sirolimus and Delayed-Graft-Function

The study was designed to compare the outcomes of sirolimus (SRL) combined with tacrolimus (TAC) and mycophenolate mofetil (MMF) combined with TAC in kidney transplantation recipients.. A literature search of PubMed, Embase, and Web of Science was performed to identify relevant studies, and the last update was on February 1, 2018. All studies with appropriate data comparing the SRL group with the MMF group were included. SRL and MMF were used in sufficient doses. Relevant information was recorded and analyzed. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the effects of SRL and MMF. Relevant outcomes, including delayed graft function, acute rejection, graft survival, seroma, anemia, lymphocele, and hyperlipidemia, were compared.. Ten studies with a total of 2357 patients (n = 1256 receiving SRL vs n = 1101 receiving MMF) were ultimately included. Our results indicated that the SRL group experienced a higher rate of hyperlipidemia (OR: 1.864; 95% CI, 1.494-2.325) and lymphocele (OR: 2.58; 95% CI, 1.49-4.47). However, no significant differences were detected regarding the rates of delayed graft function, acute rejection, graft survival, infectious complications, anemia, or seroma.. This meta-analysis suggested that SRL combined with TAC and MMF combined with TAC were equally safe and effective for the kidney transplantation recipients. However, the MMF group exhibited a marginally significant advantage of lower incidence of hyperlipidemia and lymphocele.

Topics: Adult; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lymphocele; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Topics: Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Cyclosporine; Delayed Graft Function; Endothelium, Vascular; Everolimus; Graft Rejection; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune Tolerance; Immunosuppressive Agents; Sirolimus; Tacrolimus; Transplantation Immunology

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

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

Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, results in improved long-term renal function.. This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm.. Enrollment was stopped after ≈12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean±SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1±18.7 mL/min) and CsA (66.0±15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001).. A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended.

Topics: Adult; Cyclosporine; Delayed Graft Function; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Sirolimus; Transplantation, Homologous

Reducing side effects of immunosuppressive regimens has become a priority in transplantation medicine because of the large number of patients and grafts that succumb to infection in the short term and cardiovascular disease in the long term. The Symphony study was a 12-month prospective, randomized, open-label, multi-centre, four parallel arm study that aimed to evaluate the safety and efficacy of low-dose immunosuppressive regimens compared with a standard-dose regimen in renal transplant recipients. This sub-analysis focuses on specific toxicities observed with the low-dose regimens.. Adult patients (n = 1645) scheduled to undergo renal transplantation received low-dose cyclosporine (CsA), tacrolimus (Tac) or sirolimus (SRL) in addition to daclizumab induction or standard-dose cyclosporine without induction. All patients received mycophenolate mofetil and corticosteroids. We evaluated the incidence of adverse events (AEs), tested specific group differences and assessed the relationship of selected AEs with drug levels.. The four arms had similar incidences of AEs, but serious AEs were more common with low-dose SRL and led to more discontinuations. Infections were the most common AEs, with the highest incidence in the standard-dose CsA group, in particular, cytomegalovirus (CMV) infections. Low-dose Tac had the most reports of new-onset diabetes, leucopenia and diarrhoea. Low-dose SRL negatively influenced triglycerides, wound healing, lymphocele and anaemia. We found only weak relationships between specific AEs and drug levels.. Despite the low doses, CsA, Tac and SRL retained distinct and different toxicity profiles. These findings may be of relevance for tailoring specific immunosuppressive regimens to patients with particular needs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Delayed Graft Function; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Infections; Kidney Transplantation; Lipid Metabolism; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

Concerns about delayed graft function (DGF) and wound healing complications with sirolimus has led to suggestions that everolimus introduction could be delayed after transplantation.. In a prospective, multicenter, open-label study, deceased-donor kidney transplant recipients at protocol-specified risk of DGF (defined as > or =1 dialysis session during the first week posttransplant excluding day 1) were randomized to start everolimus therapy on day 1 posttransplant (immediate everolimus [IE]), or from week 5 (delayed everolimus [DE]) with mycophenolic acid until everolimus was initiated. All patients received anti-interleukin-2 receptor antibodies, cyclosporine A, and corticosteroids. A planned 3-month analysis from this 12-month study is presented here.. One hundred and thirty-nine patients were randomized (IE 65, DE 74). The primary composite endpoint: biopsy-proven acute rejection, graft loss, death, DGF, wound healing events, or lost to follow-up at month 3, occurred in 36 IE patients (55.4%) and 47 DE patients (63.5%, P=0.387). The incidence of DGF was similar between groups (IE 24.6%, DE 24.3%; n.s.). Wound healing events of any type occurred in 40.0% and 41.9% of IE and DE patients (n.s.); events relating to initial transplant surgery occurred in 36.9% IE patients and 37.8% DE patients (n.s.), most of which were fluid collections. Study drug was discontinued due to adverse events or graft loss in 13 IE (20.0%) and 17 DE patients (23.0%).. Findings from this randomized, multicenter trial indicate that kidney function recovery, wound healing, efficacy, and tolerance are similar at 3 months posttransplant with immediate or DE in patients at protocol-specified risk of DGF.

