Systematic review and meta-analysis of calcineurin inhibitors on long-term prognosis of renal transplant patients

BackgroundExisting guidelines recommend a triple immunosuppressive regimen with calcineurin inhibitors, antimetabolites, and corticosteroids for postoperative immunosuppression in renal transplant patients. However, few studies have compared cyclosporine and tacrolimus for long-term outcomes. In this study, the meta-analysis was used to compare long-term outcomes in renal transplant patients to evaluate the use of cyclosporine vs. tacrolimus. The pros and cons of suppression programs have been analyzed.MethodsCyclosporine, tacrolimus, and kidney transplantation, were used as search terms to retrieve relevant publications in PubMed, Embase, and The Cochrane library. Two independent researchers screened and evaluated the relevant results of each search using the RevMan5.4 program to make relevant charts for the meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were used to report dichotomous variables, while mean differences (MD) and 95% confidence intervals (CI) were used to report continuous variables. The study took tacrolimus- and cyclosporine-based maintenance immunosuppression as experimental and control groups, respectively. The graft and patient survival outcomes were followed for 5 or more years.ResultsOverall, thirteen studies were included in the meta-analysis, including nine randomized controlled trials and four non-randomized controlled trials. Compared with the cyclosporine group, the incidence of rejection, drug conversion, and dyslipidemia were significantly lower in the tacrolimus group. Furthermore, there was higher glomerular filtration rates and graft survival rates in the tacrolimus group than in the cyclosporine group. In contrast, there were no significant differences between the two groups in terms of patient survival, incidence of infection, hypertension and new tumors. However, the use of tacrolimus was associated with a high risk of a new onset of diabetes.ConclusionThe meta-analysis showed that, compared with cyclosporine, tacrolimus increases the risk of a new-onset diabetes. However, tacrolimus had higher graft survival rate and better creatinine clearance than cyclosporine.     

Three-year posttransplant graft survival in renal-transplant patients with graft function at 6 months receiving tacrolimus or cyclosporine microemulsion within a triple-drug regimen

BACKGROUND: Registry data can provide valuable information about possible treatment effects; however, pretreatment differences in patient characteristics may influence treatment assignment. Careful analysis must therefore be undertaken when evaluating treatment differences in the context of nonrandomized studies so that the impact of treatment selection bias is minimized. METHODS: A multivariable risk factor analysis of adult patients registered in the US Renal Data System who received a primary renal allograft during 1995 to 1998 was undertaken to compare 3-year graft survival using tacrolimus or Neoral with mycophenolate mofetil (MMF) and steroids. RESULTS: In total, 9,449 patients were included (cadaveric donor n=6,011; living donor n=3,438). Patients (2,130) received tacrolimus, and 7,319 received Neoral. At 3 years posttransplant, the proportion of cadaveric donor recipients experiencing all causes of graft loss was 10.0% for tacrolimus and 10.6% for Neoral; for living donor recipients these figures were 6.5% and 6.7%, respectively (unadjusted Kaplan-Meier analysis). The incidence of graft failure excluding death was also similar between the two groups. With Cox proportional hazards modeling, the adjusted relative hazard of 3-year graft failure for cadaveric donor patients taking tacrolimus versus Neoral was 1.02 (95% confidence interval [CI] 0.8-1.3), and for living-donor recipients it was 1.15 (95% CI 0.8-1.8). CONCLUSIONS: These results indicate excellent 3-year graft survival for both cadaveric and living-donor renal-transplant patients receiving either Neoral or tacrolimus with MMF and steroids, with no significant differences between treatment groups. On the basis of these results, relative cost-effectiveness may become increasingly important in selection of tacrolimus or Neoral as primary immunosuppressant for renal-transplant patients.     

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.     

