Long-Term Use of Mycophenolate Mofetil is Associated With a Reduction in the Incidence and Risk of Late Rejection

To evaluate the association of long-term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998. The primary study endpoint was acute rejection beyond 1 year after transplantation. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. All multivariate analyses were corrected for potential confounding covariates. Mycophenolate mofetil was associated with a 65% decreased risk of developing late acute rejection as compared to AZA (RR = 0.35, CI 0.27-0.45, p < 0.001). The incidence of acute rejection episodes at 2 and 3 years post-transplantation was significantly lower in the MMF group (0.9% at 2 years, 1.1% at 3 years) than the AZA group (6.1% at 2 years, 9.3% at 3 years). In the primary vs. repeat late rejection analysis, MMF patients exhibited a decreased late acute rejection risk of 72% (RR = 0.28, p < 0.001) and 60%, respectively (RR = 0.40, p < 0.001). In African Americans, the late acute rejection risk was 70% lower in MMF patients than AZA patients (RR = 0.30, p < 0.001). Further study is indicated to determine the optimal duration of MMF therapy after renal allograft transplantation.     

Conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression

OBJECTIVE: In a randomized control trial of mycophenolate mofetil (MMF) versus azathioprine (AZA) with cyclosporine and steroids, we demonstrated that MMF reduced acute rejection (AR) among renal allograft recipients (RTX) who were of low to moderate risk. However, 10% had AR when converted from MMF to AZA at 6 months, postrenal transplantation (RT). Two clinical markers, abnormal serum creatinine (SCr) and proteinuria at 6 months, post-RT, were associated with AR postconversion. The present study examined the safety of such conversion in selected high-risk RTX at 1 year of MMF therapy. METHODS: Thirteen high-risk RTX receiving MMF for either high panel reactive antibody (n = 9) or following AR (n = 4), with normal SCr and no proteinuria at 1 year, were selected for conversion. The incidence of AR, adverse events, and renal parameters (SCr, creatinine clearance, proteinuria) at 6 months postconversion was evaluated. Eight high-risk RTX who did not meet these selection criteria were retrospectively reviewed and used as controls. RESULTS: Renal parameters (SCr 123 +/- 26 vs 129 +/- 27 mumol/L; pre- vs postconversion) were not significantly different; no episodes of AR or proteinuria were documented. Azathioprine was discontinued in two patients due to leukopenia. In the control group, one patient had graft loss from chronic rejection, whereas one developed posttransplant lymphoproliferative disease necessitating MMF withdrawal. CONCLUSION: These results suggest that selective conversion from MMF to AZA after 1 year is safe, even in high-risk RTX. Normal SCr and absence of proteinuria are good screening parameters to identify patients at low risk for AR following such conversion.     

Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the "creeping creatinine" study

BACKGROUND: This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. METHODS: In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. RESULTS: The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. CONCLUSIONS: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.     

Effect of mycophenolate mofetil on long-term outcomes in African american renal transplant recipients

African American renal transplant recipients have poorer graft survival. A study using the United States Renal Data Registry documented an improvement in graft survival for patients who took mycophenolate mofetil (MMF) compared with azathioprine (AZA). This analysis did not address the impact of MMF on African American renal transplant recipients. The present study aimed to quantify potential beneficial effects of MMF therapy on long-term renal allograft survival in African Americans. With the use of the United States Renal Data Registry, all adult Caucasian and African American patients who had received a primary renal transplant between 1988 and 1997 were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Primary study end points were death with a functioning graft and graft failure censored for death. A total of 57,926 patients were studied. For African Americans, 3-yr patient survival was 96.3 versus 93.2% (P<0.001) for MMF and AZA, respectively. Three-yr death-censored graft survival for African Americans was 85.8 versus 75.1% (P<0.001) for MMF and AZA, respectively. For Caucasians, 3-yr patient survival was 97.3 versus 93.2% for MMF and AZA, respectively. Three-yr death-censored graft survival for Caucasians was 90.1 versus 86.4% (P<0.001) for MMF and AZA, respectively. By multivariate analysis, MMF was associated with a significant reduction in the relative risk for all study end points in African Americans. MMF therapy is associated with both improved patient and death-censored graft survival in African American renal transplant recipients. This benefit is comparable to the benefit of MMF in Caucasian renal transplant recipients.     

Randomized trial of conversion from mycophenolate mofetil to azathioprine 6 months after renal allograft transplantation.