Topics: Aged; Delayed Graft Function; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Female; France; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Time Factors; Transplantation Tolerance; Treatment Outcome; Wound Healing

Wound complication frequently arises after kidney transplantation and its risk factors are well known. In a previous paper we analyzed these factors, and in this new retrospective study we evaluate the influence of lymphocele in the development of wound complications.. From January 2000 to December 2018, 731 consecutive kidney transplants have been performed in our center. We have analyzed the incidence of wound complication and lymphocele and their risk factors.. Out of 731 kidney transplants, we have observed wound complications in 115 patients (15.7%) and lymphocele in 158 patients (21.7%). Of these, 70 patients developed both complications (9.5%), but 6 patients have been excluded because they were in therapy with mammalian target of rapamycin inhibitors. Twenty-nine patients (45.3%) presented a first level and 35 patients (54.7%) showed second level wound complications. Lymphocele was the only present factor in just 3 cases (4.6%). The other patients showed diabetes in 28 cases (43.7%), overweight/obesity in 38 (59.3%), delayed graft function in 17 (26.5%), and 60 years or more in 38 (57.8%). The association has been found in 30 out 64 patients treated with tacrolimus (46.8%) and in 34 with cyclosporine (53.1%); 40 patients did not receive muscular layer's reconstruction (62.5%).. Our experience shows that lymphocele alone is not a predisposing factor for wound dehiscence after kidney transplantation, and they often coexist because they share the same risk factors, the most important being obesity, diabetes and delayed graft function, older age, and surgical techniques. No relation has been observed with calcineurin inhibitor therapy.

Topics: Adult; Aged; Cyclosporine; Delayed Graft Function; Diabetes Complications; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphocele; Male; Middle Aged; Obesity; Retrospective Studies; Risk Factors; Sirolimus; Surgical Wound Dehiscence; Tacrolimus

Anemia is a very common occurrence in post-renal transplant patients. Post-transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney transplantation.. Our retrospective cohort study included a total of 570 renal transplant recipients. For the definition of anemia, we adopted "the lower limit of normal for Hgb concentration of blood" proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity. Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180days after transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a total of 20 clinical factors were compared between the two groups.. In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60years old, OR=2.62, p=0.001), race (OR=2.54, p=0.001), and use of sirolimus (OR=2.01, p=0.019), antiviral agents (OR=1.96, p=0.015), thymoglobulin (OR=1.86, p=0.011), and DGF (OR=2.78, p=0.001) remained significant.. The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.

Topics: Adolescent; Adult; Age Factors; Anemia; Antilymphocyte Serum; Antiviral Agents; Cohort Studies; Delayed Graft Function; Ethnicity; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Young Adult

Tuberous sclerosis complex (TSC) is an inherited disorder caused by mutations of TSC1 or TSC2 genes, resulting in constitutive activation of the mammalian target of rapamycin (mTOR) and impairment of the cell cycle. As a consequence, hamartomatous tumors of multiple organs may develop, but generally skin, brain, kidneys, and lungs are involved. mTOR inhibitors (mTOR-I, rapamycin/everolimus) may correct underlying defects in TSC. Previous data prove benefits and safety of mTOR-I on a wide spectrum of disease manifestations and effectiveness of rapamycin in TSC patients after kidney transplantation (KT).. We report the first case of a patient with TSC receiving everolimus initiated in immunosuppressive treatment at the time of KT. In April 2012, the 34-year-old female TSC patient, after bilateral nephrectomy due to polycystic kidneys and skin lesions related to TSC, was transplanted with a renal graft from a deceased donor (PRA, 0%; MM A/B/DR,1/2/0). Initial immunosuppressive treatment consisted of basiliximab, methylprednisolone, tacrolimus, and everolimus.. The early postoperative period was complicated by delayed graft function. Creatinine level at discharge was 1.39 mg/dL, with stable graft function in subsequent months. Nine months after KT, inflammatory infiltration of the nephrectomy site (performed in 2011) with persistent effusion was observed. After 2 months of unsuccessful conservative treatment, the patient was converted from everolimus to mycophenolate mofetil with healing of local state. During 11 months of everolimus treatment, no improvement of skin presentation of TSC was noticed.. mTOR-I appear to be a treatment of choice in transplanted patients with TSC, although some complications precluding continuous mTOR-I therapy allowing its potential benefits, may appear.

