria, proteinuria and renal function were measured. To observe the pathological conditions, we performed HE (hematoxylin - eosin) and PAS (periodic acid - schiff) staining. Transcription and protein expression levels were detected by qRT - PCR (quantitative real-time polymerase chain reaction) and Wb (western blotting). The location and semi-quantitative expression levels of TRPCs, CaN (Calcineurin) and α-SMA were examined by IHC (Immunohistochemical staining).. We found that FK506 could improve hematuria, proteinuria and renal function, especially in the HF (high-dose FK506) groups. Renal pathological changes were ameliorated in the treatment groups. FK506 could significantly decrease TRPCs, CaN, phosphorylation of ERK1/2 and α-SMA expression.. Taken together, these results suggest that the therapeutic effect of FK506 on IgAN might be partially associated with the down-regulated expression of TRPC channels, CaN and phosphorylation of ERK1/2.

Topics: Animals; Calcineurin; Gene Expression; Glomerulonephritis, IGA; Hematuria; Immunosuppressive Agents; MAP Kinase Signaling System; Phosphorylation; Proteinuria; Rats; Tacrolimus; TRPC Cation Channels

Cyclosporin A (CsA) is considered as an effective treatment option for steroid-resistant or-dependent patients with adult-onset minimal change disease (MCD). However, CsA resistance or dependence is also observed in these patients. Tacrolimus (TAC) is a calcineurin inhibitor that is potent in cytokine suppression. The authors aim to evaluate the efficacy and safety of TAC therapy in CsA-resistant and-dependent adult-onset MCD patients.. Patients with adult-onset MCD were enrolled in our department from 2008 to 2012. All patients were demonstrated to be resistant to or dependent on CsA therapy. Prednisone (0.5 mg/kg per day) combined with TAC (0.05-0.1 mg/kg per day) were prescribed to these patients for at least 6 months. The primary outcome was complete or partial remission of proteinuria. Secondary outcomes included time required for complete or partial remission, adverse events, number of relapses, and TAC dosages.. A total of 11 MCD patients were enrolled in this observational study. The numbers of patients who presented with resistance to or dependence on CsA were 7 and 4, respectively. The total remission rate was 90.9% (10/11) with the complete remission rate 72.7% (8/11). Most remission patients achieved remission during the first 2 months of TAC therapy. Patients who presented with dependence on CsA had achieved complete remission with TAC therapy, while outcomes for CsA-resistant patients were four complete remissions, two partial remissions and one resistance. The adverse events were observed in this study included infection, diarrhoea, and worsened hypertension. Five patients who had remission experienced relapse.. Tacrolimus improves proteinuria remission in adults with CsA-resistant or -dependent MCD.

Topics: Adolescent; Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrosis, Lipoid; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult

Topics: Amyloidosis; Azathioprine; Creatinine; Female; Fibrinogen; Gene Expression; Genes, Dominant; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Liver Transplantation; Middle Aged; Mutation; Proteinuria; Tacrolimus; Treatment Outcome

Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles ofCNremained in each type of the cells are not well understood yet. ACNinhibitor (CNI) has been used for steroid-resistant nephrotic syndrome. ACNIis assumed to ameliorate proteinuria by preventing the overproduction of T-cell cytokines. However, recent reports suggest thatCNIhas a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell-cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized thatCNIhas an effect on theSD In this study, we analyzed the expression ofCNin physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of theSD We observed thatCNis expressed at theSDin normal rat and human kidney sections and has an interaction with nephrin. The staining ofCNat theSDwas reduced in the nephrotic model, whileCNactivity in glomeruli was increased. We also observed that the treatment with tacrolimus, aCNI, in this nephrotic model suppressed the redistribution ofCN, nephrin, and otherSDcomponents and ameliorated proteinuria. These observations suggested that the redistribution and the activation ofCNmay participate in the development of theSDinjury.

Topics: Animals; Antibodies, Monoclonal; Calcineurin; Calcineurin Inhibitors; Cell Line; Child; Disease Models, Animal; Female; Humans; Intercellular Junctions; Male; Membrane Proteins; Mice; Nephrotic Syndrome; Podocytes; Protein Transport; Proteinuria; Rats, Wistar; Tacrolimus; Time Factors

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Phospholipases A2; Prednisolone; Proteinuria; Receptors, Phospholipase A2; Recurrence; Respiratory Tract Infections; Tacrolimus; Treatment Outcome; Young Adult

Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway.

Topics: Animals; Apoptosis; Calcineurin Inhibitors; Cell Line; Cyclosporine; Male; MAP Kinase Signaling System; Mice; Nephrosis, Lipoid; Podocytes; Proteinuria; Puromycin Aminonucleoside; Rats, Sprague-Dawley; Tacrolimus

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Proteinuria; Risk Factors; Tacrolimus

Topics: Adult; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Receptors, Urokinase Plasminogen Activator; Recurrence; Rituximab; Tacrolimus

Although tacrolimus is recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of idiopathic membranous nephropathy (MN), little is known about factors that influence response and relapse of the disease after tacrolimus therapy.. Multicentre study that collected 122 MN patients with nephrotic syndrome and stable renal function treated with tacrolimus. Duration of treatment was 17.6 ± 7.2 months, including a full-dose and a tapering period.. The percentage of remission was 60, 78 and 84% after 6, 12 and 18 months of treatment, respectively. The amount of proteinuria at baseline significantly predicted remission, the lower the baseline proteinuria the higher the probability of remission. Only 10 patients (8%) received concomitantly corticosteroids, and their rate of remission was similar (80% at 18 months). Among responders, 42% achieved complete remission (CR) and 58% partial remission (PR). Almost half (44%) of the responder patients relapsed. The amount of proteinuria at the onset of tacrolimus tapering was significantly higher in relapsing patients. By multivariable analysis, the presence of a PR versus CR at the onset of tacrolimus tapering and a shorter duration of the tapering period significantly predicted relapses. Tolerance was good and the number of adverse events low.. Tacrolimus monotherapy is an effective and safe option for the treatment of MN with stable renal function. Relapses are frequent in patients with PR and can be partially prevented by a longer tapering period.

Topics: Case-Control Studies; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Incidence; Longitudinal Studies; Male; Middle Aged; Prognosis; Proteinuria; Recurrence; Remission Induction; Retrospective Studies; Tacrolimus

Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0-6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7-12.0 weeks) in combination therapy (p = 0.076). Twenty-seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6-125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen.

Topics: Adolescent; Adult; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Isoxazoles; Kidney; Leflunomide; Lupus Nephritis; Male; Mycophenolic Acid; Nephrotic Syndrome; Podocytes; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

The use of generic formulations of immunosuppressive drugs in renal transplantation has been and still is a controversial subject. The lack of clinical studies about safety and efficacy in transplant patients is one of the factors restricting the diffusion of generic drugs in the renal transplant field. Since March 2013, our transplant unit has incorporated generic tacrolimus (Adoport(®) ; Sandoz), replacing the one we were currently using (Prograf(®) ; Astellas). When carrying out our retrospective analysis comparing the two different formulations, we evaluated several clinical results: tacrolimus trough concentrations (C0) at 5-7 days; 1, 3, and 6 months post-transplantation; concentration/dose ratio at 6 months; acute rejection incidence; delayed graft function (DGF); renal function (as CKD-EPI); and proteinuria at 6 months in 120 patients (1:1 ratio of Prograf(®) versus Adoport(®) ), noticing no important differences. We also evaluated the results of protocol biopsies at 6 months in a subgroup of patients, thus verifying the safety and efficacy of this particular generic drug versus the reference product on a histological basis as well. No difference in the development of dnDSA (de novo donor-specific antibody) was found between the two groups.