Hospitalized psychoses after renal transplantation in the United States: incidence,risk factors,and prognosis

Although it is recommended that renal transplant (RT) candidates routinely undergo screening for mental health-related conditions, national statistics for psychoses after RT have not been reported. This is a historical cohort study of 39,628 renal transplant recipients in the United States Renal Data System between July 1, 1994, and June 30, 1998, and followed until December 31, 1999. Adjusted hazard ratios (AHR) for time to hospitalization for both a primary and secondary discharge diagnosis of psychoses (ICD-9 codes 290.x-299.x) after RT and mortality/graft loss after psychosis were assessed by Cox Regression. In addition, rates of psychosis were compared with 178,986 patients with Medicare as their primary payer who started chronic dialysis from April 1, 1995, to June 29, 1999. The incidence of psychoses was 7.5/1000 person-years (PY) after RT compared with 7.2/1000 PY for all patients on chronic dialysis and 9.6/1000 PY for dialysis patients aged 65 yr or younger. Among RT recipients, graft loss (AHR, 2.97; 95% CI, 2.19 to 4.02), allograft rejection, and cadaveric donation were independently associated with psychosis, which was associated with an increased risk of both death (AHR, 2.09; 95% CI, 1.71 to 2.56; P < 0.001) and graft loss (AHR, 1.79; 95% CI, 1.15 to 2.78; P = 0.01). Graft loss due to noncompliance was significantly more common after psychosis (9.0% versus 3.7% in patients not hospitalized for psychosis; P < 0.001). The incidence of hospitalized psychosis was not substantially higher after RT compared with chronic dialysis patients. Psychoses were independently associated with increased risk of death and graft loss after renal transplantation, possibly mediated through medical non-adherence.     

Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure

The optimal timing of pregnancy after kidney transplantation remains uncertain. We determined the risk of allograft failure among women who became pregnant within the first 3 posttransplant years. Among 21 814 women aged 15–45 years who received a first kidney‐only transplant between 1990 and 2010 captured in the United States Renal Data System, n = 729 pregnancies were identified using Medicare claims. The probability of allograft failure from any cause including death (ACGL) at 1, 3, and 5 years after pregnancy was 9.6%, 25.9%, and 36.6%. In multivariate analyses, pregnancy in the first posttransplant year was associated with an increased risk of ACGL (hazard ratio [HR]: 1.18; 95% confidence interval [CI] 1.00, 1.40) and death censored graft loss (DCGL) (HR:1.25; 95% CI 1.04, 1.50), while pregnancy in the second posttransplant year was associated with an increased risk of DCGL (HR: 1.26; 95% CI 1.06, 1.50). Pregnancy in the third posttransplant year was not associated with an increased risk of ACGL or DCGL. These findings demonstrate a higher incidence of allograft failure after pregnancy than previously reported and that the increased risk of allograft failure extends to pregnancies in the second posttransplant year.     

Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.     

Risk Factors for Hospitalization for Bacterial or Viral Infection in Renal Transplant Recipients—An Analysis of USRDS Data

We previously showed that children are more likely to develop viral infections post-kidney transplant while adults are more likely to develop bacterial infections. In this study we determined the overall risk factors for hospitalization with either a bacterial (HBI) or a viral infection (HVI). We analyzed data from 28 924 United States Renal Data System (USRDS) Medicare primary renal transplant recipients from January 1996 to July 2000, for adjusted hazard ratio (AHR) for HBI or HVI in the first 3 years posttransplant.For HVI, significantly higher AHR was seen with (a) recipient age <18 years (AHR 1.57, 95% CI = 1.02, 2.42), (b) donor CMV positive (AHR 1.72, 95% CI = 1.34, 2.19). For HBI, significantly higher AHR was seen with (i) delayed graft function (AHR 1.28, 95% CI = 1.076, 1.518), (ii) primary renal diagnosis chronic pyelonephritis (AHR 1.71, 95% CI = 1.18, 2.49); (iii) associated pretransplant diabetes (AHR 1.80, 95% CI = 1.53, 2.12); (iv) female gender AHR 1.63, 95% CI = 1.41, 1.88). Lower AHR for HVI was seen in CMV-positive recipients and for HBI with more recent year of transplant. Other covariates did not impact significantly in either HVI or HBI.     

Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies

BACKGROUND: Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. METHODS: A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. RESULTS: The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. CONCLUSIONS: Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.     

Tacrolimus for the treatment of gout in renal transplantation: two case reports and review of the literature.

Episodes of gout are common in the setting of renal transplantation. Hyperuricemia and gout have been associated with the use of the calcineurin inhibitor, cyclosporine. We report two cases of severe polyarticular gout resistant to conventional therapy in renal transplant recipients that resolved after switching from cyclosporine to tacrolimus-based immunosuppression. There was no alteration in renal function, and trough concentrations of both cyclosporine and tacrolimus were within the recommended range. Resolution of gout occurred within a month of discontinuation of cyclosporine and commencement of tacrolimus. Use of tacrolimus may be beneficial in the renal transplant recipient with refractory gout.     

Risk factors for allograft failure in United kingdom renal transplant recipients treated with cyclosporine A

BACKGROUND: After the introduction of cyclosporine A (CsA), 2-year graft survival of transplanted kidneys improved from less than 60% to more than 80%, but long-term graft survival and graft half-life have shown less change. This study investigates the impact of a range of demographic and treatment factors on long-term graft survival in renal recipients treated with CsA from all renal transplant centers in the United Kingdom. METHODS: Data were obtained from the Long-Term Efficacy and Safety Surveillance study of renal transplant recipients receiving CsA (Neoral; Novartis, Basel, Switzerland). A total of 1,757 de novo patients with a functioning graft at 1 year were evaluated. The endpoints considered were the need for regular dialysis or death. A stepwise stratified Cox model was used to identify the factors associated with outcome. RESULTS: Seven independent risk factors for allograft failure were identified: older recipient (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.6), male recipient (HR 1.8, 95% CI 1.2-2.7), younger donor (HR 1.7, 95% CI 1.2-2.5), above average creatinine (HR 1.9, 95% CI 1.3-2.8), chronic allograft nephropathy (HR 7.0, 95% CI 4.7-10.4), diabetic recipient (HR 2.2, 95% CI 1.2-4.1), and neoplasm after transplant (HR 1.7, 95% CI 1.2-2.6). CONCLUSION: Seven independent risk factors were found to influence graft survival. Only two of these can be modified by clinical intervention, elevated serum creatinine at 1 year and the occurrence of chronic allograft nephropathy. To influence these two factors, the optimization of immunosuppressive therapy is essential.     

Switchover to generic cyclosporine in stable renal transplant recipients: a single unit experience

BACKGROUND: The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma). METHOD: A two-period, single-sequence, cross-over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0-4 h and 0-12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8-1.25. RESULTS and CONCLUSION: A total of 38 stable renal transplant patients aged 49.79 +/- 11.38 years (mean +/- SD), who were 7.84 +/- 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 +/- 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.     

Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) still represent a major preoccupation after renal transplantation, even in the most recent years. METHODS: We analyzed the incidence, risk, and prognostic factors of PTLD in a cohort of kidney recipients using the United States Renal Data System. RESULTS: Among 25,127 Medicare patients transplanted between 1996 and 2000, 344 developed a PTLD defined as a non-Hodgkin lymphoma (1.4%). History of pretransplant malignancy (adjusted hazard ratio [AHR]=3.54, CI 2.31-5.43), younger age (AHR=1.91, CI 1.18-3.1), fewer HLA matches (AHR=1.32, CI 1.1-1.59) and treatment by ATG (AHR=1.55, CI 1.2-1.99) and OKT3 (AHR=1.37, CI 1-1.76), especially if given for rejection therapy were associated with an increased risk of PTLD. Mycophenolate and azathioprine were associated with a lower risk of PTLD (AHR=0.6, CI 0.47-0.78 and AHR=0.66, CI 0.46-0.95, respectively). IL2-receptor inhibitors and sirolimus did not modify the risk of PTLD. Patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine) have a lower risk of PTLD than those without. Patients with PTLD had poor survival (64% vs. 80% at 5 years). Older age, pretransplant malignancy and OKT3 were risk factors for death whereas treatment with mycophenolate was associated with a better survival (AHR=0.49, CI=0.28-0.82). CONCLUSIONS: Our study highlights the contribution of patient history and immunosuppression in the risk of PTLD in the era of modern immunosuppression.     