Topics: Adult; Creatinine; Delayed Graft Function; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Despite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010.. Associated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group.. There were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36-49 mL/min and 51-55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively.. Induction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.

Topics: Aged; Calcineurin Inhibitors; Cyclosporine; Delayed Graft Function; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Steroids; Tacrolimus; Tissue Donors; Transplant Recipients

Topics: Child; Cyclosporine; Delayed Graft Function; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus

Sirolimus is associated with prolonged delayed graft function (DGF) following renal transplantation and exacerbation of proteinuria. We assessed renal allograft biopsies from DGF patients treated with de novo sirolimus (n = 10) for renal tubular cell and podocyte apoptosis and expression of activated caspase-3, Bcl-2, and mTOR and compared them to biopsies from DGF patients not receiving sirolimus (n = 15). Both groups received mycophenolate mofetil, prednisone and antibody induction. Apoptosis was assessed using terminal deoxynucleodidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Caspase-3, Bcl-2, and mTOR expression were assessed by immunohistochemistry. Sirolimus treated patients had 334+/-69 TUNEL positive cells per 5 high power fields compared to 5.5+/-2.9 TUNEL positive cells in control patients (p<0.001). The number of TUNEL positive cells correlated with tubular architectural disruption. Expression of activated caspase-3, Bcl-2, or activated mTOR did not differ between groups. 60% of biopsies from sirolimus treated patients compared to 7% of biopsies from controls showed diffuse podocyte apoptosis (p = 0.007). There was no podocyte expression of activated mTOR, activated caspase-3, or Bcl-2 in either group. These data suggest that DGF patients treated with sirolimus have increased renal tubular cell apoptosis and podocyte apoptosis.

Topics: Adult; Apoptosis; Biopsy; Caspase 3; Delayed Graft Function; Drug Therapy, Combination; Epithelial Cells; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; In Situ Nick-End Labeling; Intracellular Signaling Peptides and Proteins; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Mycophenolic Acid; Podocytes; Prednisone; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome

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

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

Sirolimus has been considered to be a non-nephrotoxic agent. It may delay graft function due to a potential hindrance of the recovery from acute tubular necrosis. It remains controversial as to whether the concomitant administration of sirolimus (SRL) with calcineurin inhibitors delays graft function in Asian patients.. This study enrolled 61 patients who received primary renal transplantation. Twenty-one patients aged 38.9 +/- 11 years received early treatment with 6 mg/day sirolimus, 8 mg/kg/day cyclosporine (CsA) and prednisolone (SRL group). Forty patients with a mean age of 36.7 +/- 9 years in the control group were treated with the standard immunosuppressive therapy (8 mg/kg/day CsA, mycophonolate mofetil and prednisolone).. The creatinine level at one week following transplantation in the SRL group was not significantly different from that in the control group (4.7 +/- 1.0 versus 2.7 +/- 0.4 mg/dL, p = 0.17). Similarly, there was no significant difference in the creatinine level at week 2 (3.4 +/- 0.7 versus 2.7 +/- 0.3 mg/dL, p = 0.36), week 3 (2.0 +/- 0.3 versus 2.1 +/- 0.2 mg/dL, p = 0.76), and week 4 (1.8 +/- 0.2 versus 1.8+/-0.1 mg/dL, p = 0.92) between SRL and control groups, respectively. Similarly, the number of the patients with renal function impairment in both groups was not significantly different. The one-year patient and graft survival was 100% and 96%, respectively, in the SRL group and 100% and 98%, respectively, in the control group.. The combination of sirolimus and cyclosporine did not prolong the recovery from transplantation-associated ischemic injury in kidney graft recipient. Our study demonstrated the safety of early usage of the concomitant administration of sirolimus and cyclosporine in kidney transplantation.

Topics: Adult; Cyclosporine; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Sirolimus

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.

Topics: Adult; Biopsy; Creatinine; Delayed Graft Function; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus