Immunosuppression In Kidney Transplantation Research Articles

Long-Term Outcome of Azathioprine Versus Mycophenolate Mofetil in a Cyclosporine-Based Immunosuppression in Kidney Transplant: 10 Years Experience at Single Center

Introduction: Mycophenolate mofetil (MMF) has been used worldwide as a part of maintenance immunosuppression since initial cyclosporine-based large trials found that MMF reduced acute rejection episodes compared with azathioprine (AZA) after renal transplantation. However, long-term benefits of MMF have not been established and the follow-up period of the previous studies was within 5 years. We aimed to compare acute rejection rate and graft and patient survival of these two drugs in conjunction with cyclosporine and steroids over 10 years. Methods: We reviewed kidney transplant recipients who had been transplanted from January 1998 to January 2002. Eighty-six patients were recruited and divided into two groups (MMF group=43 vs. AZA group=43). All patients received cyclosporine and steroids concomitantly as maintenance immunosuppressive therapy. We analyzed for the incidence of biopsy-proven acute rejection, allograft function, and graft and patient survival. Results: Baseline characteristics were similar between both groups except donor type. The deceased donor was 8 patients in the MMF group and 1 patient in the AZA group. Over 10 years after transplantation, fewer biopsy-proven acute rejection occurred in MMF group than AZA group (11.6% vs. 30.2%, respectively, p=0.037). The 10-years graft survival was 93% in MMF group and 81.4% in AZA group, but the difference was not significant (p=0.113). During 10 years, one patient (2.3%) in the MMF group and 4 patients (9.3%) in the AZA group died (p=0.184). Graft function was comparable between the two groups over 10 years. There was no significant difference in the incidence of serious infections. Over the 10 year posttransplant period, 5 patients developed malignancies (one in the MMF group vs. 4 in the AZA group). Conclusions: MMF offered clinical benefit for preventing acute rejection and had similar effects on the long term graft and patient survival in kidney transplant recipients with cyclosporine-based immunosuppression.

Long-Term Outcome of Azathioprine Versus Mycophenolate Mofetil in a Cyclosporine-Based Immunosuppression in Kidney Transplant: 10 Years Experience at Single Center

Introduction: Mycophenolate mofetil (MMF) has been used worldwide as a part of maintenance immunosuppression since initial cyclosporine-based large trials found that MMF reduced acute rejection episodes compared with azathioprine (AZA) after renal transplantation. However, long-term benefits of MMF have not been established and the follow-up period of the previous studies was within 5 years. We aimed to compare acute rejection rate and graft and patient survival of these two drugs in conjunction with cyclosporine and steroids over 10 years. Methods: We reviewed kidney transplant recipients who had been transplanted from January 1998 to January 2002. Eighty-six patients were recruited and divided into two groups (MMF group=43 vs. AZA group=43). All patients received cyclosporine and steroids concomitantly as maintenance immunosuppressive therapy. We analyzed for the incidence of biopsy-proven acute rejection, allograft function, and graft and patient survival. Results: Baseline characteristics were similar between both groups except donor type. The deceased donor was 8 patients in the MMF group and 1 patient in the AZA group. Over 10 years after transplantation, fewer biopsy-proven acute rejection occurred in MMF group than AZA group (11.6% vs. 30.2%, respectively, p=0.037). The 10-years graft survival was 93% in MMF group and 81.4% in AZA group, but the difference was not significant (p=0.113). During 10 years, one patient (2.3%) in the MMF group and 4 patients (9.3%) in the AZA group died (p=0.184). Graft function was comparable between the two groups over 10 years. There was no significant difference in the incidence of serious infections. Over the 10 year posttransplant period, 5 patients developed malignancies (one in the MMF group vs. 4 in the AZA group). Conclusions: MMF offered clinical benefit for preventing acute rejection and had similar effects on the long term graft and patient survival in kidney transplant recipients with cyclosporine-based immunosuppression.

Advances in immunosuppression for kidney transplantation: new strategies for preserving kidney function and reducing cardiovascular risk.

The development of new immunosuppressants for renal transplantation is aimed not only at improving short-term outcomes, but also at achieving better safety, cardiovascular, and metabolic profiles and at decreasing nephrotoxicity. Belatacept is a fusion protein that inhibits T cell activation by binding to CD80 and CD86 antigens. Clinical trials, particularly the BENEFIT and BENEFIT-EXT studies, have shown that belatacept preserves function and structure in renal grafts. The effects of belatacept provide long-term, sustained results, and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors. Compared to calcineurin inhibitors, belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile.

Long-term Results of Conversion From Calcineurin Inhibitors to Sirolimus in 150 Maintenance Kidney Transplant Patients

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

Infectious Risks and Optimal Strength of Maintenance Immunosuppressants in Rituximab-Treated Kidney Transplantation

Background: Rituximab, an anti-CD20 antibody, effectively depletes B lymphocytes. It is not clear whether the use of conventional doses of mycophenolate mofetil (MMF), methylprednisolone and tacrolimus as maintenance immunosuppression in rituximab-treated kidney transplantation is associated with increased risk. Methods: We retrospectively evaluated 67 patients who underwent HLA-sensitized or ABO-incompatible living donor kidney transplantation after one dose of rituximab (200 or 500 mg) (group 1). Eighty-seven kidney transplant recipients who did not require rituximab served as a control (group 2). Results: Cytomegalovirus infection (16.4 vs. 5.7%, p = 0.031) and pneumonia (9.0 vs. 1.1%, p = 0.043) occurred more often in group 1, and 2 patients of group 1 died of infection. The doses of methylprednisolone and tacrolimus levels of the two groups were not different. MMF dose was reduced when serious infection occurred. The doses of MMF (in grams/day) at the following times postoperatively were lower in group 1 than in group 2: 1 month: 1.26 ± 0.42 vs. 1.40 ± 0.39, p = 0.033; 3 months: 1.14 ± 0.51 vs. 1.36 ± 0.39, p = 0.011; 6 months: 1.07 ± 0.50 vs. 1.30 ± 0.42, p = 0.012; 1 year: 0.88 ± 0.52 vs. 1.19 ± 0.44, p = 0.009; 2 years: 0.69 ± 0.55 vs. 1.25 ± 0.49, p = 0.059, but the reduction of MMF doses did not increase the incidence of acute rejection in group 1 (4.5% in group 1 vs. 9.2% in group 2, p = 0.351). If patients who died with functioning graft were excluded, graft survival was 98.5% in group 1 and 100% in group 2. Conclusions: Serious infectious complications were increased in rituximab-treated kidney transplant recipients and it might be adequate to reduce the MMF dose from the early postoperative period.

Everolimus as Primary Immunosuppression in Kidney Transplantation

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.

Histologic Inflammatory Changes on the Prostatic Gland Due to Immunosuppression for Kidney Transplantation

To determine the incidence of type IV prostatitis in patients with kidney transplantation receiving an immunosuppression regimen and to compare it with that of a nonimmunosuppressed control group. We retrospectively reviewed 216 electronic charts of patients who had undergone surgical treatment for benign prostatic hyperplasia from August 2000 to January 2006. Of the 216 patients, 183 did not receive immunosuppressive therapy and were included in the control group (group 1). The other 33 patients had undergone kidney transplantation and were included in the study group (group 2). The patient data were accessed for age at surgery, International Prostate Symptom Score, prostate volume, preoperative serum prostate-specific antigen level, history of acute urinary retention, and surgical approach (open vs transurethral resection of prostate). Histologic findings from the surgical specimens were also recorded. The mean age at surgery, mean serum prostate-specific antigen level, mean prostate volume, and mean International Prostate Symptom Score were not significantly different between both groups. However, histologic evidence of chronic prostatitis was obtained in 145 surgical specimens (78%) from group 1 and in just 3 specimens from group 2 (9%; P < .001). Moreover, nonimmunosuppressed patients had a 38.2 times greater risk of presenting with prostatitis than did the immunosuppressed patients. Immunosuppression therapy in kidney transplantation has a protective factor in the prostatitis incidence.

Disseminated Angiosarcoma of the Dialysis Fistula in 2 Patients Without Kidney Transplants

Angiosarcoma of the dialysis fistula is a rare occurrence. Of the 8 cases of angiosarcoma of the dialysis fistula reported in the literature, all occurred after kidney transplant and long-term immunosuppression therapy. We report 2 cases of disseminated angiosarcoma of the dialysis fistula in hemodialysis patients without concurrent kidney transplants or immunosuppression. Both patients presented with symptoms of pain and bleeding at the site of the thrombosed fistula. Clinicians should be aware that angiosarcoma of the dialysis fistula can occur in patients without kidney transplants.

Kidney Transplantation Outcomes in HIV Infection: The European Experience

Kidney Transplantation Outcomes in HIV Infection: The European Experience

New targets for immunosuppression in kidney transplantation: Focus on recent clinical trials

AbstractSignificant advances have been made in post‐kidney transplantation immunosuppression. The introduction of calcineurin inhibitors (CNIs) has led to a reduction in acute rejection and improved 1‐year outcomes. However, long‐term allograft survival has not improved. This may in part be due to the chronic nephrotoxicity of CNIs and negative effects on the cardiovascular and metabolic risk profile via worsening hypertension, diabetes, and dyslipidemia. New drug development now focuses on maintaining low rejection rates but maximizing long‐term allograft survival and modulating the cardio‐metabolic side effects seen with CNIs. Two small molecules are currently undergoing Phase 2 investigation. CP‐690550 (tasocitinib) is a JAK 3 inhibitor, and AEB‐071 (sotrastaurin) is a protein kinase C inhibitor. Two biologic agents are also undergoing development. Belatacept is a humanized antibody that blocks the T‐cell co‐stimulation pathway and has had promising results in both Phase 2 and 3 investigation. Alefacept is a humanized antibody that inhibits T‐cell adhesion and is currently undergoing Phase 2 investigation. This article will review the mechanisms of these drugs and outline the available trial data results.

Advances in kidney transplant immunosuppression: Emerging biologics

AbstractThere remains a need in solid‐organ transplantation for an immunosuppressive agent with a novel mechanism of action and fewer adverse consequences to replace current immunosuppressive drugs and improve long‐term patient and graft survival. There are several agents on the horizon, both small molecules and biologics, offering this promise along with ease and consistency of long‐term administration. We discuss three biologic agents currently in advanced stages of clinical trials in kidney transplantation.

Efficacy and Safety of Thymoglobulin Induction as an Alternative Approach for Steroid-Free Maintenance Immunosuppression in Pediatric Renal Transplantation

Given the recent withdrawal of daclizumab (DAC), the safety and efficacy of thymoglobulin (TMG) was tested as an alternative induction agent for steroid-free (SF) immunosuppression in pediatric kidney transplant recipients. Thirteen pediatric renal transplant recipients meeting defined high-risk criteria at transplantation were offered TMG induction and SF immunosuppression with maintenance mycophenolate mofetil and tacrolimus between October 2008 and January 2010. Patients were closely monitored at baseline, 3, 6, 9, and 12 months posttransplant for protocol biopsy and clinical outcomes. Outcomes were compared with 13 consecutively transplanted low-risk patients receiving an established DAC-based SF protocol (Sarwal et al., WA, American Transplant Congress 2003). There was a significant trend for overall decrease in the absolute lymphocyte counts in TMG group (F=5.86, mixed model group effect P=0.02), predominately at 3 months compared with DAC group (0.7±0.6 vs. 2.1±1.0, P=0.0004); however, lymphocyte count was recovered and was back to reference range by 6 months in TMG. There was trend toward more subclinical cytomegalovirus (15% vs. 0%) and BK viremia (17% vs. 0%) in the TMG group, with no differences in the incidence of subclinical Epstein Barr virus viremia (23% vs. 31%) or clinical viral disease. Mean graft function was excellent, and with a minimum follow-up of 6 months, there were no episodes of acute rejection. TMG seems to be a safe alternative induction strategy in patients for SF immunosuppression in pediatric renal transplantation. Extended follow-up and greater enrollment are necessary to fully explore the impact of TMG dosing on viral replication posttransplantation.

How the development of new biological agents may help minimize immunosuppression in kidney transplantation: the impact of belatacept

The purpose of this review is to discuss the use of belatacept as part of an immunosuppression regimen in renal transplant recipients to avoid the renal and nonrenal toxicities associated with calcineurin inhibitors (CNIs). Current immunosuppression protocols utilize CNIs that are associated with renal and cardiovascular/metabolic toxicities. Belatacept, a selective costimulation blocker, is designed to provide effective immunosuppression while avoiding the toxicities associated with CNIs. Phase III trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Two-year data demonstrate up to a 17 ml/min/1.73 m improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Belatacept-treated patients had better blood pressure control and lipid profiles compared to cyclosporine-treated patients. There were more cases of posttransplant lymphoproliferative disease in belatacept-treated patients, especially in Epstein-Barr virus-negative recipients or patients treated with lymphocyte-depleting agents. In a conversion trial from a CNI to belatacept, the mean increase in renal function was 7.0 and 2.1 ml/min/1.73 m in the belatacept and cyclosporine groups, respectively. Belatacept provides effective immunosuppression while avoiding or minimizing the untoward side effects seen with CNIs. Conversion from a CNI to belatacept posttransplantation appears to be safe and effective and results in improved renal allograft function. Data suggest that belatacept use may eventually lead to improved long-term allograft survival and decrease the overall long-term mortality by improving the cardiovascular and metabolic profile of renal transplant recipients.

Review: Pharmacodynamic monitoring of immunosuppression in kidney transplantation

Advances in immunosuppressive therapies have improved kidney transplant outcomes. However, immunosuppressant drug-induced toxicities continue to reduce tolerability and impact patient and graft survival. A major ongoing challenge in kidney transplantation is to establish ways of tailoring immunosuppressant therapy so as to maintain efficacy while minimizing toxicity. Pharmacodynamic monitoring by direct measurement of immune cell function has the potential to personalize immunosuppression. The purpose of this review is to provide the clinician with an overview of the methodology and use of immune function monitoring in the field of kidney transplantation.

HLA and kidney transplantation

This article focuses on the immunogenetics, immunology, rejection and immunosuppression in kidney transplantation. HLA matching still affects outcome data, and HLA matching improves graft survival. Graft sources and related outcomes...

Steroid-free maintenance immunosuppression in kidney transplantation: is it time to consider it as a standard therapy?

Steroid-free immunosuppression in kidney transplantation has been gaining popularity over the past decade, as documented by a continuous and steady rise in the number of kidney transplant patients discharged on steroid-free regimens. This increased interest in steroid-free immunosuppression is fueled by the recognition that half of transplant loss is related to patient death due to cardiovascular disease and/or infectious complications and that the long-term use of steroids contributes to such elevated cardiovascular morbidity and mortality. The availability of newer and more potent immunosuppressive agents has furthered such interest. Many clinical trials over the past two decades have demonstrated the feasibility of steroid-free regimens, at the expense of a slight increase in the rate of acute rejection, which is an important end point in any clinical trial of relatively short duration. The largest epidemiological study to date has reassured the transplant community that the selective use of steroid-free immunosuppression in kidney transplant patients provides no inferior outcome in patient and graft survival at intermediate term. Steroid-free regimens have the potential to improve cardiovascular risk profile. The challenges that remain are to identify the subset of kidney transplant patients who may not benefit from steroid-free immunosuppression and to demonstrate the survival advantage of steroid-free immunosuppresion in suitable kidney transplant candidates.

Balancing Efficacy and Toxicity of Kidney Transplant Immunosuppression

Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function. By performing protocol biopsies, it was demonstrated that clinical and subclinical acute cellular rejection phenomena continue to play important roles, despite the use of the powerful combination of tacrolimus, mycophenolate mofetil, and steroids. Next to immune phenomena, the importance of nonimmune factors in renal allograft histological evolution was shown in protocol biopsy studies. Both in adult and in pediatric renal allograft recipients, the characteristics of the donor kidney (donor age, size discrepancy) appeared to be major determinants of the histological and functional evolution. This impact of donor characteristics was not only important in the immediate peritransplantation period, it was also shown that higher donor age increased the risk for progressive posttransplant histological injury and calcineurin inhibitor nephrotoxicity. Systemic levels of tacrolimus, if kept within a relatively narrow target window, were not associated with a risk for calcineurin inhibitor nephrotoxicity. However, we observed a significant association between renal allograft histology and P-glycoprotein (ABCB1) gene polymorphisms and expression, suggesting a role of this protein in the individual susceptibility to calcineurin inhibitor nephrotoxicity. Finally, the interplay between immune and nonimmune phenomena was demonstrated by the association between donor origin (deceased versus living) and local renal complement gene expression, by using whole-genome expression microarrays.

Islet Alone Versus Islet After Kidney Transplantation: Metabolic Outcomes and Islet Graft Survival

Isolated islet transplantation with infusions from two to three donor pancreata and Edmonton immunosuppression consistently achieves insulin independence in patients with type 1 diabetes. The success of this protocol has been attributed to a novel combination of immunosuppressive agents and avoidance of steroids; however, the outcome of islet transplantation may differ in kidney transplant recipients who are already immunosuppressed. We compared the metabolic outcomes and graft survival of islet transplantation in our program where nine patients underwent islet transplantation alone treated with Edmonton immunosuppression and eight patients received islet after kidney (IAK) transplants under standard kidney transplant immunosuppression often including steroids. Transplants in the IAK and islet transplantation alone setting demonstrated similar islet potency (islet equivalents/unit insulin reduction) and recipients from both groups routinely gained insulin independence, functional islet mass, and duration of graft survival, however, seemed superior in the IAK group. These results suggest that better islet graft function and survival may be attained using non-Edmonton rather than Edmonton immunosuppression and can include maintenance steroid therapy.

Pediatric Kidney Transplantation Using a Novel Protocol of Rapid (6-Day) Discontinuation of Prednisone: 2-Year Results

There are few prospective studies of prednisone-free immunosuppression (IS) in pediatric kidney transplant (KTx) recipients. We studied the outcomes of a protocol using rapid discontinuation of prednisone (RDP, <1 week) and thymoglobulin induction. Twenty-one RDP recipients (mean age 14+/-3 years) received KTx between May 2002 and December 2005 and were matched with controls (n=39) for age, race, and donor source. For the RDP group, IS consisted of prednisone tapered off over 6 days, thymoglobulin, mycophenolate mofetil, and cyclosporine A (CsA). In controls, IS consisted of thymoglobulin, maintenance prednisone, azathioprine, and CsA. For the RDP group, graft survival at 1 and 2 years was 90% and 86%; for the controls, graft survival at 1 and 2 years was 92%, and 90% (P=0.86). For the RDP group, the incidence of acute rejection at 1 and 2 years was 14% and 19%; for controls, the incidence of acute rejection at 1 and 2 years was 23%, and 31% (P=0.17). Of the 18 RDP recipients with functioning grafts, 89% remain prednisone-free at follow-up. There was no significant difference between groups in recipient survival rates, incidence of hypertension, chronic allograft nephropathy, or cytomegalovirus disease. RDP using thymoglobulin, mycophenolate mofetil, and CsA in selected pediatric KTx recipients is associated with recipient and graft survival rates and acute rejection incidence comparable with quadruple drug therapy.

The cost-effectiveness of induction immunosuppression in kidney transplantation

Induction immunosuppression is perceived as an expensive therapy, so is often given only to select patients. This study evaluated the cost-effectiveness of antibody induction comparing interleukin-2 receptor antagonists (IL2Ra) to standard therapy with no induction or induction with polyclonal antibodies. A Markov model was developed to estimate costs and health outcomes [survival (life years saved, LYS) and quality-adjusted survival (QALYs)] for the alternative strategies. Outcome data were obtained from a meta-analysis of randomized trials and large-scale renal registries. IL2Ra offers improved survival of 0.21 LYS (2.5 months) and 1.42 QALYs compared with no induction, with a cost saving over 20 years of $79,302 per patient treated regardless of risk profile. The incremental benefits of IL2Ra compared with polyclonal antibody induction therapy were 0.35 LYS (4.3 months) and 0.20 QALYs, with an incremental cost of $5144 per patient. The incremental cost-effectiveness ratio (ICER) of IL2Ra compared to polyclonal induction was $14,803 per LYS and $25,928 per QALY. Sensitivity analyses showed that IL2Ra remained more effective and less expensive than no induction. When IL2Ra was compared to polyclonal induction, the model was sensitive to changes in the cost of induction and the probability of malignancy. Over the range of all other variables tested, IL2Ra was cost-effective compared to polyclonal induction. Adopting IL2Ra as induction immunosuppression for kidney transplant recipients improves survival and QALYs and is less costly than no induction. It also represents good value for money compared to polyclonal induction.