sirolimus and Renal-Insufficiency

Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.

Topics: Abatacept; Calcineurin Inhibitors; Everolimus; Humans; Immunoconjugates; Immunosuppression Therapy; Liver Transplantation; Mycophenolic Acid; Precision Medicine; Pyrroles; Quinazolines; Renal Insufficiency; Risk Factors; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin inhibitor everolimus (Zortress®, Certican®) was recently approved in the USA and a number of EU countries for use in combination with a reduced dosage of tacrolimus and corticosteroids for the prophylaxis of organ rejection in adult liver transplant recipients. Compared with standard-exposure tacrolimus, early use of everolimus plus a reduced dosage of tacrolimus did not compromise efficacy in liver transplant recipients. In addition, significantly better renal function with everolimus plus reduced-exposure tacrolimus than with standard-exposure tacrolimus was seen from 6 weeks post-transplant onwards. Everolimus plus reduced-exposure tacrolimus has an acceptable tolerability profile in liver transplant recipients.

Topics: Adrenal Cortex Hormones; Adult; Allografts; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Renal Insufficiency; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Topics: Abatacept; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Desensitization, Immunologic; Graft Rejection; Hand Disinfection; Heart Failure; HLA Antigens; Humans; Immunoconjugates; Immunomodulation; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mesenchymal Stem Cell Transplantation; Opportunistic Infections; Peritoneal Dialysis; Plasmapheresis; Postoperative Complications; Prognosis; Renal Dialysis; Renal Insufficiency; Sirolimus; Skin Neoplasms

Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs.. The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia.. We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient's natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost-effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results.. Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one.. This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained.

Topics: Clinical Trials as Topic; Colombia; Cost-Benefit Analysis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Markov Chains; Registries; Renal Insufficiency; Sirolimus; Tacrolimus; Treatment Outcome

Sirolimus is used in patients with renal insufficiency after liver transplantation (LT) and especially in those with calcineurin inhibitor (CNI)-associated nephrotoxicity. We conducted a systematic review of all randomized controlled trials and observational studies to test the hypothesis that the use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency [glomerular filtration rate (GFR) < 60 mL/minute or creatinine level ≥ 1.5 mg/dL]. We performed a search of all major databases, conference proceedings, and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was used to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus-based therapy at 1 year. Eleven studies (three randomized controlled trials and eight observational studies) met the final inclusion criteria. A nonsignificant improvement of 3.38 mL/minute [95% confidence interval (CI) = -2.93 to 9.69] was observed in methodologically sound observational studies and controlled trials reporting the primary outcome. In controlled trials, baseline GFR >50 mL/min sirolimus use was associated with an improvement of 10.35 mL/minute (95% CI = 3.98-16.77) in GFR or creatinine clearance. Sirolimus was not significantly associated with death [relative risk (RR) = 1.12, 95% CI = 0.66-1.88] or graft failure (RR = 0.80, 95% CI = 0.45-1.41), although reporting was incomplete. It was associated with a statistically significant risk of infection (RR = 2.47, 95% CI = 1.14-5.36), rash (RR = 7.57, 95% CI = 1.75-32.70), ulcers (RR = 7.44, 95% CI = 2.03-27.28), and discontinuation of therapy (RR = 3.61, 95% CI = 1.32-9.89).. Conversion to sirolimus from CNIs is associated with a nonsignificant improvement in renal function in LT recipients with renal insufficiency, although the results are limited by heterogeneity, a risk of bias, and a lack of standardized reporting.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Transplantation; Randomized Controlled Trials as Topic; Renal Insufficiency; Sirolimus; Treatment Outcome

Treatment of patients with advanced renal cell carcinoma (RCC) has changed dramatically with the advent of targeted therapeutics. Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has proven beneficial in the treatment of advanced RCC with poor prognosis. The rationale for mTOR inhibitors in treatment of RCC, the pharmacokinetics and toxicities of temsirolimus, landmark clinical trials of temsirolimus in advanced RCC, and the indications for its use in the treatment of RCC are reviewed here. The status of temsirolimus in the rapidly evolving therapeutic landscape of advanced RCC is also discussed.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Interactions; Humans; Intracellular Signaling Peptides and Proteins; Liver Failure; Liver Neoplasms; Protein Serine-Threonine Kinases; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

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

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

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

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

Lung and heart transplantation has become an accepted therapeutic option for patients with end-stage disease. However, the calcineurin-inhibitor-based immunosuppression often causes renal impairment. Therefore, sirolimus, a novel immunosuppressive agent, may serve as an alternative or complementary agent to calcineurin inhibitors. The aim of this review was to summarize the role of sirolimus in lung and heart transplantation. Although only a few, small studies have been conducted so far, the drug's mechanisms of action and low-toxicity profile make it a highly promising option.

Topics: Drug Monitoring; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Renal Insufficiency; Sirolimus

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency; Sirolimus; Tacrolimus

In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0) ml/min with everolimus versus -1.7 (15.4) ml/min in controls (P = 0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5) ml/min with everolimus (n = 37) but decreased by 1.4 (14.7) ml/min in controls (n = 62) (P = 0.001). During months 12-36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection (BPAR). Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression. Donor-specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (P = 0.281). During months 12-36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued.

Topics: Adult; Aged; Biopsy; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Fibrosis; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Treatment Outcome

This study evaluated the safety and efficacy of a sirolimus, corticosteroid, and cyclosporine reduction regimen in an open-label, 12-month trial of 420 de novo renal allograft recipients at 49 European transplant centers. One month post-transplantation, 357 patients were randomized to receive standard-dose cyclosporine (sCsA, n = 179) or reduced-dose cyclosporine (rCsA, n = 178). All patients also received sirolimus and corticosteroids. The primary end points were the rate of biopsy-confirmed acute rejection (BCAR) and renal function, as measured by serum creatinine. Baseline demographic and donor characteristics were similar between groups. BCAR rates at 12 months were not significantly different: 11.2% for rCsA patients and 16.2% for sCsA patients. Mean serum creatinine (±SEM) was significantly lower (1.75 ± 0.10 vs. 1.97 ± 0.07 mg/dl, P < 0.001), and creatinine clearance (±SEM; Nankivell method) was significantly higher (57.8 ± 1.78 vs. 49.5 ± 2.46 ml/min, P < 0.001) in patients receiving rCsA versus sCsA at 1 year, respectively. Patient and graft survival exceeded 98% in both groups. No significant differences in infection or malignancy were noted between groups. The rCsA with sirolimus and corticosteroid regimen resulted in excellent 12-month patient and graft survival, a low incidence of BCAR, and improved renal function in renal allograft recipients. Sirolimus administered with rCsA and corticosteroids provided adequate immunosuppression while reducing the potential for the nephrotoxic effects of cyclosporine. These findings may help to improve long-term renal allograft outcomes.

Topics: Adrenal Cortex Hormones; Adult; Aged; Biopsy; Creatinine; Cyclosporine; Europe; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Time Factors; Treatment Outcome

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.

Topics: Adult; Calcineurin Inhibitors; Drug Synergism; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Republic of Korea; Severity of Illness Index; Sirolimus; Transplantation Tolerance; Treatment Outcome

Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 ± 25.3 vs. 70.7 ± 25.1, p = 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-to-creatinine ratio (0.36 ± 0.69 vs. 0.15 ± 0.53, p = 0.03) and higher incidence of treated acute rejection between months 3-24 (13.4% vs. 4.7%, p = 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.

Topics: Adult; Biopsy; Creatinine; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Renal Insufficiency; Sirolimus; Tacrolimus; Treatment Outcome

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure.. This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance.. In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period.. Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Topics: Adaptor Proteins, Signal Transducing; Aged; Cyclosporine; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Scandinavian and Nordic Countries; Sirolimus; Tacrolimus; Time Factors

We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥ 3 (estimated glomerular filtration rate < 60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Dyslipidemias; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus

Patients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free "bottom-up" regimens in patients with impaired renal function undergoing liver transplantation. This is a single-center study pilot-study (PATRON07) investigating safety and efficacy of CNI-free, "bottom-up" immunosuppressive (IS) strategy in patients undergoing liver transplantation (LT) with renal impairment prior to LT.. Patients older than 18 years with renal impairment at the time of liver transplantation eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients in will receive a CNI-free combination therapy (basiliximab, MMF, steroids and delayed Sirolimus). Primary endpoint is the incidence of steroid resistant acute rejection within the first 30 days after LT. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step, 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary endpoint the regimen is regarded to be safe and efficient.. If a CNI-free-"bottom-up" IS strategy is safe and effective, this may be an innovative concept in contrast to classic top-down strategies that could improve the patient short and long-time renal function as well as overall complications and survival after LT. The results of PATRON07 may be the basis for a large multicenter RCT investigating the new "bottom-up" immunosuppressive strategy in patients with poor renal function prior to LT.http://www.clinicaltrials.gov-identifier: NCT00604357.