Topics: Adult; Aged; Antibodies; Biopsy; Cohort Studies; Delayed Graft Function; Drug Administration Schedule; Drugs, Generic; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Patient Safety; Proteinuria; Reference Values; Retrospective Studies; Tacrolimus; Thrombosis; Tissue Donors; Treatment Outcome

Several studies have reported that tacrolimus (TAC) significantly reduced proteinuria in lupus nephritis (LN) patients and mouse models. However, the mechanism for this effect remains undetermined. This study explored the mechanism of how TAC protects podocytes from injury to identify new targets for protecting renal function.. MRL/lpr mice were given TAC at a dosage of 0.1 mg/kg per day by intragastric administration for 8 weeks. Urine and blood samples were collected. Kidney sections (2 μm) were stained with hematoxylin-eosin (HE), periodic acid-Schiff base (PAS) and Masson's trichrome stain. Mouse podocyte cells (MPC5) were treated with TAC and/or TGF-β1 for 48 h. The mRNA levels and protein expression of synaptopodin and Wilms' tumor 1 (WT1) were determined by real-time PCR, Western blotting and/or immunofluorescence, respectively. Flow cytometry was used to detect cell apoptosis with annexin V. Podocyte foot processes were observed under transmission electron microscopy. IgG and C3 deposition were assessed with immunofluorescence assays and confocal microscopy.. Synaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine. TAC, however, reduced proteinuria, improved renal function, attenuated renal pathology, restored synaptopodin expression and preserved podocyte numbers. In MPC5 cells, TGF-β1 enhanced F-actin damage in podocytes and TAC stabilized it. TAC also decreased TGF-β1-induced podocyte apoptosis in vitro and inhibited foot process fusion in MRL/lpr mice. In addition, our results also showed TAC inhibited glomerular deposition of IgG and C3.. This study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis.

Topics: Animals; Apoptosis; Cell Line; Complement C3; Cytoprotection; Cytoskeleton; Drug Evaluation, Preclinical; Female; Immunoglobulin G; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice, Inbred MRL lpr; Microfilament Proteins; Podocytes; Protein Stability; Proteinuria; Tacrolimus

Podocyte injury plays central roles in proteinuria and kidney dysfunction, therefore, identifying specific biomarker to evaluate earlier podocyte injury is highly desirable. Podocyte-secreted angiopoietin-like-4 (Angptl4) mediates proteinuria in different types of podocytopathy. In the present study, we established an experimental minimal change disease (MCD) rat model, induced by adriamycin (ADR) and resulted in definite podocyte injury, to identify the dynamic changes in Angptl4 expression. We also investigated the direct effects of tacrolimus on Angptl4 and podocyte repair. We determined that the glomerular Angptl4 expression was rapidly upregulated and reached a peak earlier than desmin, an injured podocyte marker, in the ADR rats. Furthermore, this upregulation occurred prior to heavy proteinuria and was accompanied by increased urinary Angptl4. We observed that the Angptl4 upregulation occurred only when podocyte was mainly damaged since we didn't observe little Angptl4 upregulation in MsPGN patients. In addition, we observed the glomerular Angptl4 mainly located in injured podocytes rather than normal podocytes. Moreover, we found that tacrolimus treatment significantly promoted podocyte repair and reduced glomerular and urinary Angptl4 expression at an earlier stage with a significant serum Angptl4 upregulation. And similar results were confirmed in MCD patients. In conclusion, this study represents the first investigation to demonstrate that Angptl4 can predict podocyte injury at earlier stages in MCD and the identification of earlier podocyte injury biomarkers could facilitate the prompt diagnosis and treatment of patients with podocytopathy, as well as determination of the prognosis and treatment efficacy in these diseases.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Disease Models, Animal; Doxorubicin; Humans; Kidney Glomerulus; Nephrosis, Lipoid; Podocytes; Proteinuria; Rats; Tacrolimus

Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are the targets of the microRNA-30 family (miR-30s). We found that these 5 genes are highly expressed as mRNA, but the level of the proteins is low in normal podocytes. Conversely, protein levels were markedly elevated in podocytes from rats treated with puromycin aminonucleoside (PAN) and from patients with focal segmental glomerulosclerosis (FSGS). In both FSGS patients and PAN-treated rats, miR-30s were downregulated in podocytes. In cultured podocytes, PAN or a miR-30 sponge increased TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 expression; calcium influx; intracellular Ca2+ concentration; and calcineurin activity. Moreover, NFATC3 nuclear translocation, synaptopodin degradation, integrin β3 (ITGB3) activation, and actin fiber loss, which are downstream of calcium/calcineurin signaling, were induced by miR-30 reduction but blocked by the calcineurin inhibitor FK506. Podocyte-specific expression of the miR-30 sponge in mice increased calcium/calcineurin pathway component protein expression and calcineurin activity. The mice developed podocyte foot process effacement and proteinuria, which were prevented by FK506. miR-30s also regulated calcium/calcineurin signaling in cardiomyocytes. Together, our results identify miR-30s as essential regulators of calcium/calcineurin signaling.

Topics: Animals; Apoptosis; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Cells, Cultured; Doxorubicin; Gene Expression Regulation; Glomerulosclerosis, Focal Segmental; Humans; Mice; Mice, Transgenic; MicroRNAs; Myocytes, Cardiac; NFATC Transcription Factors; Podocytes; Proteinuria; Rats; RNA, Messenger; Tacrolimus; Transfection; TRPC Cation Channels

To determine the effect of Salvia przewalskii extract (SPE) from total phenolic acids on puromycin aminonucleoside (PAN)-induced rat podocyte injury.. The rats were divided into groups that were treated with either PAN only or PAN followed by tacrolimus or SPE. We evaluated the effects of SPE on podocyte injury 5, 10, 15 and 21 days following treatment.. (1) Proteinuria was observed starting on day 5 in all groups. The peak levels of proteinuria differed among the groups with tacrolimus and high-dose SPE, which significantly decreased proteinuria relative to the PAN and low- and medium-dose SPE groups. The proteinuria in each group decreased by day 15 and returned to a normal level by day 21. (2) H&E and PAS staining revealed no abnormality in glomerular morphology. With electron microscopy, we observed foot process effacement in the rats of all groups starting on day 5, but rats in the tacrolimus and high-dose SPE groups exhibited a lower degree. (3) IHC staining of nephrin and podocin revealed unaffected expression and better linear distributions in the high-dose SPE and tacrolimus groups. Western blot analysis confirmed that SPE could improve the expression of proteins. (4) The mRNA levels of nephrin and podocin in the tacrolimus and high-dose SPE groups were significantly higher than that in the others.. In our study, we first demonstrated the ability of SPE to reduce proteinuria, preserve the morphology and structure of podocytes and retain the levels of slit diaphragm proteins on PAN-induced rat podocytes injury.

Topics: Animals; Camphanes; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Panax notoginseng; Phytotherapy; Podocytes; Proteinuria; Puromycin; Rats, Sprague-Dawley; Saliva; Salvia miltiorrhiza; Tacrolimus

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Coloring Agents; Disease Progression; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Peroxidase; Proteinuria; Renal Insufficiency; Tacrolimus; Treatment Outcome

Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus.

Topics: Allografts; Amyloidosis; Diagnosis, Differential; Everolimus; Female; Humans; Immunoglobulin G; Immunoglobulin lambda-Chains; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Middle Aged; Paraproteinemias; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Proteinuria; Tacrolimus; TOR Serine-Threonine Kinases

BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood.. Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy.. Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk.. Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

Topics: Adult; Aged; Allografts; Antibodies, Monoclonal; Azathioprine; Basiliximab; BK Virus; Cohort Studies; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Polyomavirus Infections; Proteinuria; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Tacrolimus; Tumor Virus Infections; Viremia

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular condition leading to end-stage renal disease (ESRD) and the third most common cause of ESRD in pediatric patients.. This is a retrospective study consisting of 22 pediatric patients with FSGS and heavy proteinuria. After demonstrating steroids resistance, the patients were treated with tacrolimus, targeting a trough level 5-8 ng/mL. The primary outcome is the induction of remission with tacrolimus.. Thirteen patients (59%) achieved remission (complete in 31.8% and partial in 27.2%) and 12 patients showed stable or improved renal function over an average follow-up of 2.9 years (range: 0.5-7 years). There was no significant difference in response rate between African American and Caucasian patients. None of the patients had significant side-effect to tacrolimus and none of the repeat biopsies showed an increase in interstitial fibrosis compared to baseline. The best renal outcome was for patients who achieved complete remission. Partially responsive patients had improved renal function compared with resistant patients.. Tacrolimus is a viable option in the treatment of children with idiopathic steroid resistant FSGS.

Topics: Adolescent; Child; Child, Preschool; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant; Male; Proteinuria; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

Calcineurin inhibitors are effective immunosuppressants. They also reduce proteinuria in glomerular diseases but are potentially nephrotoxic. Short-term data suggest that tacrolimus (TAC) combined with corticosteroids is effective in LN, but long-term data are lacking. This study examined the long-term outcomes and tolerability of TAC for the treatment of LN.. We retrospectively reviewed 29 LN patients who received TAC treatment for 46.9 months (s.d. 37.9).. In 17 patients with class III/IV or V LN and persistent proteinuria >2 g/day despite induction immunosuppression, response rates after 12 and 24 months of add-on TAC treatment were 66.7% and 80.0%, respectively. In 10 patients with nephrotic syndrome due to class V LN who were given prednisolone and TAC as initial treatment, the response rate was 60.0% and 90.0% after 12 and 24 months, respectively. TAC facilitated steroid minimization in two patients with lupus podocytopathy. As a group, proteinuria decreased from 3.6 g/day (s.d. 2.6) to 1.0 (s.d. 1.1) (P < 0.05). Four patients developed end-stage renal failure, with 3-, 5- and 8-year renal survival rates of 93%, 83% and 83%, respectively. In the remaining patients, serum creatinine and estimated GFR remained stable after 36 months. One patient with pre-existing chronic renal failure developed TAC nephrotoxicity. Four renal flares occurred, all associated with low TAC blood levels. Six patients (20.1%) had deterioration of hypertension and one patient (3.4%) had new-onset diabetes mellitus. Six patients (20.1%) had infections that required hospitalization. Two deaths occurred: one due to pneumonia and one to breast cancer.. The results suggest efficacy of TAC in LN, especially in reducing proteinuria, and its role as a long-term maintenance agent warrants further investigation.

Topics: Adult; Creatinine; Drug Evaluation; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Prednisolone; Proteinuria; Retrospective Studies; Tacrolimus; Treatment Outcome

Tacrolimus is an anticalcineurinic agent with potent immunosuppressive activity that has recently been shown to have the added benefit of reducing proteinuria in membranous nephropathy (MN) patients. However, its potential mechanisms remain unknown. To reveal the mechanism, rat cohorts were administered tacrolimus or vehicle from days 7 to 28 after the induction of passive Heymann nephritis (PHN). PHN induction resulted in heavy proteinuria and increased expression of desmin, a marker of injured podocytes. We also showed that the glomerular expression of angiopoietin-like-4 (Angptl4) was markedly upregulated in PHN rats and human MN followed by an increase in urine Angptl4 excretion. In addition, increased Angptl4 expression may be related to podocyte injury and proteinuria. Furthermore, upregulated Angptl4 expression primarily colocalized with podocytes rather than endothelial or mesangial cells, indicating that podocytes may be the source of Angptl4, which then gradually migrated to the glomerular basement membrane over time. However, tacrolimus treatment markedly reduced glomerular and urinary Angptl4, accompanied by a reduction in the established proteinuria and the promotion of podocyte repair. Additionally, glomerular immune deposits and circulating IgG levels induced by PHN clearly decreased following tacrolimus treatment. In conclusion, this is the first demonstration that the calcineurin inhibitor tacrolimus can reduce Angptl4 in podocytes accompanied by a decrease in established proteinuria and promotion of podocyte repair in MN.

Topics: Adult; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Calcineurin Inhibitors; Disease Models, Animal; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Male; Middle Aged; Podocytes; Proteinuria; Rats; Tacrolimus; Up-Regulation; Young Adult

Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Dietary fish oil may minimize nephrotoxicity caused by long-term use of calcineurin inhibitors. The purpose of the present study was to evaluate the effects of omega-3 fatty acids on calcineurin inhibitor nephrotoxicity in rats that had normal kidney function or chronic kidney failure.. Rats that had normal kidney function or chronic renal failure that was induced by mass reduction surgery were treated with tacrolimus without or with fish oil, fish oil alone, or olive oil. Kidney function and histology were evaluated after 14 days.. Mean body weight loss, serum creatinine, change in serum creatinine, and rate of decrease in creatinine clearance were greater in normal rats that received than did not receive tacrolimus. Tacrolimus nephrotoxicity was greater in rats that had chronic renal failure than normal kidney function, but the mean change in serum creatinine was significantly lower in rats with chronic renal failure that were treated with tacrolimus and fish oil than tacrolimus alone. Fish oil supplementation was associated with fewer abnormal histopathologic lesions in the kidneys of tacrolimustreated rats that had normal kidney function or chronic renal failure (not signifant).. Fish oil may be protective against the development of kidney dysfunction and histopathologic changes in rats treated with tacrolimus.

Topics: Animals; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytoprotection; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Proteinuria; Rats, Wistar; Tacrolimus; Time Factors

The presence of human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene-A (MICA) antibodies after transplantation is correlated with rejection episodes, proteinuria, and renal allografts loss. We assessed the clinical value of high-dose tacrolimus on post-transplant HLA and MICA antibodies and proteinuria after renal transplantation.. Post-transplant sera of 310 renal transplantation patients who were negative for antibodies prior to transplant were tested by Luminex flow cytometry for HLA antibodies and MICA antibodies posttransplant. Once a patient was found to be antibody positive (Ab+), tacrolimus was dosed at two different concentrations: high tacrolimus Ab+ group (11 ± 1.36 ng/mL average tacrolimus trough) or low tacrolimus Ab+ group (7 ± 1.28 ng/mL average tacrolimus trough). Antibody negative (Ab-) patients were also studied and were given comparable tacrolimus doses to the low tacrolimus Ab+ group (7 ± 1.28 ng/mL average tacrolimus trough). Proteinuria was measured using the pyrogallol method. All patients were followed for 5 years after renal transplantation. Associations between tacrolimus, proteinuria, and survival were analyzed.. In the HLA or MICA Ab+ patients, proteinuria decreased after 5 years in the high tacrolimus Ab+ group unlike the low tacrolimus Ab+ group. Allograft survival in the high tacrolimus Ab+ group was significantly higher than the low tacrolimus Ab+ group and was similar to that of the Ab- group.. High-dose tacrolimus might play a role in improving allograft survival in HLA or MICA Ab+ post-transplant patients. Increasing tacrolimus concentration might be a plausible treatment for Ab+ post-transplant patients.

Topics: Adult; Biomarkers; Calcineurin Inhibitors; Drug Monitoring; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Predictive Value of Tests; Proteinuria; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Standard treatment for class III, IV, and V lupus nephritis (LN) is a combination of oral corticosteroids and mycophenolate mofetil (MMF). There is an estimated failure rate of 16%. Several small studies have looked at the use of tacrolimus in class III, IV, and V LN, both as induction treatment and as maintenance in patients refractory to other treatments. The majority of these studies were conducted in Asian patients. We discuss a cohort of eight female patients of various ethnicities with biopsy proven LN. All patients were evaluated retrospectively. Six were started on tacrolimus after failing to respond to MMF and corticosteroids, and one was started on tacrolimus alone because treatment options were limited by pregnancy. Five were Caucasian, one African American, one Hispanic, and one Vietnamese. Mean tacrolimus dose was 3.3mg daily (range 2-5 mg) titrated to a mean level of 3-6 ng/dl (range 3-6.6 ng/dl) for a mean of duration of 16 months (range 2-54 months). Six patients experienced complete remission (proteinuria <0.33 g/day), and two patients had a partial remission (minimum of 50% reduction in baseline proteinuria). Albumin increased an average of 32%. Average C3/C4 levels were 64/15 mg/dL, respectively, prior to treatment, and 95/25 mg/dL following treatment. No treatment-limiting adverse effects were reported. Our case series supports the growing body of evidence that tacrolimus is an effective therapy in LN patients with refractory proteinuria. Further studies are required to establish the long-term safety and efficacy of tacrolimus.

Topics: Adult; Female; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Retrospective Studies; Tacrolimus; Young Adult

Topics: Antihypertensive Agents; Cyclophosphamide; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Fatigue; Glomerulosclerosis, Focal Segmental; Gynecomastia; Humans; Hypertension; Male; Mastodynia; Middle Aged; Muscle Weakness; Mycophenolic Acid; Prednisone; Proteinuria; Tacrolimus

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

Topics: Algorithms; Cyclophosphamide; Drug Resistance; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Prednisolone; Proteinuria; Secondary Prevention; Tacrolimus; Treatment Outcome

Tacrolimus has been reported to be effective in refractory nephrotic syndrome, such as focal segmental glomerulosclerosis and membranous nephropathy. Some IgA nephropathy (IgAN) patients with massive proteinuria showed resistance to steroids and/or cytotoxic immunosuppressants based on the supportive therapy with renin- angiotensin system blockade. The efficacy and safety of tacrolimus in such refractory IgAN patients are extremely ambiguous, and the mechanism of tacrolimus improving proteinuria remission needs to be investigated.. 14 refractory IgAN patients were enrolled. The patients received tacrolimus (0.05-0.1 mg/kg/day) and prednisone (0.5 mg/kg/day) for at least 6 months. Synaptopodin and calcineurin expression were detected in renal tissues of patients who received re-biopsy. A puromycin aminonucleoside (PAN)-induced human podocyte injury model was applied to investigate the possible role of tacrolimus in proteinuria remission.. Of the 14 patients enrolled, 3 were withdrawn because serum creatinine increased over 30% baseline. In 11 patients treated with tacrolimus over 6 months, 9 showed complete or partial remission and 7 achieved remission within 1 month. In renal tissues, the expression of calcineurin increased while synaptopodin decreased and recovered partially after tacrolimus therapy. In an in vitro study, F-actin disrupted in human podocytes after stimulation of PAN, while calcineurin increased and synaptopodin decreased. After co-treatment with tacrolimus the reorganization of F-actin and the expression of calcineurin and synaptopodin recovered.. Tacrolimus showed a rapid proteinuria remission in refractory IgAN patients. The possible mechanism of tacrolimus to proteinuria remission might be podocyte cytoskeleton stabilization through inhibition of calcineurin expression.

Topics: Actins; Adolescent; Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Calcineurin; Cells, Cultured; Cytoskeleton; Drug Resistance; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Podocytes; Prednisone; Proteinuria; Remission Induction; Synaptophysin; Tacrolimus; Young Adult

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

Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.. We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.. All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.. This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

Topics: Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Middle Aged; Pilot Projects; Prednisolone; Proteinuria; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; 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

To study the clinical and pathological features of Denys-Drash syndrome (DDS).. Three DDS cases who were treated in our department from December 2009 to June 2011 were subjected to this study by reviewing of literature.. Both case 1 and case 2 were female, with karyotype 46, XX. Case 3 was male with bilateral cryptorchidism. The ages of nephropathy onset of the three cases were 1 year and 9 months, 2 years and 8 moths, and 3 months respectively. Proteinuria in case 2 and case 3 were evidenced to be resistant to steroid. Case 1 was partially responsive to tacrolimus, plasma albumin and cholesterol were improved, although proteinuria was persistent after Tacrolimus was administered. Remission was achieved in case 2 after administration of cyclosporine A and later tacrolimus, and her renal function remains normal till present (4 years and 9 months). Residue renal histology revealed diffused mesangial sclerosis (DMS) in all three patients. All of the three patients had developed right unilateral Wilms tumor. A novel WT1 missense mutation exon 9 c.1213C > G was detected in case 1. WT1 exon 9 c.1168C > T nonsense mutation and exon 8 c.1130A > T missense mutation were detected in case 2 and case 3, respectively.. The clinical manifestation of nephropathy in DDS is variable. The majority present with early onset nephropathy and reach renal failure before the age of 4 years. But in a few patients, nephropathy can also be present much later and progress slowly. Proteinuria in DDS is resistant to steroid but is responsive to calcineurin inhibitors, including Cyclosporine A. The effectiveness of tacrolimus was also observed in this study. DDS is evidently caused by WT1 mutation. DMS is the characteristic renal pathological change in DDS.

Topics: Cyclosporine; Denys-Drash Syndrome; Fatal Outcome; Female; Genes, Wilms Tumor; Heterozygote; Humans; Infant; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sclerosis; Tacrolimus; Treatment Outcome; Wilms Tumor; WT1 Proteins

After the completion of a double-blind placebo-controlled trial, tacrolimus (TAC) was approved for the treatment of lupus nephritis (LN) in Japan. However, the approved maximal dose, 3 mg/day, is almost half the dose used for induction therapy outside Japan. In this study, we retrospectively evaluated the efficacy and safety of low-dose TAC (≤3 mg/day) for induction therapy in 13 adult patients (2 men and 11 women) with active LN. Eight patients were treated for LN flares. Twelve patients underwent renal biopsies: 8 with class IV, 2 with class III + V, 1 with class IV + V, and 1 with class V renal histology, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. The mean initial doses of prednisone and TAC were 34.6 ± 14.5 and 2.7 ± 0.6 mg/day, respectively. All the patients achieved a complete remission (CR) at 7.7 ± 6.7 months (mean ± SD) after the last administration of TAC, except for 2 patients who discontinued TAC treatment; 1 because of worsening systemic lupus erythematosus and 1 because of hypertension. Two patients experienced a flare-up after achieving CR. The mean blood TAC concentration 12 h after the last administration (C12) was significantly lower among the patients with flare-ups than among those with a sustained CR (1.5 ± 1.5 vs. 5.1 ± 1.9 ng/mL, P = 0.034). These data showed that low-dose TAC was effective for induction therapy in patients with active LN, although a lower TAC concentration may be associated with a poor outcome.

Topics: Adrenal Cortex Hormones; Adult; Angiotensin II Type 1 Receptor Blockers; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus

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

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.

Topics: Administration, Oral; Animals; Cell Line; Complement Membrane Attack Complex; Cytoprotection; Desmin; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Glomerulonephritis, Membranous; Heymann Nephritis Antigenic Complex; Immunoglobulin G; Immunosuppressive Agents; Mice; NADPH Oxidases; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Podocytes; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Signal Transduction; Tacrolimus; Time Factors

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

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Immunotactoid glomerulopathy is a glomerular disorder typified by hollow cylindrical and sometimes spherical microtubular deposits, with a diameter of 30-40 nm, but up to 90 nm, often in a parallel arrangement or in intersecting bundles. These patients frequently end up receiving kidney transplants due to progressive renal insufficiency. Known to recur in renal transplant recipients with variable outcomes, its treatment options are limited. Classically steroids, cyclophosphamide, mycophenolate mofetil, and plasma exchanges have been used to treat these recurrences. More recently, rituximab has been suggested as a treatment and has demonstrated improved outcomes in other glomerular diseases. Herein we describe a case of a middle-aged female renal transplant recipient for end-stage renal disease secondary to immunotactoid glomerulopathy, who experienced a recurrence of this condition in the transplanted kidney. Following a failure of conventional therapy we administered a course of rituximab, resulting in a reduction and stabilization of her serum creatinine level while her proteinuria persisted.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Prednisone; Proteinuria; Recurrence; Rituximab; Tacrolimus; Transplantation, Homologous

Treatment of adults with steroid-dependent minimal change nephrotic syndrome (SD-MCNS) can be a significant challenge. Cyclophosphamide (CYC) and cyclosporin (CYA) are often effective steroid-sparing agents. Tacrolimus (TAC) may be another treatment option.. This open, prospective cohort study enrolled Chinese adults with SD-MCNS. At the start of the study, we administered TAC or intravenous CYC together with prednisone (0.5 mg/kg/day), the dose of which was tapered off throughout the study. The TAC cohort received oral TAC (target trough blood level of 4-8 ng/ml) for 24 weeks and the CYC cohort received intravenous CYC (750 mg/m(2) body surface) once every 4 weeks for 24 weeks.. Twenty-six patients met the criteria for enrollment (14 patients in the CYC group and 12 patients in the TAC group). One patient from each group discontinued treatment because of a drug-related side effect. Complete remission (CR) after the 24-week therapeutic period was 76.9% (10/13) in the CYC group and 90.9% (10/11) in the TAC group. The mean time required for CR in the TAC group was significantly less than in the CYC group (P = 0.031). Eight of 13 (61.5%) patients in the CYC group and 8 of 11 (72.7%) patients in the TAC group successfully stopped steroids and changed their status from steroid dependence. Sixty percent (6/10) of the CYC patients and 50% (5/10) of the TAC patients who achieved CR maintained remission during the follow-up period of 23.0 +/- 10.1 months. Four (40%) CYC patients and five (50%) TAC patients experienced relapses, and two CYC patients experienced frequent relapses.. A 24-week course of TAC is a favorable steroid-sparing agent for treatment of Chinese adults with SD-MCNS. Therapy with TAC accompanied by a tapering dose of prednisolone appears to yield quicker remission than treatment with CYC together with prednisone.

Topics: Administration, Oral; Adult; Chi-Square Distribution; China; Creatinine; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Nephrosis, Lipoid; Probability; Proteinuria; Recurrence; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Tacrolimus; Treatment Outcome

Persistent proteinuria in patients with quiescent lupus can result from membranous lupus nephritis and/or glomerular scarring following previous flares. This pilot study examined the effects of tacrolimus over two years in six patients with membranous/inactive lupus nephritis and persistent proteinuria despite angiotensin inhibition/blockade. Tacrolimus treatment reduced proteinuria and increased serum albumin (time effect, P = 0.047 and 0.032 respectively). Compared with baseline levels, proteinuria improved by more than 50% in five patients (83.3%) and hypoalbuminaemia was corrected in four patients. The efficacy was most prominent in four patients with biopsy-proven membranous lupus nephritis, whose protienuria improved by over 80%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment, despite non-excessive blood levels. These data suggest that tacrolimus is an effective treatment for proteinuria due to membranous lupus nephritis, but should probably be reserved for patients who are refractory to other non-nephrotoxic treatments, in view of the potential risk of subclinical nephrotoxicity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Antinuclear; Autoantigens; Blood Glucose; Blood Pressure; Complement C3; Creatinine; DNA; Drug Evaluation; Drug Resistance; Female; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Diseases; Lipids; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Proteinuria; Retrospective Studies; Serum Albumin; Tacrolimus; Treatment Outcome

Topics: Antibodies, Monoclonal; Child, Preschool; Cyclosporine; Diagnostic Errors; Dwarfism; Granuloma; Hematuria; Humans; Immunosuppressive Agents; Infliximab; Male; Nephritis, Interstitial; Nephrosis, Lipoid; Nephrotic Syndrome; Obesity; Prednisolone; Proteinuria; Puberty, Delayed; Recurrence; Remission Induction; Tacrolimus; Tumor Necrosis Factor-alpha

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

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.

Topics: Adult; Anemia, Megaloblastic; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Blood Proteins; Combined Modality Therapy; Cyclophosphamide; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Plasmapheresis; Proteinuria; Sepharose; Staphylococcal Protein A; Tacrolimus

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Topics: Analysis of Variance; Blood Pressure; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sodium; Sodium Chloride, Dietary; Tacrolimus

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

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

We examined our renal transplant population for glomerular diseases demonstrated on biopsy between January 1993 and April 2002, focusing on transplant glomerulopathy (TGP). Of 1156 patients followed in our clinics during this period, glomerular disease was diagnosed in 132 cases (11.4%). Glomerulonephritis was diagnosed in 86 transplants (7.4%), with IgA nephropathy (IgAN) being the commonest diagnosis [32 cases (2.8%)]. Thirty-one cases (2.7%) of biopsy-proven TGP were analyzed for associated factors compared with 27 cases (2.3%) of recurrent IgAN. Transplant glomerulopathy was less frequent with mycophenolate mofetil (MMF) and/or tacrolimus, whereas recurrent IgAN showed no such tendency (P= 0.02). Peritubular capillary (PTC) C4d deposition was observed in six of 24 cases (25%) with TGP but none with recurrent IgAN (P= 0.02). Peritubular capillary basement membrane (BM) multilayering was significantly greater in TGP (4.92 +/- 2.94) than in recurrent IgAN (1.86 +/- 1.04) (P < 0.001). The graft survival of TGP was worse than recurrent IgAN (P= 0.05). The association of TGP with BM multilayering and C4d deposits in PTC suggests a generalized disorder of the graft microcirculation and its BM, owing to antibody-mediated rejection in at least some cases. Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN.

Topics: Age Factors; Basement Membrane; Biopsy; Capillaries; Complement C4b; Female; Graft Survival; Humans; Immunoglobulin A; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Kidney Transplantation; Male; Mycophenolic Acid; Nephrons; Peptide Fragments; Proteinuria; Tacrolimus; Time Factors

Focal segmental glomerulosclerosis (FSGS) commonly presents with nephrotic syndrome (NS), and spontaneous remission is rare. NS is a poor prognostic marker for renal survival, and has serious extra-renal complications. Rapid remission using drugs with minimal side effects is desirable. Tacrolimus (Tac) has a more potent immunosuppressive effect and may be less toxic at therapeutic doses than ciclosporin (CsA). Although CsA has a role in the treatment of FSGS, there are limited data regarding the use of Tac monotherapy in this setting, and this is limited to experience in children.. We prospectively report the outcome for six adult patients with FSGS treated with Tac from first presentation with NS, and for a further five adult patients in remission on CsA converted to Tac in an attempt to arrest a progressive decline in renal function on CsA.. All six patients treated with Tac from presentation with NS achieved remission after 6.5 +/- 5.9 months. The serum albumin for the group increased from 26.8 +/- 4.6 to 37.7 +/- 1.9 g/l (P = 0.003), and there was a significant reduction in the mean 24 h urinary protein excretion from 11.0 +/- 4.5 to 2.8 +/- 2.5 g (P = 0.003). All remissions were partial with a mean reduction in 24 h urinary protein of 75.2 +/- 16.8%. There was a non-significant reduction in MDRD GFR from 71.7 +/- 22.4 to 55.9 +/- 9.7 ml/min/1.73 m(2) (P = 0.07), which manifest within the first 3 months of Tac treatment but renal function was subsequently stable. The mean follow-up for the group was 12.8+/-5.5 months. Two of the five patients converted from CsA to Tac maintained complete remission, and the remaining three patients in partial remission had further reductions in proteinuria. There was an improvement in renal function concomitant with conversion to Tac in each case, with an overall improvement in MDRD GFR for the group of +1.9+/-1.1 ml/min/1.73 m(2)/month.. Tac rapidly and effectively induced remission of NS in FSGS. Conversion from CsA to Tac indicates that Tac might be a more potent agent with less nephrotoxicity in this setting.

Topics: Adult; Albuminuria; Cyclosporine; Diabetic Nephropathies; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Proteinuria; Tacrolimus; Time Factors; Treatment Outcome

To study the efficacy and safety of tacrolimus in primary membranous nephropathy.. We describe 3 patients with primary membranous nephropathy who were either resistant to or could not tolerate steroid with or without cytotoxic agents. They were treated with tacrolimus 0.2 mg/kg/day for 6 months. The dosage of tacrolimus was adjusted to keep a whole blood tacrolimus level of 5-10 ng/ml.. One patient had almost complete disappearance of proteinuria while the other 2 had at least 50% reduction in proteinuria. Proteinuria increased again in 2 of the patients after tacrolimus was stopped, but in neither of them proteinuria returned to the pretreatment level 6 months after tacrolimus was stopped.. We conclude that tacrolimus may have a modest efficacy in the treatment of resistant membranous nephropathy.

Topics: Adult; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Proteinuria; Tacrolimus

Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 +/- 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection (P = 0.0193) and CAN (P = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.

Topics: Adult; Biopsy; Creatinine; Cyclosporine; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Prognosis; Proteinuria; Tacrolimus; Transplantation, Homologous; Treatment Outcome

We have previously reported that CD4 T lymphocytes and their cytokines contribute to development of Thy 1.1 glomerulonephritis (GN). FK506 is reported to suppress the production of Th1 cytokines. The aims of this study were to elucidate the role of Th1 cytokines on mesangial alteration and to examine whether FK506 is available for therapy of mesangial proliferative GN.. The effects of daily treatments of FK506 from day -5 and from day +1 of Thy 1.1 GN induction on glomerular alterations were analyzed.. FK506 treatment with 1.0 and 0.3 mg/kg body weight (BW) daily from day 1 to day 4 significantly reduced the glomerular expression of mRNA for interferon-gamma (IFN-gamma; 1.0 mg/kg BW FK506, 32.4% to the placebo group, P < 0.01) and IL-2 (55.6%, P < 0.01) on day 5. FK506 treatment from day -5 of GN induction reduced proteinuria and glomerular alteration in a dose-dependent manner. Although no side effects were detected in rats with 0.3 mg/kg BW of FK506 treatment from day +1, the treatment also ameliorated proteinuria (day 14, 3.7 +/- 0.89 vs. 19.8 +/- 12.3 mg/100 g BW/day P < 0.05) and glomerular alterations [total cell number, 63.1 +/- 3.1 vs. 80.2 +/- 7.4, P < 0.01; matrix expansion, 0.90 +/- 0.30 vs. 1.34 +/- 0.27, P < 0.05; alpha-smooth muscle actin (alphaSMA) expression; 1.20 +/- 0.12 vs. 1.96 +/- 0.29, P < 0.01] on day 14.. Th1 cytokines may play an important role in the development of mesangial proliferative glomerulonephritis, and could be targets for therapy. FK506 might be available for clinical use.

Topics: Animals; Antibodies, Monoclonal; Cytokines; Dose-Response Relationship, Drug; Female; Glomerulonephritis; Immunosuppressive Agents; Kidney Glomerulus; Proteinuria; Rats; Rats, Wistar; Tacrolimus; Th1 Cells; Thy-1 Antigens; Time Factors

Cyclosporin is associated with significant chronic nephrotoxicity, manifest in the long term mainly as renal fibrosis. There have been claims that tacrolimus is a less fibrotic drug than cyclosporin, and this study was designed to determine the effect of the two drugs on the expression of fibrosis-associated genes.. Male Wistar rats underwent clamping of the right renal pedicle for 45 min together with left nephrectomy; this model has previously been shown to be associated with upregulation of fibrosis-associated genes. Experimental groups (six animals per group) received cyclosporin A 10 mg/kg daily, tacrolimus 0.2 mg/kg daily or no treatment. Animals were killed at 16 weeks, and the renal cortical expression of fibrosis-associated genes was studied by means of quantitative reverse transcriptase-polymerase chain reaction.. Tacrolimus-treated animals developed significantly less proteinuria and had lower serum creatinine levels than those receiving cyclosporin. Tacrolimus administration also significantly reduced the expression of transforming growth factor beta and tissue inhibitor of metalloproteinases 1, both the products of genes associated with fibrosis. Although cyclosporin treatment reduced levels of the matrix-degrading enzymes, matrix metalloproteinase (MMP) 2 and MMP-9, this was not statistically significant.. Tacrolimus has less nephrotoxicity than cyclosporin in this model. It also appears to have less fibrogenic potential, and this may have implications for the choice of long-term immunosuppressant in renal transplantation.

Topics: Animals; Creatinine; Cyclosporine; Fibrosis; Gene Expression; Immunosuppressive Agents; Kidney Diseases; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Proteinuria; Rats; Rats, Wistar; Renal Artery; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus; Transforming Growth Factor beta

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Enalapril; Glomerulosclerosis, Focal Segmental; Immune System; Immunosuppressive Agents; Interleukin-2; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Tacrolimus; Tetrazoles; Triglycerides

Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway (BN) rats. The effects of a new immunosuppressant, FK 506, on this model of glomerulonephritis were studied. BN rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/week). FK 506 was inoculated subcutaneously daily from day 15 to day 28. Animals were divided into 4 groups: group 1, rats were treated with normal saline alone and sacrificed on day 28; group 2, rats were treated with HgCl2 alone and sacrificed on day 14; group 3, rats were treated with HgCl2 alone and sacrificed on day 28, and group 4, rats were treated with HgCl2 and FK 506 (from day 15 to day 28) and sacrificed on day 28. Rats developed proteinuria by day 7, which reached a plateau level by day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Treatment with FK 506 (1 mg/kg s.c. daily) resulted in a remarkable reduction in proteinuria on day 28 (493.5 +/- 48.3 vs. 24.4 +/- 13.5 mg/day) and an improvement in the morphological lesions. These findings suggest that FK 506 could be useful in the treatment of some human glomerulonephritides.

Topics: Animals; Autoimmune Diseases; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney; Kidney Function Tests; Male; Mercuric Chloride; Microscopy, Electron; Proteinuria; Rats; Rats, Inbred BN; Tacrolimus

The influence of the Ipr(cg) gene on the development of Sjögren's syndrome was followed up to 5 months of age in male and female mice of MRL, CBA and C3H strains. In MRL-Ipr(cg) mice, focal mononuclear cell infiltration started at 2 months and became conspicuous after 3 months of age in the lacrimal and submandibular glands but was minimal in the parotid and sublingual glands, even at 5 months of age, without any apparent sex effects found. In CBA and C3H mice carrying the Ipr(cg) gene, this manifestation of Sjögren's syndrome was much less prominent, indicating that the participation of some genes of the MRL strain may be indispensable for the development of Sjögren's syndrome in mice carrying this gene. In MRL-Ipr(cg) mice, an immunosuppressive agent, FK506, improved the serological abnormalities (decreased levels of anti-double-stranded DNA antibody of IgG2a and IgG3 subclasses) and proteinuria. It also reduced the manifestations of Sjögren's syndrome when it was intraperitoneally administered three times weekly at a dose of 2 mg/kg from 6 weeks (before disease onset) until 5 months of age (the termination of the experiment). Although VP8.2+ T cells have been demonstrated to be responsible for causing several autoimmune diseases, the selective deletion of Vp8.2+ T cells with the superantigen encoded by mouse mammary tumor virus did not affect the disease severity at all, suggesting that this T cell repertoire may not play a crucial role in induction of Sjögren's syndrome.

Topics: Animals; Antibodies, Antinuclear; DNA; Enzyme-Linked Immunosorbent Assay; fas Receptor; Female; Flow Cytometry; Immunoglobulin G; Immunosuppressive Agents; Lacrimal Apparatus; Male; Mice; Mice, Inbred C3H; Mice, Inbred CBA; Mice, Inbred MRL lpr; Proteinuria; Sjogren's Syndrome; Submandibular Gland; Tacrolimus

There have been no reports on the effect of FK5 06, a new immunosuppressive agent, on experimental membranous glomerulonephritis (MN) induced by an exogenous antigen. Therefore we investigated the effects of FK506 on MN induced by cationized bovine serum albumin (C-BSA) in rats.. Two weeks after the rats were immunized with 1 mg of C-BSA and Freund's complete adjuvant, they received intravenous injections of 3 mg/kg of C-BSA 3 times weekly for 4 weeks. Rats were divided into four groups: group A (n = 5) received intramuscular injections of 3 mg/kg of FK506 daily for 5 days beginning 2 days before the first immunization; group B (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 2 weeks after the first immunization; and group C (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 4 weeks after the first immunization. Group D (n = 5) received no FK506 and served as the control group. Rats were sacrificed 8 weeks after the first immunization.. Administration of FK506 in the preimmunization stage almost completely suppressed the development of MN in group A. Histological findings in groups B and C were similar to those in group D, the control group. However, urinary protein excretion was significantly lower in group B (24+/-46 mg/day) and C (220+/-44 mg/day) than in group D (330+/-61 mg/day). Expression of intracellular adhesion molecule-1 in glomeruli and the number of leukocyte functioning-associated molecules-1 were significantly decreased in groups A, B, and C compared with the control group. Administration of FK506 was not associated with any significant side-effects or histological abnormalities. The whole-blood trough levels of FK506 in groups B and C were 9.1 ng/ml and 9.2 ng/ml respectively.. The efficacy of FK506 was significantly increased when the drug was administered in the early phase of immunization in this model. The present study suggests that FK506 may be useful in patients with intractable nephrotic syndrome such as MN.

Topics: Animals; Creatinine; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Glomerulonephritis, Membranous; Immunosuppressive Agents; Injections, Intramuscular; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Lymphocyte Function-Associated Antigen-1; Proteinuria; Rats; Rats, Wistar; Serum Albumin; Serum Albumin, Bovine; Tacrolimus

Topics: Adult; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Proteinuria; Tacrolimus

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Proteinuria; Tacrolimus

Topics: Creatinine; Homeostasis; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocytes; Magnesium; Proteinuria; Reference Values; Serum Albumin; Tacrolimus; Time Factors

The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellular adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.

Topics: Animals; Antibodies, Heterophile; Basement Membrane; Complement C3; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Leukocytes; Lymphocyte Activation; Lymphocyte Function-Associated Antigen-1; Male; Nephritis; Proteinuria; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-2; Tacrolimus

The effects of FK506, a new immunosuppressive agent, on the development of lupus dermatoses were investigated in the autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mouse, which is an animal model for the spontaneous development of skin lesions similar to those of human lupus erythematosus (LE). FK506 reduced the incidence of skin lesions, lupus nephritis, the titre of serum anti-double-stranded DNA antibodies and the massive T cell proliferation. The incidence and magnitude of IgG deposition at the dermoepidermal junction were not changed. These results suggest that FK506 is a promising immunosuppressive agent for the control of autoimmune skin diseases.

Topics: Animals; Antibodies, Antinuclear; Disease Models, Animal; Female; Immunoglobulin G; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Mice; Proteinuria; Splenomegaly; Tacrolimus

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.

Topics: Animals; Antibodies, Antinuclear; Antigens, Surface; Base Sequence; CD3 Complex; CD4 Antigens; CD8 Antigens; Cyclophosphamide; Cytokines; DNA Primers; Female; Gene Expression; Kidney; Leukocyte Common Antigens; Lupus Erythematosus, Systemic; Mice; Mice, Mutant Strains; Molecular Sequence Data; Proteinuria; Survival Analysis; T-Lymphocyte Subsets; Tacrolimus

Seven patients with steroid-resistant nephrotic syndrome were treated with FK 506 monotherapy. Four patients were children with focal sclerosing glomerulonephritis (FSGS). Three of these had evidence for chronic progressive renal disease consisting of interstitial fibrosis and tubular atrophy on pretreatment renal biopsies. Two patients had also failed cyclosporin A (CsA), two cyclophosphamide, and one chlorambucil prior to treatment with FK 506. Three patients were adults with mesangial proliferative, membranoproliferative, and membranous glomerulonephritis. Three patterns of response were noted: (1) a reduction in proteinuria to normal levels; (2) partial response (50% reduction) or; (3) no improvement. All patients except one experienced at least a 50% reduction in protein excretion at some time during FK 506 therapy. Two of the children and one adult reduced protein excretion to essentially normal values. One patient had no sustained reduction in protein excretion and is considered to be a treatment failure, although her protein excretion was approximately 50% of pretreatment values intermittently. The drug was generally well tolerated. The most common side-effect was nephrotoxicity, which was reversible. These encouraging results suggest that FK 506 monotherapy may be effective in controlling the proteinuria of some patients with steroid-resistant nephrotic syndrome. The use of this drug may extend our understanding of the role of T lymphocytes and cytokines in the pathogenesis of glomerulonephritis. Further study of this agent in a larger population of patients is warranted.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Drug Resistance; Female; Humans; Male; Nephrotic Syndrome; Pilot Projects; Proteinuria; Tacrolimus

Topics: Azathioprine; Biopsy; Creatinine; Cyclosporine; Graft Rejection; Humans; Kidney Transplantation; Nephrotic Syndrome; Pilot Projects; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Transplantation, Homologous

We evaluated the effect of the novel immunosuppressive agent, FK506, which is known to inhibit T cell immunity, on the development of lupus nephritis in MRL/MpJ-lpr/lpr (MRL/l) mice. FK506 was administered subcutaneously (1 mg/kg body weight) from 12 to 20 weeks of age in 13 MRL/l mice with spontaneous lupus nephritis. Nine animals receiving no treatment were used as the control. FK506 significantly reduced the development of proteinuria, lowered the level of BUN, and suppressed the elevation of serum anti-dsDNA antibodies. Histopathological study showed that FK506 significantly inhibited the progression of glomerular hypercellularity and crescent formation. Glomerular deposition of C3 was significantly reduced in the FK506-treated mice compared to the nontreated controls. These findings suggest that FK506 may protect against progression of lupus nephritis in MRL/l mice, an animal model of systemic lupus erythematosus.

Topics: Animals; Blood Urea Nitrogen; Female; Fluorescent Antibody Technique; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred Strains; Organ Size; Proteinuria; Spleen; Tacrolimus

FK506 is a recently-developed immunosuppressive drug. The aim of the present work was to investigate the effects of FK506 in experimental autoimmune glomerulonephritis (active Heymann nephritis) in rats. Active Heymann nephritis was induced in female Lewis rats by two immunizations with the homologous brush border vesicles (BBVs) at day 0 and day 28 (groups I, II, V, and VI). Rats of groups III and IV received the third immunization at day 56. In rats of groups I and III, FK506 was injected (1 mg/kg/day IM) from day 0 for 14 days. In rats of groups II and IV, significant proteinuria was observed (group II, 112.8 mg/16 hours; group IV, 55.4 mg/16 hours) at the time the rats were killed (day 84). Coarse subepithelial immune deposits (IDs) were found in these rats. In contrast, urinary protein excretion remained within normal range (less than 3.0 mg/16 hours) in groups I and III rats, and tiny subepithelial IDs were only occasionally seen. Circulating anti-BBV antibody levels were markedly lower in group I and III rats than in those of groups II and IV during the period between day 14 and day 56. To investigate the effects of FK506 on the proteinuric rats, FK506 (1 mg/kg/day, IM) was administered every day for 2 weeks beginning on day 56 (group V).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibodies; Creatine; Disease Models, Animal; Female; Glomerulonephritis; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Microvilli; Proteinuria; Rats; Rats, Inbred Lew; Tacrolimus

Topics: Adolescent; Adult; Child, Preschool; Creatinine; Drug Resistance; Humans; Kidney Function Tests; Kidney Transplantation; Middle Aged; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

The aim of the present work was to study the effects of a new immunosuppressive drug, FK506, in accelerated nephrotoxic serum glomerulonephritis. Glomerulonephritis was induced in female Wistar rats by the preimmunization with normal rabbit IgG (Day-4) and the subsequent intravenous injection of rabbit anti-GBM serum (Day 0). Without treatment with FK506, rats developed proteinuria at Day 6 and onward. Rat anti-rabbit IgG was strongly detected at Day 6 and the titer was maintained through Day 20. Moderate hypercellularity and focal crescent formation were observed at Day 20. Rats injected intramuscularly with 0.3 or 1 mg/kg of FK506 did not develop proteinuria and the anti-rabbit IgG titer was much less or was undetectable throughout the experiments. These data suggest that FK506 is effective in the present model of glomerulonephritis.

Topics: Animals; Anti-Bacterial Agents; Creatinine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Kidney; Proteinuria; Rats; Rats, Inbred Strains; Tacrolimus

FK506 is a new drug which has potent immunosuppressive activity. We studied its immunosuppressive effects on active Heymann's nephritis and the autologous phase of Masugi nephritis. The induction of active Heymann's nephritis was completely suppressed by FK506 injected simultaneously with the antigen (day 1) and then daily for 14 days at a dose of 0.64 mg/kg per day or more. With a lower dosage of this agent, antibody production and immune deposits in the glomerular basement membrane occurred despite the suppression of proteinuria. Similar results were obtained in rats on other treatment schedules (1-7 days or day 8-14 days duration). Rats that were prevented from developing Heymann's nephritis or the autologous phase of nephrotoxic antiserum nephritis by FK506 treatment exhibited a suppressed immune response to a second immunization of the same antigen even 4 weeks after cessation of drug administration: however, they developed antibodies when inoculated with other antigens. Rat peripheral leucocyte counts and serum creatinin were not remarkably influenced by the administration of FK506. These results indicate that FK506 has potent immunosuppressive activity, and it is suggested that it is able to induce an antigen-specific immunotolerance.

Topics: Animals; Anti-Bacterial Agents; Basement Membrane; Creatinine; Dose-Response Relationship, Drug; Female; Immune Tolerance; Immunoglobulin G; Immunosuppressive Agents; Kidney; Leukocyte Count; Nephritis; Proteinuria; Rats; Rats, Inbred WKY; Tacrolimus; Time Factors

A novel immunosuppressive compound extracted from the fermentation broth of Streptomyces tsukubaensis belongs to the macrolide family. We gave this drug (FK-506) to MRL/lpr and NZB X NZW F1 (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE), to investigate its effect on the course of the disease. This drug showed potential to prolong the lifespan, to reduce proteinuria, and to prevent the progression of nephropathy. Appreciable differences in the levels of anti-dsDNA antibodies between treated and control animals were nil.

Topics: Animals; Autoantibodies; DNA; Immunoglobulin G; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Proteinuria; Pyridines; Spleen; Tacrolimus