Use of anti-CD25 monoclonal antibody in combination with rapamycin to eliminate cyclosporine treatment during the induction phase of immunosuppression.

BACKGROUND: Cyclosporine and tacrolimus are associated with drug-induced renal dysfunction that may exacerbate recovery from ischemic injuries during the first month posttransplant. We sought to use anti-CD25 (anti-interleukin-2 receptor) monoclonal antibodies in combination with sirolimus (rapamycin) to avoid cyclosporine therapy during the early postoperative period in six renal transplant recipients deemed to be at high risk for delayed graft function. METHODS: Six consecutive patients deemed to be at high risk for delayed graft function were treated with rapamycin (2-12 mg/day), anti-CD25 monoclonal antibodies, and steroids, withholding inception of cyclosporine therapy until the serum creatinine fell below 3.0 mg/dl. RESULTS: During the first 2 months posttransplant, none of the patients displayed clinical or histopathological evidence of acute allograft rejection episodes, cytokine release syndrome, or hypersensitivity reactions. None of the patients received even empiric bolus or high-dose steroid therapy for a presumed rejection episode. All patients recovered renal graft function within 8 weeks posttransplant. To date all patients have stable renal graft function. Five patients have serum creatinine levels between 0.8 to 1.3 mg/dl at 6 months and the other patient has a serum creatinine level of 1.7 mg/dl at present follow-up of 2 months posttransplant. CONCLUSION: During the early posttransplant period anti-CD25 monoclonal antibodies combined with rapamycin and steroids offer a promising baseline therapy to avoid cyclosporine exposure and facilitate recovery from ischemic/reperfusion injuries.     

Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine

Calcineurin inhibitors potentially contribute to risk of cardiovascular events through the development of new-onset diabetes mellitus, hypertension and hyperlipidemia. The exact extent to which calcineurin inhibitors affect these risk factors is difficult to establish since pre-existing renal disease and concomitant immunosuppressive agents (such as steroids or TOR inhibitors) also exert an effect. Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus, which has been borne out in large-scale registry analyses. However, the risk of hypertension is approximately 5% higher with cyclosporine than tacrolimus, as is the risk of hyperlipidemia. Statin therapy is effective in treating dyslipidemia and has significant benefits in renal transplant patients. An individualized approach to choice of calcineurin inhibitor, by which cyclosporine or tacrolimus are selected based on the patient's particular risk profile, may thus help to reduce the toll of cardiovascular mortality among renal transplant recipients in the future.     

Impact of Immunosuppressive Medication on the Risk of Renal Allograft Failure due to Recurrent Glomerulonephritis

Recurrent glomerulonephritis is a major problem in kidney transplantation but the role of immunosuppression in preventing this complication is not known. We used data from the United States Renal Data System to examine the effect of immunosuppressive medication on allograft failure due to recurrent glomerulonephritis for 41 272 patients undergoing kidney transplantation from 1990 to 2003. Ten-year incidence of graft loss due to recurrent glomerulonephritis was 2.6% (95% confidence interval [CI]: 2.3–2.8%). After adjusting for important covariates, the use of cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus or prednisone was not associated with graft failure due to recurrent glomerulonephritis. There was no difference between cyclosporine and tacrolimus or between azathioprine and mycophenolate mofetil in the risk of graft failure due to recurrent glomerulonephritis. However, any change in immunosuppression during follow-up was independently associated with graft loss due to recurrence (adjusted hazard ratio 1.30, 95% CI: 1.06–1.58, p = 0.01). In patients with a pretransplant diagnosis of glomerulonephritis, the risk of graft loss due to recurrence was not associated with any specific immunosuppressive medication. The selection of immunosuppression for kidney transplant recipients should not be made with the goal of reducing graft failure due to recurrent glomerulonephritis.     

Mycobacterium Tuberculosis Infection Incidence in Hospitalized Renal Transplant Patients in the United States, 1998–2000

The incidence, risk factors, and prognosis for Mycobacterium tuberculosis (MTB) infection have not been reported in a national population of renal transplant recipients. We performed a retrospective cohort study of 15,870 Medicare patients who received renal transplants from January 1, 1998 to July 31, 2000. Cox regression analysis derived adjusted hazard ratios (AHR) for factors associated with a diagnosis of MTB infection (by Medicare Institutional Claims) and the association of MTB infection with survival. There were 66 renal transplant recipients diagnosed with tuberculosis infection after transplant (2.5 cases per 1000 person years at risk, with some falling off of cases over time). The most common diagnosis was pulmonary TB (41 cases). In Cox regression analysis, only systemic lupus erythematosus (SLE) was independently associated with TB. Mortality after TB was diagnosed was 23% at 1 year, which was significantly higher than in renal transplant recipients without TB (AHR, 4.13, 95% CI, 2.21, 7.71, p < 0.001). Although uncommon, MTB infection is associated with a substantially increased risk of mortality after renal transplantation. High-risk groups, particularly those with SLE prior to transplant, might benefit from intensified screening.     

AZA/Tacrolimus Is Associated with Similar Outcomes as MMF/Tacrolimus among Renal Transplant Recipients

There have been several retrospective studies indicating benefits associated with mycophenalate mofetil (MMF) compared to azathioprine (AZA) for renal transplant recipients. However, these analyses evaluated outcomes prior to changes in utilization patterns of concomitant immunosuppression. Recent prospective trials have indicated similar outcomes among patients treated with MMF and AZA. The aim of this study was to evaluate outcomes in a broad group of patients in the more recent era. We evaluated adult solitary renal transplant recipients from 1998 to 2006 with the national SRTR database. Primary outcomes were time to patient death and graft loss, complications and renal function. Models were adjusted for potential confounding factors, propensity scores and stratified between higher/lower risk transplants and concomitant immunosuppression. Adjusted models indicated a modest risk among AZA patients for graft loss (AHR = 1.14, 95% CI 1.07–1.20); however, this was not apparent among AZA patients also treated with tacrolimus (AHR = 0.97, 95% CI 0.85–1.11]. One-year acute rejection rates were reduced for patients on MMF versus AZA (10 vs. 13%, p < 0.01); there were no statistically significant differences of malignancies, renal function or BK virus at 1 year. The primary findings suggest the association of MMF with improved outcomes may not be apparent in patients also receiving tacrolimus.     

Hospitalized avascular necrosis after renal transplantation in the United States

BACKGROUND: The national incidence of and risk factors for hospitalized avascular necrosis (AVN) in renal transplant recipients has not been reported. METHODS: This historical cohort study consisted of 42,096 renal transplant recipients enrolled in the United States Renal Data System (USRDS) between 1 July 1994 and 30 June 1998. The data source was USRDS files through May 2000. Associations with hospitalizations for a primary diagnosis of AVN (ICD-9 codes 733.4x) within three years after renal transplant were assessed in an intention-to-treat design by Cox regression analysis. RESULTS: Recipients had a cumulative incidence of 7.1 episodes/1000 person-years from 1994 to 1998. The two-year incidence of AVN did not change significantly over time. Eighty-nine percent of the cases of AVN were due to AVN of the hip (733.42) and 60.2% of patients with AVN underwent total hip arthroplasty (THA); these percentages did not change significantly over time. In the Cox regression analysis, an earlier year of transplant, African American race [adjusted hazard ratio (AHR), 1.65, 95% confidence interval (CI) 1.33 to 2.03], allograft rejection (AHR 1.67, 95% CI 1.35 to 2.07), peritoneal dialysis (vs. hemodialysis; AHR 1.44, 95% CI 1.15 to 1.81), and diabetes (AHR 0.41, 95% CI 0.27 to 0.64) were the only factors independently associated with hospitalizations for AVN. CONCLUSIONS: The incidence of AVN did not decline significantly over time in the renal transplant population. Patients with allograft rejection, African American race, peritoneal dialysis and earlier date of transplant were at the highest risk of AVN, while diabetic recipients were at a decreased risk.     