BACKGROUND: In the first year after renal allograft transplantation, triple therapy immunosuppression with cyclosporin (CsA), prednisone (P), and mycophenolate mofetil (MMF) is superior to a triple therapy treatment that includes azathioprine (AZA) instead of MMF. Whether long-term treatment with CsA-P-MMF is better than treatment with CsA-P-AZA is a matter of debate, as 3-year graft survival is similar in MMF- and AZA-treated patients. The purpose of the present study was to examine the short-term effect of changing MMF to AZA in low-risk renal allograft recipients 6 months after transplantation. METHOD: This was a randomized, open-label single-centre study, recruiting 48 low risk renal allograft recipients on CsA-P-MMF therapy 6 months after transplantation, comparing the outcome with continued MMF treatment (2 g b.i.d.) (group A, n=22) or switching MMF to AZA (1 mg/kg) treatment (group B, n=26). RESULTS: The outcome after a 6-months follow-up of patients in group A and group B was similar. Treatment failure rates (defined as clinically diagnosed acute rejection episodes) were 4.5% in group A and 3.8% in group B. There were no patient deaths and no graft failures during the 6-months observation period. Graft function was excellent and similar in both groups. CONCLUSION: Replacing MMF with AZA 6 months after transplantation in low-risk renal allograft recipients is safe and is not associated with altered graft function in the short term.     

Impact of Cyclosporine Reduction With MMF: A Randomized Trial in Chronic Allograft Dysfunction. The ''Reference'' Study

Long-term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA-based therapy with a serum creatinine between 1.7-3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 x 10(-4) vs. -3.0 x 10(-4), respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy-proven acute rejection occurred. One patient in each group lost his graft because of biopsy-proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group. In CAD, the reduction of CsA in the presence of MMF results in significant improvement in renal function during a 2-year follow-up.     

Six-year follow-up of azathioprine and mycophenolate mofetil use during the first 6 months of renal transplantation

Long-term follow-up examination to test whether therapy with mycophenolate mofetil (MMF) or azathioprine (AZA) during the first year translates into different graft or patient survival and graft function is important. Therefore, 6-year follow-up data of a group of 80 consecutive renal transplant recipients were analyzed. The first group of 40 patients was treated with AZA, cyclosporine and prednisone and the second group with MMF, cyclosporine and prednisone for the first 6 months. Graft failure rates were compared during follow-up. Creatinine, inverse slope of creatinine (delta/creatinine) and 24-hour proteinuria at 6 years post transplantation were compared. The Kaplan-Meier analyses for death-censored and non-censored graft failure showed no difference between the groups. Creatinine values at 6 years for the AZA Group were 139 +/- 36 micromol/l (95% CI 125.9-151.2 micromol/l) and for the MMF Group 149 +/- 52 micromol/l (95% CI 133.9-164.9 micromol/l). Delta/creatinine and 24-hour proteinuria at 6 years did not differ between the two groups. We conclude that an initial 6-month treatment with MMF as opposed to AZA reduced the early rejection rate, but did not result in superior long-term graft function or survival after 6 years of follow-up observation.     

Mycophenolate Mofetil versus Azathioprine in the Maintenance Therapy of Lupus Nephritis

Background. Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus. Renal involvement contributes to both morbidity and mortality of the patients as well as indirectly through side effects of therapy directed at the renal lesions. The aim of the study was to evaluate the efficacy of mycophenolate mofetil (MMF) and azathioprine (AZA) in the maintenance therapy of lupus nephritis. Methods. Thirty-two patients from our center with diagnosed lupus nephritis World Health Organization Class III, IV, V were treated with IVC (0.75–1g/month) for six months in addition to steroid therapy, and then with AZA (n?=?15) or MMF (n?=?17) as a maintenance therapy. The efficacy of two drugs was compared with changes in serum creatinine, creatinine clearance, 24 hour urine protein excretion, cholesterol, anti-dsDNA antibody, and urine sediment. Results. Mean follow-up time was 41.5 + 7 months. The total remission occurred in 84% of patients (82% with MMF and 87% with AZA), with a complete remission rate of 59.3% (58% with MMF and 60% with AZA) and a partial remission rate of 25% (22% with MMF and 27% with AZA). The urinary protein excretion before MMF treatment was 1.9 + 1 g/dL and decreased significantly to 0.91 + 0.6 g/dL (p?=?0.028) after treatment, and decreased from 1.58 + 0.7g/dL to 0.4 + 0.23g/dL in the AZA group (p?=?0.04). The serum creatinine level decreased from 1.32 + 0.7 mg/dL to 1.12 + 0.68 mg/dL in the MMF group (p?=?0.23), and decreased from 0.91 + 0.23mg/dL to 0.88 + 0.23 mg/dL in the AZA group (p?=?0.49). There was no significant change between two groups (p?=?0.1). The serum cholesterol decreased from 229 + 57 mg/dL to 171 + 9 mg/dL (p?=?0.002), and serum triglyceride level decreased from 228 + 116 mg/dL to 98 + 35 mg/dL (p?=?0.004) in the MMF treatment, but no significant change was seen in AZA group. There was no significant difference between the two groups considering the rates of doubling of serum creatinine, progression to end-stage renal failure, relapses, and documented side effects, as well. Conclusion. Both therapeutic approaches with MMF or AZA, in combination with corticosteroids, are effective as a maintenance therapy for lupus nephritis.     

Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.     

Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: a 2-year follow-up

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.     