Topics: Antibodies, Monoclonal; Basiliximab; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Patient Selection; Pilot Projects; Recombinant Fusion Proteins; Renal Insufficiency; Research Design; Sirolimus; Steroids; Treatment Outcome

Whether drug-eluting stents are effective and safe in patients with moderate renal insufficiency (RI) is unknown. We performed a pooled analysis of data from 3 blinded randomized trials of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs; SIRIUS, C-SIRIUS, E-SIRIUS) that included 1,510 patients. Clinical and angiographic outcomes were stratified by the presence of RI defined by creatinine clearance calculated by the Cockcroft-Gault formula (normal ≥ 90, mild 60 to 89, moderate < 60 ml/min). Patients with baseline creatinine > 3.0 mg/dl were excluded from these trials. Baseline mild RI was present in 517 patients (34.7%, mean creatinine clearance 75.7 ml/min) and moderate RI in 228 patients (15.3%, mean creatinine clearance 47.2 ml/min). Treatment with SESs resulted in lower rates of 8-month angiographic restenosis rates in patients with RI (mild RI 6.7% vs 42.6%, p < 0.001; moderate RI 9.7% vs 39.7%, p < 0.001) and without baseline RI (7.7% vs 37.2%, p < 0.001). One-year target vessel revascularization rates were similarly decreased with SESs in patients with (mild RI 4.7% vs 24.2%, p < 0.001; moderate RI 5.5% vs 26.9%, p < 0.001) and without (8.1% vs 22.4%, p < 0.001) RI, and this benefit was maintained at 5 years. Compared to patients with normal or mild RI, patients with moderate RI had higher rates of overall mortality and cardiac death at 1 year and 5 years (death 2.6% vs 0.6%, p <0.01, and 17.5% vs 6.3%, p < 0.01, at 1 year and 5 years, respectively; cardiac death 1.3% vs 0.2%, p = 0.05, and 6.6% vs 3.4%, p = 0.04, at 1 year and 5 years, respectively). However, there was no differential effect of SESs versus BMSs on any safety end point. In conclusion, patients with moderate RI have a nearly threefold increase in 5-year mortality after percutaneous coronary intervention compared to patients without RI. The effectiveness of SESs in decreasing restenosis compared to BMSs in patients with moderate RI was preserved and rates of death and myocardial infarction were not adversely affected.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Restenosis; Double-Blind Method; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Severity of Illness Index; Sirolimus; Stents

The RIFT study aimed to observe the impact of renal insufficiency (RI) on the incidence of stent thrombosis (ST) after percutaneous coronary intervention.. The RIFT study enrolled 1,174 patients undergoing revascularization exclusively with sirolimus-eluting stents. The occurrence of ST and major adverse cardiac events were compared between patients with (n = 309) and without (n = 865) RI, and independent predictors of ST were also identified.. During follow-up (mean 18.9 +/- 9.2 months), the rate of ST was significantly higher in patients with than without RI [5.5% (n = 17) vs. 1.7% (n = 15), p < 0.001], and the presence of severe RI (estimated glomerular filtration rate <30 ml/min.1.73 m(2)) was an independent predictor of ST (odds ratio = 4.5, 95% confidence interval 1.4-15, p = 0.011). In patients with RI and diabetes or left ventricular ejection fraction (LVEF) <50%, the incidence of ST was significantly increased [13.0% (n = 10) vs. 3.6% (n = 7), p = 0.010; 11.6% (n = 8) vs. 1.9% (n = 3), p = 0.004, respectively] compared to those with diabetes or LVEF <50% alone. The influence of RI on ST was not significant in patients with multivessel disease, calcified or bifurcation lesions, and target lesion revascularization.. These findings substantiate the importance of long-term antiplatelet therapy for patients with RI after drug-eluting stent implantation.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Disease-Free Survival; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Platelet Aggregation Inhibitors; Predictive Value of Tests; Prospective Studies; Renal Insufficiency; Risk Factors; Severity of Illness Index; Sirolimus; Thrombosis

To evaluate the patency of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) in the treatment of atherosclerotic renal artery stenosis (RAS).. Between November 2001 to June 2003, 105 consecutive symptomatic patients (53 men; mean age 65.7 years) with RAS were treated with either a bare-metal (n=52) or a drug-eluting (n=53) low-profile Palmaz-Genesis peripheral stent at 11 centers in a prospective nonrandomized trial. The primary endpoint was the angiographic result at 6 months measured with quantitative vessel analysis by an independent core laboratory. Secondary endpoints were technical and procedural success, clinical patency [no target lesion revascularization (TLR)], blood pressure and antihypertensive drug use, worsening of renal function, and no major adverse events at 1, 6, 12, and 24 months.. At 6 months, the overall in-stent diameter stenosis for BMS was 23.9%+/-22.9% versus 18.7%+/-15.6% for SES (p=0.39). The binary restenosis rate was 6.7% for SES versus 14.6% for the BMS (p=0.30). After 6 months and 1 year, TLR rate was 7.7% and 11.5%, respectively, in the BMS group versus 1.9% at both time points in the SES group (p=0.21). This rate remained stable up to the 2-year follow-up but did not reach significance due to the small sample. Even as early as 6 months, both types of stents significantly improved blood pressure and reduced antihypertensive medication compared to baseline (p<0.01). After 6 months, renal function worsened in 4.6% of the BMS patients and in 6.9% of the SES group. The rate of major adverse events was 23.7% for the BMS group and 26.8% for the SES at 2 years (p=0.80).. The angiographic outcome at 6 months did not show a significant difference between BMS and SES. Renal artery stenting with both stents significantly improved blood pressure. Future studies with a larger patient population and longer angiographic follow-up are warranted to determine if there is a significant benefit of drug-eluting stents in treating ostial renal artery stenosis.

Topics: Aged; Angioplasty, Balloon; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Europe; Female; Follow-Up Studies; Humans; Hypertension; Kidney Function Tests; Male; Metals; Middle Aged; Prospective Studies; Prosthesis Design; Radiography; Recurrence; Renal Artery; Renal Artery Obstruction; Renal Insufficiency; Research Design; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

The aim was to evaluate feasibility and safety of calcineurin inhibitor-free immunosuppression in high-risk donor kidney transplantation with sequential sirolimus introduction. Kidney transplant patients (n=76) with a donor aged >60 years, donor with acute renal failure, or a nonheartbeating donor were included. Immunosuppression consisted of antithymocyte globulin or basiliximab, mycophenolate mofetil, prednisone, and sequential introduction of sirolimus. One-year patient survival was 96.2% and 95.8%; graft survival was 94.2% and 91.7%; acute rejection rates were 21.2% and 12.4%; delayed graft function was 21.2% and 66.7%; and creatinine clearance was 58+/-20 mL/min and 56+/-21 mL/min for the brain-dead donor group and the nonheartbeating donor group, respectively. Most adverse events were infections, but also three lymphoceles, three urinary fistulas, three wound seromas. Sequential sirolimus introduction in high-risk donor kidney transplantation was found to lead to good patient and graft survival and incidence of acute rejection and delayed graft function.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisone; Recombinant Fusion Proteins; Renal Insufficiency; Risk Factors; Sirolimus

This pilot study was designed to evaluate the safety and efficacy of converting from a calcineurin inhibitor (CI) to a sirolimus (SRL)-based regimen in established renal transplant recipients with moderate renal insufficiency. Sixty renal transplant recipients on CI-based immuno-suppression with a serum creatinine (SCr) between 159 and 265 microM (1.8 and 3.0 mg/dL) and a glomerular filtration rate (GFR) between 30 and 70 mL/min were enrolled. SRL dosing was dependent upon concomitant immunosuppressive therapy. The mean patient age was 45 yr and the mean time from transplant to study enrollment was 60.8 months (range: 7-198). The median SCr was 168 microM (1.9 mg/dL) and the median GFR was 51 mL/min. Twelve months after conversion the patient and graft survival rates were 96.7% and 95%, respectively. The incidence of biopsy-proven acute rejection was 3.3% (two cases reported, Banff grades IA and IB). The median SCr and median creatinine clearance were 168 microM (1.9 mg/dL) and 53 mL/min, respectively. Hyperlipidemia, diarrhea, peripheral edema, rash, and anemia were the most commonly reported adverse events. Patients with moderate renal insufficiency can be converted from CI to SRL-based therapy and maintain renal function over a 1-yr period.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Renal Insufficiency; Sirolimus; Survival Analysis; Tacrolimus; Treatment Outcome

This study evaluates sirolimus in preserving renal function in 28 patients who developed renal insufficiency after liver transplantation. Patients with a creatinine level higher than 1.8 mg/ml were eligible for conversion. Of the 28 patients, 7 (25%) did not tolerate sirolimus, 6 (21%) progressed to end-stage renal disease (ESRD), and 14 (50%) have been maintained on sirolimus with stable renal function. The 28 patients overall had a decline in creatinine of 0.38 mg/dl (P = 0.029) at week 4, with a small increase by week 24. However, the subset of 14 patients who did not develop ESRD had a decline in creatinine that persisted to week 48. While the differences between those who developed ESRD and those with stable renal function were not statistically significant, the patients who developed ESRD had a higher creatinine at conversion (2.8 vs 2.3) and a lower creatinine clearance (36 vs 53 ml/min). Patients receiving sirolimus had a persistent rise in cholesterol (P < 0.05). The use of sirolimus to preserve renal function was limited by patients unable to tolerate drug- (25%) and patients who developed ESRD (21%). A subgroup of patients (50%) had an improvement in creatinine that persisted for 48 weeks.

Topics: Calcineurin; Calcineurin Inhibitors; Creatinine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Time Factors; Treatment Outcome

Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients. Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54+/-10 years; 4.3+/-2.3 years after transplantation) with severe disease.. At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (n=22) versus continued current immunosuppression (n=24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a >25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689+/-261; control, 630+/-207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (P<0.001). There was no difference in baseline or subsequent anti-HLA class I or II antibody production.. In this patient cohort with cardiac vasculopathy, treatment with rapamycin slowed disease progression probably by its antiproliferative and antimigratory effects.

Topics: Arterial Occlusive Diseases; Autoantibodies; Cardiac Catheterization; Cohort Studies; Coronary Artery Disease; Cyclosporine; Disease Progression; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Neoplasms; Prospective Studies; Renal Insufficiency; Sirolimus; Survival Analysis; Treatment Outcome

Renal allograft recipients generally need to take several immunosuppressive agents for life. Calcineurin inhibitors and glucocorticosteroids are the mainstays of most regimens but have undesirable chronic effects. We postulated that aggressive T-cell depletion combined with the newer immunosuppressant sirolimus would permit transplantation without multidrug treatment. We therefore tested T-cell depletion with rabbit antithymocyte globulin followed by sirolimus monotherapy in 12 patients in an open-label study. This approach was tolerated well, and all patients achieved excellent renal function, and most did not need chronic steroid treatment or calcineurin inhibitors. Rejection was typically correlated with low concentrations of sirolimus, indicating continued dependence on maintenance immunosuppression.

Topics: Adult; Animals; Antilymphocyte Serum; Creatinine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Period; Rabbits; Renal Insufficiency; Sirolimus

For patients with pure red cell aplasia (PRCA), cyclosporine (CsA) is the first line therapy. Occasionally, some patients who suffer from renal insufficiency cannot tolerate CsA. To explore the efficacy and tolerance of sirolimus treatment for those patients, twelve PRCA patients with renal insufficiency from May 2014 to May 2018 in Peking Union Medical College Hospital were enrolled, treated with sirolimus, and followed up at the median time of 16 (10-50) months. Eleven patients (91.7%) responded to sirolimus, with 58.3% complete response (CR) and 41.7% partial response (PR). The median time to achieve the optimum effect was 4 (1-7) months. The serum creatinine level remained stable or even reduced during the treatment period for eleven patients. Seven patients (58.3%) reported adverse events during sirolimus therapy, including increased blood glucose, infection, skin rash, elevated triglyceride or total cholesterol, and elevated serum creatinine compared with baseline. No treatment-related death was noticed during the follow-up time. Three patients relapsed with an overall response rate of 75.0% at 1 year. These results suggested that sirolimus was effective and tolerable for patients with PRCA complicated with renal insufficiency.

Topics: Adult; Aged; Aged, 80 and over; Creatinine; Cyclosporine; Drug Eruptions; Drug Evaluation; Drug Substitution; Female; Humans; Hyperglycemia; Hypertriglyceridemia; Immunosuppressive Agents; Male; Middle Aged; Recurrence; Red-Cell Aplasia, Pure; Remission Induction; Renal Insufficiency; Retrospective Studies; Sirolimus; Treatment Outcome

Patients with chronic kidney disease (CKD are frequently excluded from coronary artery disease trials. The aim of this assessment was to study the clinical outcomes of polymer-free sirolimus-eluting stent implantations in patients with impaired renal function.Large-scale, international, single-armed, multicenter, 'all comers' observational studies (ClinicalTrials.gov Identifier: NCT02629575 and NCT02905214) were used for this post-hoc subgroup analysis to compare the clinical outcomes in patients with normal renal function (NRF) to those with renal insufficiency (CKD, dialysis dependence). The accumulated target lesion revascularization rate was the primary endpoint at 9 to 12 months whereas the accumulated major adverse cardiac event, stent thrombosis (ST) and procedural success rates were part of the secondary endpoints.There were 6791 patients with NRF, whereas 369 patients had CKD and 83 patients were dialysis dependent. The target lesion revascularization rate at 9 to 12 months was significantly higher in dialysis patients (2.1% vs 3.3% vs 6.7%, P = .011). The accumulated major adverse cardiac events rates in the dialysis and in the CKD group were significantly higher as compared to patients with NRF (13.3% vs 4.0%, P < .001; 6.5% vs 4.0%, P = .024). Finally, ST rates (NRF: 0.7%, CKD: 0.6%, dialysis: 1.3%) were not statistically different between subgroups (P = .768). All-cause cumulative mortality rates were 3.3% (CKD) and 4.0% (dialysis) respectively.Percutaneous coronary interventions with polymer-free, ultra-thin strut sirolimus-eluting stents have comparable revascularization rates in CKD and dialysis dependent patients as compared to percutaneous coronary interventions with other 2nd generation drug-eluting stents. ST and all-cause mortality rates were low as compared to available literature references.

Topics: Aged; Asia; Coronary Artery Disease; Drug-Eluting Stents; Europe; Female; Humans; Male; Prosthesis Design; Renal Insufficiency; Sirolimus; Treatment Outcome

The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population.. Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin-eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0-3).. The ratio of covered struts and mean fibrin area of 2nd DES were 0.69±0.05 and 658.0±173.4μm. Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation.

Topics: Aged; Aneurysm, Ruptured; Colitis, Ischemic; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Fibrin; Heart Failure; Humans; Inflammation; Japan; Male; Middle Aged; Neointima; Pancreatitis; Pneumonia; Renal Insufficiency; Risk Factors; Sepsis; Sirolimus; Treatment Outcome

Renal failure causes morbidity and mortality after lung transplantation and is aggravated by exposure to nephrotoxic immunosuppressant (IS) drugs. We report an off-label experience using belatacept for lung transplant recipients with severe renal insufficiency to reduce nephrotoxic IS exposure. We analyzed data retrospectively from a consecutive series of lung transplant patients with renal insufficiency in whom belatacept treatment was initiated between June 2012 and June 2014 at the University of Maryland Medical Center. Eight patients received belatacept because of acute or chronic renal insufficiency (median) GFR 24 (IQR 18-26). Glomerular filtration rate (GFR) remained stable in two patients and increased in five. One patient with established renal and respiratory failure received only the induction dose of belatacept and died 4 months later of respiratory and multisystem organ failure. Calcineurin inhibitor or sirolimus exposure was safely withheld or reduced without moderate or severe acute rejection during ongoing belatacept in the other seven patients. FEV1 remained stable over the 6-month study interval. Belatacept use appears to permit safe transient reduction in conventional immunosuppressive therapy and was associated with stable or improved renal function in a small retrospective series of lung transplant recipients with acute or chronic renal insufficiency.

Topics: Abatacept; Aged; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Lung Diseases; Lung Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Sirolimus; Treatment Outcome

We evaluated the efficacy and toxicity of mammalian target rapamycin inhibitors in Korean patients with metastatic renal cell carcinoma (mRCC) with chronic renal insufficiency not requiring dialysis.. Korean patients with mRCC and chronic renal insufficiency not requiring dialysis treated with everolimus or temsirolimus between January 2008 and December 2014 were included. Patient characteristics, clinical outcomes, and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) durations were evaluated according to the degree of renal impairment.. Mammalian target rapamycin inhibitors were efficacious and did not increase toxicity in Korean patients with mRCC and chronic renal insufficiency not requiring dialysis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neoplasm Metastasis; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Mammalian target of rapamycin inhibitors (mTORi) prevents cytomegalovirus (CMV) infection in kidney transplant (KT) patients. From May 2010 to December 2013, all KT recipients were retrospectively analysed. Maintenance immunosuppression regimen was divided into mTORi or calcineurin inhibitors (CNI)-based regimen. Since June 2011, CMV-seropositive recipients (R+) treated with high-intensity immunosuppression and mTORi did not receive anti-CMV prophylaxis. We analysed 350 consecutive patients, of which 95 (27%) received mTORi and 255 (73%) CNI-based immunosuppression. A Cox-regression multivariate analysis showed that the use of mTORi-based immunosuppression during all follow-up reduced the risk of CMV infection (HR 0.36, 95% CI 0.15-0.89, P = 0.028) and confirmed in a propensity score-matched cohort (HR 0.4, 95% CI 0.1-0.9, P = 0.047). Early discontinuation of mTORi increased the risk of CMV infection (HR 3.2; 95% CI 1.7-6.0) in univariate analysis. The incidence of CMV infection was not higher among CMV R+ patients on mTORi and requiring high-intensity immunosuppression when CMV prophylaxis was not given. The use of mTORi protected for CMV infection in KT patients, allowing to avoid antiviral prophylaxis for R+ patients receiving high-intensity immunosuppression. The increased risk of CMV infection after early discontinuation of mTORi warrants further research.

Topics: Adult; Aged; Antilymphocyte Serum; Calcineurin Inhibitors; Cytomegalovirus Infections; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Propensity Score; Proportional Hazards Models; Renal Insufficiency; Retrospective Studies; Risk; Sirolimus; Spain; TOR Serine-Threonine Kinases

We examined integrated national transplant registry, pharmacy fill, and medical claims data for Medicare-insured kidney transplant recipients in 2000-2011 (n = 45 164) from the United States Renal Data System to assess the efficacy and safety endpoints associated with seven early (first 90 days) immunosuppression (ISx) regimens. Risks of clinical complications over 3 years according to IS regimens were assessed with multivariate regression analysis, including the adjustment for covariates and propensity for receipt of a nonreference ISx regimen. Compared with the reference ISx (thymoglobulin induction with tacrolimus, mycophenolate, and prednisone maintenance), sirolimus-based ISx was associated with significantly higher three-year risks of pneumonia (adjusted hazard ratio, aHR 1.45; P < 0.0001), sepsis (aHR 1.40; P < 0.0001), diabetes (aHR 1.21; P < 0.0001), acute rejection (AR; adjusted odds ratio, aOR 1.33; P < 0.0001), graft failure (aHR 1.78; P < 0.0001), and patient death (aHR 1.40; P < 0.0001), but reduced skin cancer risk (aHR 0.71; P < 0.001). Cyclosporine-based IS was associated with increased risks of pneumonia (aHR 1.17; P < 0.001), sepsis (aHR 1.16; P < 0.001), AR (aOR 1.43; P < 0.001), and graft failure (aHR 1.39; P < 0.001), but less diabetes (aHR 0.83; P < 0.001). Steroid-free ISx was associated with the reduced risk of pneumonia (aHR 0.89; P = 0.002), sepsis (aHR 0.80; P < 0.001), and diabetes (aHR 0.77; P < 0.001), but higher graft failure (aHR 1.35; P < 0.001). Impacts of ISx over time warrant further study to better guide ISx tailoring to balance the efficacy and morbidity.

Topics: Adolescent; Adult; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Pneumonia; Renal Insufficiency; Risk; Sepsis; Sirolimus; Tacrolimus; United States; Young Adult

Renal insufficiency (RI) is an independent risk factor for the adverse cardiovascular events. Long-term clinical outcome of percutaneous coronary intervention (PCI) in patients with RI is unknown especially in the era of first generation drug-eluting stents (DES). This study aims at comparing clinical outcomes between sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) based on large scaled registry.. Patients who underwent PCI with DES from January 2004 to December 2009 in the Catholic University of Korea-PCI (COACT) registry were prospectively enrolled. A group of 1,033 patients with RI, defined as estimated glomerular filtration rate under 60 mL/min, were analyzed. Major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR) according to the type of stents were compared.. Median follow-up period was 810 days (interquartile range: from 361 to 1,354 days). A group of 612 (59.2%) patients were treated with SES and 421 (40.8%) patients were treated with PES. The PES vs. SES group had significantly higher rate of MACE (35.9% vs. 28.3%, p = 0.01). In multivariate Cox hazard regression analysis, PES vs. SES group had significantly higher rate of MACE (adjusted hazard ratio [AHR] 1.29, 95% confidence interval [CI] 1.02-1.64, p = 0.033), particularly pronounced by all-cause death (AHR 1.34, 95% CI 1.008-1.770; p = 0.044). In further analysis with propensity score matching, overall findings were consistent.. In patients with RI, PCI using PES provides poorer clinical outcomes than SES in terms of MACE and all-cause death.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Prosthesis Design; Registries; Renal Insufficiency; Republic of Korea; Risk Factors; Sirolimus; Survival Rate; Time Factors

The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus.. To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis.. A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%).. Patients switched to sirolimus had improved survival (P < 0.001) and slower progression to cirrhosis (P = 0.001). In patients with HCC (n = 91), sirolimus duration rather than strategy was an independent predictor of survival (P = 0.001) and extended time to HCC recurrence (33 vs. 16 months). Patients switched for renal dysfunction showed improvement in serum creatinine (140-108 μmol/L, P = 0.001). Those remaining on CNI-therapy were more likely to develop post-transplant diabetes (P = 0.03).. These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome.

Topics: Adult; Aged; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Comorbidity; Disease Progression; Female; Hepacivirus; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Sirolimus

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

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

Angiomyolipoma (AML) is a benign mesenchymal tumor composed of blood vessels, smooth muscle, and mature adipose tissue. AMLs in the kidney allografts are rare. We report a case of AML that was incidentally found 1 year after transplantation. Abdominal computed tomography showed a 4-cm renal tumor with contrast enhancement and an early washout pattern, resembling a renal cell carcinoma. Tumor biopsy proved a lipid-poor AML. Tumor diameter decreased to 2.4 cm after 6 months of treatment with sirolimus. Sirolimus not only reduces tumor size, but also benefits a transplant patient who needs immunosuppression.

Topics: Adult; Angiomyolipoma; Biopsy; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Nephrectomy; Renal Insufficiency; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i.. In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences.. Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07).. In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.

Topics: Aged; Calcineurin; Calcineurin Inhibitors; Cohort Studies; Drug Substitution; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases

Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.. The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.. We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.. Statistical analyses were performed using Cox regression and the Kaplan-Meier method.. We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively.. We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.. In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.

Topics: Aged; Antineoplastic Agents; Axitinib; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma, Renal Cell; Diphosphonates; Disease-Free Survival; Female; Humans; Hypocalcemia; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Niacinamide; Pamidronate; Phenylurea Compounds; Prognosis; Pyrroles; Renal Insufficiency; Retrospective Studies; Sirolimus; Sorafenib; Sunitinib; Survival Rate; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Zoledronic Acid

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.

Topics: Adult; Aged; Calcineurin Inhibitors; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Renal Insufficiency; Retrospective Studies; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

Topics: Female; Humans; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Risk Assessment; Sirolimus

Topics: Female; Humans; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Risk Assessment; Sirolimus

The development of de novo renal cell carcinoma (RCC) in a transplanted kidney is a rare condition. Currently, this is the second case report of a 41-year-old man in whom carcinoma of a renal allograft was detected by contrast-enhanced ultrasound (CEUS). An abdominal CT scan was not conclusive enough to differentiate between septal enhancement of a cyst and a low vascularized tumor. CEUS confirmed a solid, homogeneously enhancing but hypoechoic and hypovascular lesion compared to the surrounding kidney parenchyma without septal enhancement. Therefore, the patient underwent nephron-sparing surgery (NSS), affirming papillary RCC type 2. Graft function remained unchanged postoperatively; 12 months after NSS, no local recurrence or distant metastasis was described. CEUS seems to be a minimally invasive and efficient imaging option if other diagnostic tools cannot clearly exclude RCC, with the advantage of wide-ranging use, especially in cases of impaired renal function.

Topics: Adult; Carcinoma, Renal Cell; Contrast Media; Everolimus; Humans; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Neoplasm Metastasis; Nephrons; Postoperative Period; Recurrence; Renal Insufficiency; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Ultrasonography

Topics: Biopsy; Creatinine; Cyclosporine; Female; Humans; Hyperoxaluria, Primary; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Oxalates; Postoperative Complications; Renal Dialysis; Renal Insufficiency; Sirolimus; Transplantation, Homologous; Treatment Outcome

The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CNI dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CNI dosage in a dose-dependent manner (P < 0.001, r = -0.807). Neutrophil count increased significantly (P < 0.05) with a reduction in the dosage of MMF (P = 0.009, r = -0.671). Cytomegalovirus antigenemia remained negative after EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Dose-Response Relationship, Drug; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Middle Aged; Mycophenolic Acid; Practice Guidelines as Topic; Renal Insufficiency; Retrospective Studies; Sirolimus; Survival Rate; Time Factors; Treatment Outcome; Young Adult

Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity.. Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model.. The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups.. In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity.

Topics: Adult; Black or African American; Creatinine; Cyclosporine; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multicenter Studies as Topic; Mycophenolic Acid; Odds Ratio; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Assessment; Sirolimus; Treatment Outcome

Patients undergoing chronic hemodialysis (HD) are at high risk of restenosis and cardiac events after percutaneous coronary intervention (PCI). This study compared the clinical efficacy of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) in patients undergoing HD. Between June 2004 and January 2010, the clinical outcomes of 41 consecutive patients on HD who underwent PCI with SES (62 lesions) were compared with those of 38 consecutive patients on HD who underwent PCI with PES (54 lesions). Patient and lesion characteristics were similar between both groups. The target lesion revascularization (TLR) (SES 36.6 % vs. PES 15.8 %; P = 0.037) was significantly higher with SES (36.6 %) than with PES (15.8 %) (P = 0.037), particularly in the context of severe calcified lesions that required rotational atherectomy (SES 72.7 % vs. PES 16.7 %; P = 0.0067). However, 1 year after PCI, there was no difference between the two groups in all-cause death, myocardial infarction or major adverse cardiac events. Patients undergoing HD are at a high risk of restenosis after PCI, even when using a drug-eluting stent. The TLR was higher with SES than with PES, particularly when used for severe calcified lesions that required rotational atherectomy.

Topics: Aged; Aged, 80 and over; Coronary Angiography; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Renal Dialysis; Renal Insufficiency; Sirolimus; Treatment Outcome

Lymphangiogenesis occurs in renal allografts and it may be involved in the maintenance of the alloreactive immune response and thus participate in the development of chronic kidney allograft injury. Sirolimus (SRL) has been shown to inhibit lymphangiogenesis. The aim of this study was to describe lymphangiogenesis and its regulation during the development of chronic kidney allograft injury and to investigate the effect of SRL on allograft lymphangiogenesis and chronic kidney allograft injury. A rat renal transplantation model was used. Allografts treated with cyclosporine A or with SRL were analyzed in various time points. Syngenic transplantations were used as controls. Kidney function was followed with serum creatinine. Histology was analyzed by Chronic Allograft Damage Index (CADI). Immunohistochemistry was used to detect lymphatic vessels, VEGF-C and VEGFR-3. In cyclosporine-treated allografts VEGF-C/VEGFR-3 pathway was strongly upregulated leading to extensive lymphangiogenesis 60 days after transplantation. Lymphangiogenesis correlated positively with the CADI score. Sirolimus efficiently inhibited lymphangiogenesis, improved graft function and attenuated the development of chronic kidney allograft injury when compared with cyclosporine. In conclusion, lymphangiogenesis is associated with chronic kidney allograft injury and SRL is a potent inhibitor of lymphangiogenesis in renal allografts. Inhibition of lymphatic proliferation could mediate the nephroprotective properties of SRL.

Topics: Animals; Chronic Disease; Cyclosporine; Graft Rejection; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lymphangiogenesis; Male; Microscopy, Fluorescence; Rats; Rats, Wistar; Renal Insufficiency; Sirolimus; Time Factors; Transplantation, Homologous; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3

First-generation drug-eluting stents have been proven to be very effective for the treatment of bare-metal stent in-stent restenosis (BMS ISR). Efficacy of second-generation drug-eluting stents in this setting remains less well defined. This study compared 3-year clinical outcomes after treatment of BMS ISR using second-generation everolimus-eluting stents (EES) to first-generation paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES).. This was a retrospective observational study. A total of 264 consecutive patients with BMS ISR underwent percutaneous coronary intervention using EES (75 patients), PES (95 patients), or SES (94 patients) from 2003 to 2009. The primary endpoint of the study was survival free of major adverse cardiac events (MACE) at 3 years. Secondary endpoints were survival free of need for revascularization of the target lesion and definite stent thrombosis. Clinical follow-up could be obtained in 99% of patients.. Baseline clinical and angiographic parameters were comparable between the three groups. MACE at the 3-year follow-up were 27, 30, and 27%, for the EES, PES, and SES groups, respectively (P=0.874). The target lesion revascularization rates for EES, PES, and SES groups were 15, 20, and 23%, respectively (P=0.429). Rates of definite stent thrombosis at the 3-year follow-up were comparable between the three groups at 0, 2.1, and 1.0%, respectively (P=0.437). Rates of myocardial infarction and death were also similar between the three groups. Diabetes mellitus was the only independent predictor of MACE at the 3-year follow-up (odds ratio=1.14, 95% confidence interval 1.00-1.30; P=0.038), whereas renal insufficiency was the only independent predictor for death (odds ratio=1.10, 95% confidence interval 0.850-1.274; P=0.011).. Second-generation EES is as effective and safe as the first-generation PES or SES in the treatment of BMS ISR. Diabetes mellitus is the only independent predictor for MACE at the long-term follow-up.

Topics: Aged; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Diabetes Mellitus; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Myocardial Revascularization; Paclitaxel; Percutaneous Coronary Intervention; Renal Insufficiency; Retrospective Studies; Sirolimus; Stents

Chronic renal failure (CRF) is associated with increased cardiovascular mortality, and medial vascular smooth muscle cell (VSMC) hypertrophy, proliferation, and calcification play a pivotal role in uremic vasculopathy. Glucose transporter-1 (GLUT1) facilitates the transport of glucose into VSMCs, and GLUT1 overexpression associated with high glucose influx leads to a stimulation of VSMC proliferation. However, the role of GLUT1 in uremic vasculopathy remains unclear. This study aimed to identify changes in the expression of GLUT1 in VSMCs in the setting of experimental uremia and investigate whether Akt/tuberous sclerosis complex subunit 2 (TSC2)/mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (S6K) signaling, which plays a crucial role in VSMC proliferation and glucose metabolism, is involved in the regulation of GLUT1 expression.. In vivo experimental CRF was induced in Wistar rats by 5/6 nephrectomy, and the GLUT1 expression in aortic tissue was determined by the reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemical staining. Indoxyl sulfate (IS) is a uremic retention solute proven with pro-proliferative effect on rat VSMCs, and we further studied the expression of GLUT1 in rat A7r5 rat embryonic aortic cells stimulated by IS in the presence or absence of phloretin, a GLUT1 inhibitor, to explore the pathogenic role of GLUT1 in uremic vasculopathy. The contribution of Akt/TSC2/mTOR/S6K signaling in modifying the GLUT1 expression was also assessed.. Eight weeks after 5/6 nephrectomy, aortic tissue obtained from CRF rats exhibited increased wall thickness and VSMC hypertrophy, hyperplasia, and degeneration. Compared with the sham-operated control group, the messenger (m)RNA and protein abundance of GLUT1 were both markedly increased in CRF rats. In vitro, IS induced a significant increase in expression of GLUT1 protein as well as pro-proliferative cyclin D1 and p21 mRNA and a modest increase in expression of antiapoptotic p53 mRNA in A7r5 cells, whereas inhibition of GLUT1 mediated glucose influx reduced the pro-proliferative and antiapoptotic effects of IS. In addition to increased GLUT1 expression, IS significantly suppressed Akt and TSC2 phosphorylation after 6-hour and 12-hour treatment, but increased S6K phosphorylation after 3-hour treatment. Inactivation of mTOR downstream signaling by rapamycin treatment inhibited S6K phosphorylation and abolished the stimulatory effect of IS on GLUT1 expression.. In vivo and in vitro experimental CRF displayed prominent GLUT1 upregulation in VSMCs. The uremic toxin IS stimulated proliferation of VSMCs possibly through induction of GLUT1 expression. The Akt/TSC/mTOR/S6K signaling pathway may be one of the mechanisms underlying the upregulation of GLUT1 expression in uremic VSMCs.

Topics: Animals; Aorta; Apoptosis; Blotting, Western; Cell Line; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Glucose; Glucose Transporter Type 1; Hyperplasia; Hypertrophy; Immunohistochemistry; Indican; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Phloretin; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases; RNA, Messenger; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Uremia

It is unknown whether drug-eluting stents (DES), in comparison with bare-metal stents (BMS), improve clinical outcomes of ST-elevation myocardial infarction (STEMI) patients with renal insufficiency. We aimed to compare the clinical outcomes of BMS versus DES, as well as sirolimus-eluting stents (SES) versus paclitaxel-eluting stents (PES), in STEMI patients with renal insufficiency.. From the Korea Acute Myocardial Infarction Registry, 874 STEMI patients with renal insufficiency (glomerular filtration rate < 60 ml/min) comprising 116 patients with BMS and 758 patients with DES (430 SES and 328 PES) implantation were selected. Major adverse cardiac events (MACE) within 1 year, defined as composite of all-cause mortality, nonfatal myocardial infarction and target lesion revascularization were compared. In addition to multivariate adjusted analysis, propensity analysis for stent choice was performed.. With a median follow-up of 342 days, 116 MACE occurred. MACE was more frequent in the BMS group than in the DES group before (HR [95% CI]=2.3 [1.3-3.8]) and after propensity score matching (HR [95% CI]=2.0 [1.0-3.8]). The difference of MACE was mainly driven by a higher rate of target lesion revascularization rate in the BMS group. In comparison between SES and PES, there was no significant difference between the 2 groups in propensity score-matched populations (HR [95% CI]=0.7 [0.4-1.1]).. In STEMI patients with renal insufficiency, DES implantation exhibits a favorable 1 year clinical outcomes than BMS implantation, however, no difference was found between SES and PES.

Topics: Aged; Drug-Eluting Stents; Female; Humans; Male; Myocardial Infarction; Paclitaxel; Prospective Studies; Prosthesis Design; Registries; Renal Insufficiency; Republic of Korea; Sirolimus; Stents; Treatment Outcome

There is few information on the long-term efficacy and safety of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared to bare metal stents (BMS) in all-comer percutaneous coronary intervention (PCI)-patients complicated by renal insufficiency (RI).. Our aim was to assess the 6-year clinical outcome of PCI-patients with RI treated exclusively with BMS, SES, or PES in our academic hospital.. A total of 1382 patients, included in three cohorts of consecutive PCI-patients (BMS = 392; SES = 498; PES = 492), were categorized by creatinine clearance calculated by the Cockroft-Gault formula (normal kidney function ≥ 90; mild RI = 60-89; moderate RI < 60) and systematically followed for the occurrence of major adverse cardiac events (MACE).. Mortality rates were significantly higher for patients with moderate RI compared to mild RI and normal kidney function at 6 years (Kaplan-Meier estimate: moderate RI (34%) vs. mild RI (12%), P < 0.001; moderate RI (34%) vs. normal kidney function (8%), P < 0.001). After multivariate Cox-regression analysis, SES and PES decreased the occurrence of target-vessel revascularization (TVR) and MACE at 6 years in patients with a normal creatinine clearance compared to BMS [adjusted hazard ratio (aHR) = 0.48, 95% CI: 0.28-0.84; aHR = 0.75, 95% CI: 0.57-0.97, respectively] with no significant effect on mortality. Safety- and efficacy end points were comparable for the three stent types in patients with mild- and moderate renal function.. Patients with a normal creatinine clearance had significant improvement in TVR and MACE rates after SES- or PES implantation compared to BMS at 6 years. However, there was no superiority of both drug-eluting stents over BMS in safety and efficacy end points for patients with impaired renal function.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Chi-Square Distribution; Coronary Artery Disease; Creatinine; Drug-Eluting Stents; Female; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney; Male; Metals; Middle Aged; Multivariate Analysis; Netherlands; Paclitaxel; Patient Safety; Proportional Hazards Models; Prosthesis Design; Registries; Renal Insufficiency; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome

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

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

Renal impairment (RI) is a predictor of poor outcomes in patients with cardiovascular disease, but its influence in the setting of percutaneous coronary intervention and zotarolimus-eluting stent (ZES) implantation has not been described. This study evaluated the impact of RI on clinical outcomes in patients participating in the E-Five Registry.. E-Five was a prospective, multicenter, global registry of 8,314 patients; 2,116 patients were followed to 2 years.. Patients (excluding those who had undergone renal transplantation) were grouped according to renal function (normal function/mild RI, serum creatinine <110 μmol/L; moderate RI, 110-200 μmol/L; severe RI, >200 μmol/L) and their outcomes evaluated retrospectively. Major adverse cardiac events (MACE; i.e., death, myocardial infarction, emergency cardiac bypass surgery, or target lesion revascularization) and stent thrombosis events at 1 and 2 years were compared between groups.. The 1-year MACE rate in patients with mild RI was 6.8%, compared with 8.9 and 18.1% in patients with moderate and severe RI (P = 0.002 across groups). At 2 years, death occurred in 16% of those with severe RI, compared with 2.0 and 4.7% in those with mild and moderate RI (P = 0.002). There was no significant difference in the rates of target lesion revascularization or target vessel failure.. Greater severity of RI at intervention is associated with greater mortality and MACE but unchanged revascularization rates after ZES implantation.

Topics: Aged; Asia; Biomarkers; Cardiovascular Agents; Coronary Artery Bypass; Coronary Artery Disease; Coronary Thrombosis; Creatinine; Drug-Eluting Stents; Europe; Female; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney; Logistic Models; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Registries; Renal Insufficiency; Retrospective Studies; Risk Factors; Severity of Illness Index; Sirolimus; South America; Time Factors; Treatment Outcome

Life expectancy after pediatric renal transplantation remains lower than that of the normal population largely due to cardiovascular morbidity and mortality. Hyperlipidemia is a potentially modifiable risk factor for cardiovascular morbidity. Retrospective chart review of all available pediatric renal transplant patients (26) in a single center with assessment of anthropometry, renal function, steroid, calcineurin or mTOR inhibitor exposure and Ω3 FA supplementation. Eighteen transplant recipients without Ω3 FA supplementation served as control. Nutrition and supplement surveys were conducted with standardized questionnaires. Fasting cholesterol values were compared using the latest value prior to start of Ω3 FA and at last follow-up. Eight patients (five receiving mTOR inhibitor) started Ω3 FA supplementation at a mean dose of 29.2 ± 12 mg of EPA/kg and 16.1 ± 7.4 mg DHA/kg body weight. Median duration of treatment was 2.5 yr (range 0.8-5.9 yr) and their total fasting cholesterol at last follow-up dropped significantly from 5.08 ± 0.97 (control group 3.77 ± 0.81, p = 0.0084) to 4.17 ± 0.54 mm (p = 0.0158). High-density lipoprotein cholesterol increased not significantly from 1.74 ± 0.49 to 2.02 ± 0.93 mm. No patient had increased bleeding. Supplementation of omega-3 FAs may reduce hyperlipidaemia after pediatric renal transplantation.

Topics: Adolescent; Calcineurin Inhibitors; Child; Cholesterol; Diet; Fatty Acids, Omega-3; Female; Humans; Hyperlipidemias; Kidney Transplantation; Male; Prevalence; Renal Insufficiency; Retrospective Studies; Risk Factors; Sirolimus; Steroids

The use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function.. This prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion.. Ninety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04).. Despite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

Topics: Aged; Biomarkers; Calcineurin Inhibitors; Cause of Death; Creatinine; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Prospective Studies; Recovery of Function; Renal Insufficiency; Signal Transduction; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Female; Humans; Kidney; Male; Percutaneous Coronary Intervention; Renal Insufficiency; Sirolimus

To investigate the clinical outcomes of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in patients on dialysis.. Between May 2004 and December 2008, 95 patients on dialysis with 124 lesions were treated with PES alone, and were compared to 184 patients on dialysis with 244 lesions treated with SES alone, retrospectively. One-year major adverse cardiac event (MACE) including stent thrombosis, target lesion revascularisation (TLR), myocardial infarction (MI) and cardiac death were compared. Baseline characteristics were similar except for previous CABG (p = 0.02) and reference vessel diameter (p = 0.04). During hospitalisation, all cause death was more frequently observed in the PES group (p = 0.004). In-hospital MACE was not significantly different (p = 0.8). The incidence of 1-year MACE in the PES group was lower than that in the SES group (14.7%, 28.3%, p = 0.04), mainly due to the reduction of TLR (11.6%, 25.0%, p = 0.03). Rates of stent thrombosis (0%, 2.7%, p = 0.1), MI (1.1%, 3.8%, p = 0.2), and cardiac death (3.2%, 4.4%, p = 0.6) were not significantly different.. PES appears to be more efficient in reducing angiographic and clinical restenosis in dialysis patients compared with SES.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Hospital Mortality; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Proportional Hazards Models; Prosthesis Design; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Thrombosis; Time Factors; Treatment Outcome

Hemodialysis patients were recognized as a high-risk group for restenosis after percutaneous coronary intervention in the era of the bare-metal stent. Recently, sirolimus-eluting stents (SES) have reduced restenosis and target lesion revascularization (TLR); however, it has been reported that their efficacy in hemodialysis patients is limited. The purpose of this study was to investigate whether paclitaxel-eluting stents (PES) improved angiographic outcomes of hemodialysis patients compared with SES. This study is a retrospective cohort study. We analyzed 54 hemodialysis patients with 87 lesions implanted with PES from February 2007 to September 2008, and 49 hemodialysis patients with 68 lesions implanted with SES from August 2004 to January 2007. Angiographic follow-up after 8-10 months was obtained for 59 lesions (67.8%) in the PES group and 43 lesions (63.2%) in the SES group. At baseline, the PES patients had more peripheral artery disease compared with the SES group (66.7 vs. 34.7%; p = 0.0012). There were no significant differences in the angiographic characteristics or procedural index. The binary restenosis rate was lower in lesions implanted with PES than in those with SES (13.6 vs. 39.5%; p = 0.034). Accordingly, the TLR rate was lower in lesions implanted with PES than with SES (9.3 vs. 26.5%; p = 0.041). Our results suggest that PES is more effective than SES in reducing restenosis and TLR in hemodialysis patients.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Paclitaxel; Proportional Hazards Models; Prosthesis Design; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Sirolimus; Time Factors; Treatment Outcome

Experimental findings indicate that sirolimus (SRL) inhibits longitudinal growth by mechanisms potentially related to its inhibitory effects on both cell proliferation and expression of vascular endothelial growth factor (VEGF). The aim of this study was to investigate the growth pattern of kidney-transplanted children treated with SRL in a multicenter observational clinical study. Height, change in height SD (Δ height) and growth velocity of pediatric patients with renal transplant were calculated at 0, 6, 12, and 24 months after starting SRL. Controls of kidney-transplanted children not treated with SRL were matched by age, gender, renal function, and dose of corticosteroids. Sixty-eight children (34 SRL, 34 controls) were enrolled in the study. Nephrotoxicity was the most frequent indication to start therapy with SRL. SRL exerted an adverse effect on growth as demonstrated by significantly lower (p < 0.05) growth velocity (cm/year) and smaller change in height SD in the SRL group after 6 (4.08 vs. 6.56 and -0.05 vs. 0.14), 12 (4.44 vs. 6.11 and -0.03 vs. 0.28) and 24 (4.53 vs. 6.03 and -0.04 vs. 0.53) months of treatment. This study suggests that SRL therapy may interfere with growth of kidney-transplanted children. This undesirable effect needs to be taken into account when considering a switch to SRL and confirmed in further prospective trials including larger number of patients.

Topics: Child; Female; Graft Rejection; Growth Disorders; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Sirolimus; Transplantation, Homologous

CNI have improved the outcome of LT. However, their inherent potential to nephrotoxic and sometimes-inadequate immunosuppressive effect has lead to the usage of newer drugs like SRL. Aim of this study was to review children who received SRL. Thirty-seven (20 women) children post-LT, median age 10.4 yr (0.8-17.4) with a minimum follow-up of six months comprised the study group. Indications for SRL were biopsy-proven resistant acute allograft rejection (n = 12), early CR (n = 12), and CNI-induced nephropathy with MMF intolerance (n = 11). In two patients, the indication was the recurrence of BSEP disease in the allograft. In patients with acute rejection, AST normalized in 10/12 patients. In patients with CR, AST normalized in 6/12 patients. Those with renal impairment showed improvement in their creatinine levels from a mean baseline of 99-56.7 μm (p = 0.03) and their mean cystatin C was 1.02 after SRL. Side effects leading to discontinuation of SRL were seen in three patients. SRL was effective in rescuing patients with acute and chronic allograft rejection and improving renal function in CNI-induced nephropathy group.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Chronic Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immune System; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Pediatrics; Renal Insufficiency; Sirolimus; Treatment Outcome

Drug-eluting coronary stents (DES) have gained widespread use for the treatment of coronary artery disease. However, because of safety concerns and frequent "off-label" use data from "real life," registries are necessary to monitor indications and outcome of DES in daily clinical practice.. We evaluated data from the German Cypher Stent Registry. A total of 10,894 patients treated with at least one sirolimus-eluting stent (SES) at 152 hospitals were included. Follow-up at a median of 6.4 months was available in 10,006 patients (92%). Median age was 64.8 years and 75.5% were male. Per lesion a mean of 1.09 +/- 0.41 SES were implanted with a mean length of 21.1 +/- 11.5mm. During follow-up, death rate was 1.8% and the rates of myocardial infarction or stroke were 2.1% and 0.5%. Any target vessel revascularization (TVR) was performed in 8.0% of patients. Independent predictors for death, myocardial infarction, or stroke were: cardiogenic shock, acute coronary syndromes, reduced left ventricular function, renal insufficiency, diabetes mellitus, advanced age, three-vessel disease, degree of stenosis, and prior myocardial infarction. Predictors for a TVR were: two- or three-vessel disease, target vessel = coronary bypass, advanced age, stent diameter, ostial lesions, indication in-stent restenosis, renal failure, and target vessel = left anterior descended artery.. These results demonstrate that SES use in clinical practice is safe and effective. The main predictors of clinical events during follow-up are clinical parameters whereas as predictors of TVR mainly are angiographic parameters.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Confidence Intervals; Coronary Artery Bypass; Coronary Artery Disease; Coronary Stenosis; Diabetes Mellitus; Drug-Eluting Stents; Female; Germany; Humans; Immunosuppressive Agents; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Prospective Studies; Registries; Renal Insufficiency; Risk Factors; ROC Curve; Severity of Illness Index; Shock, Cardiogenic; Sirolimus; Stroke; Treatment Outcome; Ventricular Function, Left

No data are available comparing the long-term outcome of sirolimus-eluting stents (SESs) versus paclitaxel-eluting stents (PESs) in patients with moderate to severe renal insufficiency. The incidence of major adverse cardiac events (MACE), including death, myocardial infarction, and target vessel revascularization, during long-term follow-up were studied in patients with a glomerular filtration rate of <60 ml/min/1.73 m(2), as measured by the Modification of Diet in Renal Disease (MDRD) study equation, who also underwent percutaneous coronary intervention with drug-eluting stents. Of 428 patients studied, PESs were placed in 287 patients and SESs in 141 patients. Stepwise Cox regression analyses were performed to identify significant independent risk factors for MACE. At 47 + or - 19 months of follow-up, MACE had occurred in 49 (17%) of 287 patients in the PES group (mean age 71 + or - 11 years, 55% men) and in 31 (22%) of 141 patients in the SES group (mean age 71 + or - 12 years, 53% men). No significant difference was found in the MACE rate between the PES and SES groups. This persisted even after controlling for stent length, lesion complexity, and other co-morbidities. Also, all-cause mortality was not significantly different between the PES and SES groups (7.1% vs 8.5%, respectively). In conclusion, during long-term follow-up of patients with moderate to severe renal insufficiency, the rates of MACE and all-cause mortality were similar in the PES and SES groups.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Renal Insufficiency; Retrospective Studies; Sirolimus

Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation.. The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up.. The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

Topics: Aged; Calcineurin Inhibitors; Creatinine; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Patient Selection; Renal Insufficiency; Reoperation; Retrospective Studies; Sirolimus; Time Factors

Topics: Calcineurin Inhibitors; Cyclosporine; Everolimus; Humans; Liver Transplantation; Renal Insufficiency; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Most patients with high MELD scores have impaired renal function prior to transplantation.. A retrospective case control study was conducted with initial low immunosuppression, which was increased when patients rejected or were clinically stable beyond day 30 ('bottom-up').. Thirty patients with impaired renal function were included. Fifteen were treated with de novo cyclosporine A (CsA; group A), and 15 had 'bottom-up' immunosuppression (group B). Baseline renal function was similar: serum creatinine (SCr) median 1.8 mg/dl (range: 1.5-4.0 mg/dl; group A) versus 2.4 mg/dl (range: 1.5-4.0 mg/dl; group B; p = 0.24). The requirement for renal replacement therapy was significantly lower in group B (p = 0.032). Ten received 'bottom-up' immunosuppression [4 CsA/1 sirolimus (Sir) 'on demand' after rejection, 5 Sir (stable)] beyond day 30. By months 6 and 12 (1.6 mg/dl vs. 1.2 mg/dl), SCr values were significantly better in group B (p = 0.006). Renal function in group B did not differ between patients receiving CsA or Sir. Overall complication rates, survival and biopsy-proven acute rejection were similar, although BANFF scores were higher in group B (p = 0.004).. Successful implementation of 'bottom-up' immunosuppression in liver transplant recipients with high lab-MELD scores and renal dysfunction at the time of transplantation has the potential to substantially improve short- and long-term outcomes.

Topics: Adult; Aged; Case-Control Studies; Creatinine; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pilot Projects; Renal Insufficiency; Retrospective Studies; Sirolimus; Treatment Outcome

Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity.. We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min.. Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events.. Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Dose-Response Relationship, Drug; Heart Transplantation; Humans; Immunosuppressive Agents; Registries; Renal Insufficiency; Retrospective Studies; Safety; Sirolimus; Spain

To investigate the efficacy of conversion from calcineurin-inhibitor (CNI) to rapamycin in liver recipients with CNI-associated renal insufficiency.. This retrospective study examined the liver transplant recipients who had switched from CNI to rapamycin between January 2004 and June 2008 in the first affiliated hospital of Sun Yat-sen University. The data of renal function before and after the conversion were analyzed by Wilcoxon sum rank test, and rapamycin-related adverse effects were also observed.. Compared with that before conversion, the renal funtion 4 months after the conversion improved significantly (P<0.05). The blood lipid level 3 months after the conversion increased significantly (P<0.05) but were well controlled.. Rapamycin can be used safely as a good alternative in liver transplant recipients with CNI-related renal insufficiency.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Sirolimus; Young Adult

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

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

Sirolimus is a potent immunosuppressive drug that has been shown to decrease the incidence of rejection post renal transplantation. Dyslipidemia is a well recognized side effect of sirolimus therapy, which may have an impact on patient survival and post-transplant cardiac morbidity and mortality. It is unknown whether sirolimus-induced dyslipidemia is aggravated by concomitant use of tacrolimus which may also affect lipid profile. To compare sirolimus induced dyslipidemia in tacrolimus based vs. tacrolimus free regimens in renal transplant recipients.. Patients who received sirolimus post kidney transplantation for at least nine sequential months were included in our retrospective study. Forty-eight renal transplant recipients were divided into 2 groups based on the immunosuppressive regimen; Group 1 received prednisone, sirolimus and mycophenolate mofetil, while Group 2 received prednisone, sirolimus, mycophanolate mofetil and tacrolimus. Lipid profile was assessed pre-transplantation and at one, three, six and nine months post sirolimus therapy.. Both groups showed significant but comparable elevation in total cholesterol, LDL-C and triglycerides with sirolimus therapy. The elevation was evident starting from the first month of sirolimus administration and remained to the ninth month at the end of the follow up period. At first month, mean triglycerides was 2.68 and 2.6 mmol/L (P>0.1) and mean total cholesterol was 6.3 and 5.7 mmol/L in group 1 and 2 (P>0.1); respectively. By the ninth month, triglycerides level was 2.6 and 3.9 mmol/L (P>0.1) while mean total cholesterol level was 6.2 and 6.1 mmol/L (P>0.1) in group 1 and 2 respectively. Lipid-lowering agents and total steroids dose were similar in both groups.. Hypercholesterolemia and hypertriglyceridemia secondary to sirolimus therapy is independent from concomitant tacrolimus use. Lipid-profile should be monitored in all renal transplant recipients receiving sirolimus as early as first month regardless of the immunosuppressive regimen used.

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus

While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity.. Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion.. Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 +/- 12.48 micromol/L to 130.1 +/- 5.573 micromol/L), and over the next 60 days after conversion (97.86 +/- 11.69 micromol/L to 90.7 +/- 8.95 micromol/L) (P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period.. SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Safety; Sirolimus; Tacrolimus

This study describes our experience with proliferation signal inhibitors in de novo heart transplant recipients with significant renal impairment. To circumvent further nephrotoxicity, calcineurin inhibitors were avoided in the peri-operative period.. Immunosuppression in 20 patients was with a proliferation signal inhibitor (sirolimus, 14; everolimus, 6), an anti-mitotic drug, and corticosteroids from the time of transplantation. Induction was used in 9 patients (45%). All patients had preoperative significant renal dysfunction (mean glomerular filtration rate <30 ml/min/1.73 m(2)), and 4 patients required dialysis.. Post-operatively, the glomerular filtration rate significantly increased (>65 ml/min/1.73 m(2) at Month 1, remaining stable thereafter). No patients required dialysis after the first month of transplantation. Mean follow-up was 500 days. Rejection episodes occurred in 11 patients (55%), and 4 patients died (2 of rejection, although 1 death occurred 48 days after conversion to conventional treatment with tacrolimus). Half of the patients were eventually converted to conventional calcineurin-inhibitor therapy because of proliferation signal inhibitor adverse events.. Although this immunosuppressive approach was associated with a somewhat high rate of rejection and frequent side effects, it represents an attractive alternative in the complicated peri-operative setting of patients with significant renal impairment. This approach could serve as a temporary bridge to a conventional treatment.

Topics: Administration, Oral; Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cell Division; Everolimus; Glomerular Filtration Rate; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Function Tests; Renal Insufficiency; Retrospective Studies; Sirolimus

Everolimus has been prescribed both for initial and maintenance therapy after cardiac transplantation. Herein, we present our initial experience with everolimus as maintenance therapy after cardiac transplantation.. We retrospectively included all of our patients in whom therapy was changed from calcineurin inhibitors to everolimus between September 2006 and October 2007. We analyzed their baseline clinical characteristics, indications for conversion to everolimus therapy, and beneficial vs adverse effects of the maneuver.. In 16 heart transplant recipients, therapy was changed to everolimus because of allograft vasculopathy (n = 8), renal failure (n = 4), or sirolimus toxicity (n = 4). Treatment with everolimus was initiated at a mean (SD) of 79.8 (52.7) months (range, 10-163 mo) after transplantation. The initial dose was 1.4 (0.2) mg (range, 1.0-1.5 mg), and the maintenance dose was 1 (0.31) mg (range, 0.5-1.5 mg). Follow-up was 7.28 (3.22) months (range, 0.5-13 mo). Observed side effects included hypertriglyceridemia, hypertension, and edema. Only 1 of 4 patients included because of sirolimus intolerance did not tolerate everolimus; renal dysfunction did not worsen in any of these 4 patients. No allograft vasculopathy was observed.. Renal function seem to stabilize after conversion to everolimus therapy in patients with previous progressive dysfunction. The safety profile was proved in all patients, although conclusions cannot be established about the evolution of allograft vasculopathy.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Retrospective Studies; Sirolimus; T-Lymphocytes

Although multifactorial anemia is common following orthotopic liver transplantation (OLT), the late introduction of sirolimus (SRL) has been associated with high rates of anemia, whose pathogenic mechanisms have not been fully studied. Herein we have described a case of severe anemia in an HIV+ OLT patient who was switched from calcineurin inhibitors (CNI) to SRL due to severe nephrotoxicity. After 22 weeks of SRL, hemoglobin levels dropped 4 g/dL to a nadir of 6.5 g/dL. After discarding other causes for anemia, we concluded that it displayed the features of anemia of a chronic inflammatory state (ACIS): decreased mean corpuscular volume (MCV), low serum iron despite high ferritinemia, and elevated fibrinogen and C-reactive protein (CRP) levels. SRL trough levels were never above the therapeutic range. After blood transfusions and erythropoietin (EPO) use, SRL was maintained within the lower range of therapeutic levels, with significant improvement in renal function. As described among kidney transplant recipients, SRL-related anemia in this HIV+ patient with CNI nephrotoxicity after OLT showed features of ACIS. Blood transfusions and EPO use allowed SRL maintenance.

Topics: Adaptor Proteins, Signal Transducing; Anemia; Blood Transfusion; C-Reactive Protein; Calcineurin; Erythropoietin; HIV Seropositivity; Humans; Immunosuppressive Agents; Inflammation; Iron; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Transferrin

Sirolimus, an effective and non-nephrotoxic immunosuppressant, may have an antiproliferative effect on renal tubular cells and increase their apoptosis, thus hindering the recovery of an injured kidney. The aim of this study was to evaluate the impact of combined sirolimus and cyclosporine therapy on the incidence and duration of delayed graft function and long-term graft function.. The study group consisted of 23 renal transplant recipients treated with a sirolimus-cyclosporine-prednisone regimen (sirolimus group). The reference group was composed of 23 patients treated with azathioprine-cyclosporine-prednisone. Because of a long cold ischemia time, all the patients were at high risk of developing delayed graft function.. There was an equal frequency of delayed graft function in the sirolimus group compared with the reference group (39% vs 34.8%). The duration of delayed graft function was longer in sirolimus group compared with the reference group (21.2 +/- 12.2 days vs 6.8 +/- 2.5 days) (P < .004). The serum creatinine level at the 12th month was higher in patients with delayed graft function than it was in the remaining patients, independent of the immunosuppression protocol. One and 5-year graft survival rates were 100% and 87% in the sirolimus group, and 95% and 74% in the reference group. The 5-year patient survival rate was 100% in both groups.. Sirolimus significantly retards the recovery from posttransplant renal failure, but it does not increase the incidence of delayed graft function. Sirolimus therapy should be initiated after recovery from posttransplant renal failure. Sirolimus treatment is beneficial for long-term graft survival.

Topics: Adult; Cold Ischemia; Creatinine; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Renal Insufficiency; Sirolimus; Survival Rate; Time Factors; Transplantation, Homologous; Treatment Outcome

Sirolimus-eluting stents (SES) have been demonstrated to reduce restenosis. However, there have been few studies evaluating the impact of renal insufficiency on the angiographic as well as clinical outcomes after SES implantation.. This study was composed of 304 consecutive patients having 361 lesions who underwent percutaneous coronary intervention with SES. The patients were divided into 3 groups according to renal function (group 1 [n = 204]; creatinine clearance (Ccr) > or = 60 ml/min, group 2 [n = 69]; Ccr < 60 ml/min, group 3 [n = 31]; hemodialysis). Clinical and angiographic follow-up were evaluated at 8 months.. Clinical follow-up was obtained in all patients and angiographic follow-up was obtained in 283 patients (93.1%). Patients in group 3 showed a higher incidence of previous coronary artery bypass graft surgery, and there were more female gender, hypertensive, and less hyperlipidemia in this group. Late lumen loss at 8 months was significantly different among the 3 groups (group 1; 0.16 +/- 0.46 mm, group 2; 0.44 +/- 0.62 mm, group 3; 0.81 +/- 0.88 mm, P < 0.0001). Major adverse cardiac events (MACE) were documented in 22 patients (10.8%) in group 1, 13 patients (18.8%) in group 2, and 12 patients (38.7%) in group 3, respectively (P = 0.0002).. Neointimal growth following SES implantation is more pronounced in patients with renal insufficiency, especially those undergoing dialysis, compared with patients with normal renal function. Regardless of the beneficial effect of SES, the increased risk of MACE mainly due to high incidence of target vessel revascularization in the subgroup of patients with renal insufficiency should be taken into account.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Artery Disease; Creatinine; Female; Follow-Up Studies; Humans; Kidney Function Tests; Male; Middle Aged; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Topics: Angioedema; Coronary Disease; Drug Interactions; Drug Monitoring; Everolimus; Heart Diseases; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Lipids; Lung Diseases, Interstitial; Renal Insufficiency; Sirolimus; Skin Diseases; Transplantation, Homologous; Wound Healing

Many patients receiving allogeneic stem cells develop chronic graft-versus-host disease (cGVHD), which remains as the main cause of morbidity and mortality. Although the first line of therapy is generally with steroids, it is not well known how to manage refractory cases. Those patients are usually treated with alternative experimental agents. Sirolimus (Rapamycin), a new immunosuppressive agent, inhibits signal transduction and cell cycle progression after binding to FKBP12. We report a retrospective analysis with sirolimus in transplant recipients with cGVHD refractory to previous immunosuppressive therapy. Forty-seven patients with refractory or relapsed cGVHD were treated with the combination of sirolimus and calcineurin inhibitors (n = 33), mycophenolate (n = 9), or prednisone (n = 5). Thirty-eight of 47 (81%) patients had clinical responses (complete = 18, partial = 20). The main toxicity was mild renal failure, particularly at the start of therapy. Four patients who presented thrombotic microangiopathy were managed with plasmapheresis and the discontinuation of sirolimus and calcineurin inhibitors. Statistical analysis showed the type of cGVHD onset and presirolimus clinical status as the main variables influencing the response to treatment. The Kaplan-Meier estimate of survival was 57.4% at 3 years. The current study shows the efficacy and safety of sirolimus in refractory cGVHD patients. Further investigation is warranted to elucidate the role of sirolimus in cGVHD, and find the best combination (sirolimus + calcineurin inhibitors versus others) for therapeutic use.

Topics: Adult; Calcineurin Inhibitors; Chronic Disease; Drug Evaluation; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Salvage Therapy; Sirolimus; Survival Analysis; Thrombosis; Treatment Outcome

The long-term safety and efficacy of drug-eluting stents (DES) have been questioned recently.. Between July 2002 and June 2005, 10,629 patients undergoing elective percutaneous coronary intervention with either DES (n=3064) or bare-metal stents (BMS, n=7565) were enrolled in a prospective registry comprising 13 hospitals. We assessed the cumulative incidence of major adverse cardiac events (death, acute myocardial infarction, and target-vessel revascularization) and angiographic stent thrombosis during 2-year follow-up. A propensity score analysis to adjust for different baseline clinical, angiographic, and procedural characteristics was performed. The 2-year unadjusted cumulative incidence of major adverse cardiac events was 17.8% in the DES group and 21.0% in the BMS group (P=0.003 by log-rank test). Angiographic stent thrombosis was 1.0% in the DES group and 0.6% in the BMS group (P=0.09). After adjustment, the 2-year cumulative incidence of death was 6.8% in the DES group and 7.4% in the BMS group (P=0.35), whereas the rates were 5.3% in DES and 5.8% in BMS for acute myocardial infarction (P=0.46), 9.1% in DES and 12.9% in BMS for target-vessel revascularization (P<0.00001), and 16.9% in DES and 21.8% in BMS for major adverse cardiac events (P<0.0001). Independent predictors of target-vessel revascularization in the DES group were diabetes mellitus (hazard ratio 1.36, 95% confidence interval 1.06 to 1.76), renal failure (hazard ratio 1.69, 95% confidence interval 1.06 to 2.69), and reference vessel diameter (hazard ratio 0.64, 95% confidence interval 0.45 to 0.93).. In this large real-world population, the beneficial effect of DES in reducing the need for new revascularization compared with BMS extends to 2 years without evidence of a worse safety profile.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Combined Modality Therapy; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Coronary Vessels; Diabetes Mellitus; Drug Implants; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Registries; Renal Insufficiency; Risk Factors; Sirolimus; Stents; Ticlopidine; Treatment Outcome

Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. This study aimed to determine whether sirolimus is effective and safe in treating renal insufficiency related to tacrolimus after liver transplantation.. Tacrolimus for primary immunosuppression was used in 16 patients after liver transplantation. Patients with a creatinine level higher than 132.6 micromol/L were eligible for conversion to sirolimus. Simultaneously, the dose of tacrolimus was decreased to half. Blood urea nitrogen, creatinine, tacrolimus level, liver function and rejection episodes were monitored dynamically.. All patients showed improvement of renal function after conversion to sirolimus. Blood creatinine level was reduced from 146.8+/-92.4 to 105.3+/-71.3 micromol/L (P<0.05). One patient had an acute rejection episode that was successfully treated with pulsed corticosteroids and low-dose tacrolimus. The side-effects of sirolimus included hyperlipidemia (4 patients) and leukocytopenia (2).. Sirolimus can be safely used in liver transplant recipients suffering from tacrolimus-related renal insufficiency.

Topics: Adult; Calcineurin; Creatinine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Tacrolimus

Nephrotoxicity is a complication of patients undergoing orthotopic liver transplantation. Herein we present several factors that play an important role in this complication.

Topics: Adult; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus

This case report describes the successful treatment of severe plaque psoriasis with etanercept in a patient who underwent a liver transplant. It also addresses the concerns that arise in the treatment of chronic inflammatory dermatologic disease accompanied by multiple organ disorders.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 1; Etanercept; Graft Rejection; Humans; Immunocompromised Host; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Psoriasis; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Sirolimus; Tacrolimus

Stent thrombosis (ST) is a serious complication of drug-eluting stent (DES) implantation regardless of the timing (acute, subacute, or late). The correlates of ST with DES are not yet completely elucidated.. From a total cohort of 2974 consecutive patients treated with DES since April 2003, we identified 38 patients who presented with angiographic evidence of ST (1.27%). The ST occurred acutely in 5 patients, subacutely (< or =30 days) in 25 patients, and late (>30 days) in 8 patients. The clinical, angiographic, and procedural variables of these patients were compared with the remaining 2936 consecutive patients who underwent DES implantation and did not experience ST during a follow-up of 12 months. Logistic regression analysis was conducted to determine the correlates of ST. Compared with patients without ST, patients with ST had a higher frequency of diabetes, acute postprocedural renal failure, and chronic renal failure. There were more bifurcation lesions, type C lesions, and a trend for smaller-diameter stents. Discontinuation of clopidogrel was higher in these patients (36.8% versus 10.7%; P<0.0001). The mean duration to ST from the stent implantation was 8.9+/-8.5 days in subacute and 152.7+/-100.4 days in late thrombosis cases. Mortality was significantly higher in patients with ST compared with those without ST at 6 months (31% versus 3%; P<0.001). Multivariate analysis detected cessation of clopidogrel therapy, renal failure, bifurcation lesions, and in-stent restenosis as significant correlates of ST (P<0.05).. ST continues to be a serious complication of contemporary DES use. Careful management is warranted in patients with renal failure and in those undergoing treatment for in-stent restenosis and bifurcations. Special focus on clopidogrel compliance may minimize the incidence of ST after DES implantation.

Topics: Aged; Angiography; Case-Control Studies; Clopidogrel; Drug Delivery Systems; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Paclitaxel; Renal Insufficiency; Sirolimus; Stents; Thrombosis; Ticlopidine; Treatment Outcome

Calcineurin inhibitor (CI)-based immunosuppression has prolonged the survival of heart transplant recipients. However, CI-induced renal injury remains as a major problem in these patients. Sirolimus is an immunosuppressant with no significant impact on renal function. A limited number of recent papers have showed that the switch from CI to sirolimus improved renal function in late follow-up of heart transplant patients with CI-related nephrotoxicity.. Ten heart transplant recipients with CI-induced nephrotoxicity (creatinine 3.9+/-1.8 mg/dl) at a median of 701 (465 to 1325) days posttransplant had CI switched to sirolimus (target though levels 10 to 14 ng/ml) while mycophenolate mofetil (MMF, 3g/day) was maintained and adjusted according to white blood cell count.. This maneuver caused a marked decrease in serum creatinine (P<0.00001) at 30 (1.2+/-0.4 mg/dl), 90 (1.3+/-0.4 mg/dl) and 180 (1.3+/-0.4 mg/dl) days post-conversion and a significant decrease in serum potassium levels (5.1+/-0.5 at baseline vs. 3.9+/-0.3 at 180 days, P<0.00005). After the drugs switch no changes in hemoglobin levels, white blood cell count, platelets count, blood glucose and glutamic oxaloacetic transaminase plasma levels were observed. Total cholesterol increased from 242+/-28 to 290+/-117 mg/dl (P>0.05) after 90 days and decreased to 216+/-58 mg/dl at day 180 (P>0.05) after statins dose adjustment. Rejection and infection rates were not modified by sirolimus.. Conversion to a sirolimus-based immunosuppression regimen associated with MMF allowed striking renal function recovery in heart transplant recipients with calcineurin inhibitor-induced renal impairment at midterm follow-up.

Topics: Adult; Aspartate Aminotransferases; Blood Glucose; Calcineurin Inhibitors; Cholesterol; Creatinine; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Sirolimus

Topics: Abdominal Injuries; Adult; Colon; Drug Interactions; Fatal Outcome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Sirolimus; Tomography, X-Ray Computed; Vasculitis, Leukocytoclastic, Cutaneous

To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune, rapamycin) in a consecutive cohort of 248 liver allograft recipients.. Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.. The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT. Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.. The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Calcineurin; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phosphoproteins; Renal Insufficiency; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Transplantation, Homologous

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

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

Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Cell Division; Disease Progression; Immunosuppressive Agents; Male; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Renal Insufficiency; Sirolimus

Topics: Adult; Androgens; Cohort Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Steroids; Testosterone; Time Factors

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

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

Sirolimus has been an important addition to immunosuppressive regimens utilized in kidney transplantation. However, sirolimus can potentiate calcineurin inhibitor (CNI) nephrotoxicity by some still uncertain mechanisms. Studies have demonstrated that withdrawal of a CNI under sirolimus immunosuppression can improve renal function. However, it has yet to be demonstrated that withdrawal of sirolimus from such a regimen can also improve renal function and reverse progressive functional deterioration. We studied 17 patients who developed deterioration of renal function while on a CNI and sirolimus. Once an established deterioration in renal function was noted, sirolimus was withdrawn from the regimen and replaced with mycophenolate mofetil. Out of 17 patients with a negative slope in 1/cr, 15 demonstrated a positive treatment effect (change to a positive slope). On aggregate, renal function improved by 18% (creatinine 2.75-2.24 mg/dL), LDL cholesterol improved, as did hematocrit values after withdrawal. The majority of patients on a CNI and sirolimus regimen who experience deterioration in renal function demonstrate improvement in renal function after withdrawal of sirolimus. This strategy may be particularly useful in those patients where CNI withdrawal is considered to be of high immunologic or metabolic risk.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Sirolimus; Time Factors; Withholding Treatment

Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. Our clinical experience has revealed sirolimus to be an effective agent in treating renal insufficiency related to calcineurin inhibitor toxicity.. We performed a retrospective review of the medical records of OLT recipients suffering from chronic renal insufficiency and treated with sirolimus at the University of Miami.. Fourteen patients (nine men and five women) of mean age 57 years who had been treated with tacrolimus for at least 30 days were converted to sirolimus after developing nephrotoxicity. Mean creatinine clearances collected on day 0, 30, 60, and 90 after conversion were 40.1 mL/min, 49.6 mL/min, 53.9 mL/min, and 51.4 mL/min, respectively. Episodes of acute cellular rejection were not increased during the sirolimus conversion.. This retrospective review suggests that OLT patients suffering from tacrolimus-related renal insufficiency successfully converted to sirolimus may benefit from this therapy.

Topics: Creatinine; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Retrospective Studies; Sirolimus