Cyclosporine Microemulsion and Tacrolimus are Associated with Decreased Chronic Allograft Failure and Improved Long-term Graft Survival as Compared with Sandimmune

Tacrolimus and cyclosporine in the microemulsion formulation Neoral have demonstrated improvements in acute rejection rates after renal transplantation compared with conventional cyclosporine formulation, Sandimmune. To evaluate whether these drugs are also associated with improvements in chronic allograft failure (CAF) rates, we retrospectively analyzed 32,040 primary renal allograft recipients reported to the United States Renal Data System (USRDS) between 1994 and 1997. Graft loss secondary to CAF was defined as graft loss beyond 6 months post-transplant, censored for death, acute rejection, thrombosis, infections and noncompliance. A Cox proportional hazard model was used to investigate the relationship between graft loss secondary to CAF and the use of conventional cyclosporine formulation, as opposed to cyclosporine microemulsion and tacrolimus (Prograf). The analysis was corrected for confounding variables, such as acute rejection, sex, race, human leukocyte antigen (HLA) mismatch, % panel reactive antibodies (PRA), delayed graft function (DGF), cold ischemia time, induction therapy, dialysis time, etiology of end-stage renal disease, cytomegalovirus (CMV) risk group, donor source, era effect, and mycophenolate mofetil (MMF) use. Cyclosporine microemulsion use was associated with a significantly lower relative risk (RR = 0.6, Cl = 0.5-0.7) for CAF as opposed to conventional cyclosporine formulation. Likewise tacrolimus as compared with conventional cyclosporine formulation was associated with a significantly lower relative risk (RR = 0.7, CI = 0.6-0.8) for CAF. Conventional cyclosporine formulation treatment was associated with a 87.6% adjusted CAF-free survival rate at 4 years. Both tacrolimus and cyclosporine microemulsion were associated with a significantly better adjusted CAF-free survival at 4years (91.4 and 92.4%, respectively). Both cyclosporine microemulsion and tacrolimus are associated with improved graft survival and a decreased relative risk for CAF when compared with the older conventional cyclosporine formulation. This association is independent of the use of MMF or changes in era.     

Associations of characteristics of renal transplant recipients with clinicians' perceptions of adherence to immunosuppressant therapy

BACKGROUND: The objective of the study was to determine surveillance criteria for renal transplant recipients (RTRs) at highest risk for immunosuppressant therapy nonadherence. METHODS: Retrospective analyses were performed on follow-up data in the United States Renal Data System. Those who received transplants between January 1, 1995 and December 31, 2002, had at least 36 months of follow-up data, and did not receive a second renal transplant were included in the analyses. The risk of nonadherence was estimated by random effects logistic regression while controlling for age, gender, race, education, donor type, primary insurance, time since transplant, and immunosuppressant medications using the STATA software (College Station, TX). Association between nonadherence and graft failure was also examined. RESULTS: A total of 53,997 individuals met the inclusion criteria. About 6% of RTRs were reported nonadherent. Nonadherence risk increased with time posttransplant and decreased with age (P<0.001). RTRs who were male, nonwhite, or used mycophenolate mofetil or tacrolimus were more likely to be nonadherent with odds ratios (OR) of 1.36, 1.99, 1.13, and 1.31, respectively (P<0.05) than RTRs who used cyclosporine, steroids, azathioprine, or had Medicare (P<0.05). Nonadherent RTRs were more likely to experienced graft failure (P<0.001). CONCLUSIONS: Interventions to improve adherence should target younger RTRs, male RTRs, nonwhite RTRs, and those not on Medicare to reduce risk of graft failure.