Comparison of long-term actual renal allograft survival in mycophenolate mofetil and azathioprine-based triple drug immunosuppression protocols

INTRODUCTION: The use of mycophenolate mofetil (MMF) in renal transplantation results in a 50% lower incidence of acute rejection compared to azathioprine (AZA). However, the graft survival reports are conflicting: the European trial and US database analysis suggest better survival with MMF, an observation that was not seen in the US and tricontinental studies. METHODS: We retrospectively reviewed our single-center experience (60% African-Americans) comparing the serum creatinine (SCr) values and 3-year actual graft survival with MMF versus AZA-based immunosuppression. Group I included patients transplanted between January 1990 and December 1992 on cyclosporine (CSA), AZA, and steroids; group II subjects, from January 1996 to December 1998 on CSA, MMF, and steroids. We analyzed SCr and all causes of graft losses at 3, 6, 12, 18, 24, and 36 months posttransplantation. RESULTS: The patient demographics were similar in both groups as was the mean SCr values at different times. The time-group interaction for SCr, the Kruskal-Wallis test for SCr for different categories (<1.5, 1.5 to 2.0, 2.0 to 2.5, and >2.5 mg/dL) and the all-cause graft loss between the two groups were not significantly different. CONCLUSION: Our results failed to show better long-term actual graft survival despite the 6-year interval between the two groups. These findings agree with the results of the United States and the tricontinental studies. A lower incidence of acute rejection early after transplantation observed with MMF may not always translate into a long-term benefit, possibly due to the influence of nonimmunological factors, such as hypertension, calcineurin inhibitor toxicity, more frequent cytomegalovirus infections, and increased attempts to withdraw steroids using MMF-based protocols.     

Cyst decompression surgery for autosomal dominant polycystic kidney disease.

A prospective study was undertaken to evaluate the efficacy of surgical cyst decompression for retarding the progression of renal failure and for the management of chronic pain associated with autosomal dominant polycystic kidney disease (ADPKD). Thirty patients with ADPKD and pain (14 patients), renal insufficiency (4 patients), or both (12 patients) underwent unilateral (19 patients) or bilateral (11 patients) cyst reduction surgery. The patients were monitored for 21 +/- 2 months postoperatively. The probability of being painfree was 80% at 1 yr and 62% at 2 yr. Preoperative and 1-to 3-month postoperative serum creatinine levels and GFR (clearance of insulin or (125I) iothalamate) were not significantly different (2.2 +/- 0.3 versus 2.2 +/- 0.3 mg/dL and 49 +/- 8 versus 54 +/- 9 mL/min/1.73 m2, respectively). One-year serum creatinine levels remained unchanged in patients with normal preoperative renal function (1.0 +/- 0.07 versus 1.0 +/- 0.05 mg/dL), whereas those with preoperative progressive renal insufficiency had no difference in the mean slope of reciprocal serum creatinine plots preceding and after surgery (-0.008 +/- 0.001 versus -0.009 +/- 0.002 dL/mg/month). In patients who underwent unilateral surgery, split function isotope scans showed no change in function of the operated kidney when compared with the nonoperated kidney. Surgical cyst decompression provides effective relief of chronic pain without compromising renal function. However, the data in this article do not support the use of this procedure to slow progression of renal insufficiency in ADPKD.     

A comparison of discharge immunosuppressive drug regimens in primary cadaveric kidney transplantation

BACKGROUND: Finding the best combination of immunosuppression is an important challenge in kidney transplantation. Current short-term (1- and 3-year) allograft survival is quite good, making it difficult to determine differences in therapeutic regimens without large sample sizes. Using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network database, the current study provides substantial statistical power to analyze the outcomes for different immunosuppressive regimens. METHODS: To compare the effects of four discharge regimens (cyclosporine and azathioprine [CYA+AZA], CYA and mycophenolate mofetil [MMF], tacrolimus [TAC]+AZA, and TAC+MMF) on long-term survival, a multivariate Cox regression analysis was conducted on 19246 primary cadaveric kidney transplants during 1995 to 1998. RESULTS: Compared with CYA+AZA, the combination of CYA+MMF was associated with a 10% reduced risk of graft loss (relative risk [RR] 0.90, 95% confidence limit [CL] 0.84-0.96, P<0.001), whereas TAC+AZA was associated with an 18% reduced risk (RR 0.82, 95% CL 0.67-1.005, P=0.06) and TAC+MMF with a 20% reduced risk of graft loss (RR 0.80, 95% CL 0.71-0.89, P<0.001). All three regimens benefited patients regardless of delayed graft function (DGF) or early acute rejection status. In addition, in the absence of DGF, the combinations of CYA+MMF, TAC+AZA, and TAC+MMF were associated with a reduced risk of mortality compared with CYA+AZA. CONCLUSIONS: The major finding of this study was improved graft and patient survival associated with TAC+MMF and CYA+MMF in patients with or without DGF or early acute rejection.     

Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine.

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost-effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation. Forty-three stable patients on chronic MMF therapy as part of an open-label, long-term safety study were converted to either commercially available MMF (CellCept) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined. Twenty-three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p = 0.002. Additionally, mean scores (1-5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5+/-0.6 before and 1.2+/-0.4 after conversion in MMF group vs. 1.3+/-0.5 before and 1.7+/-0.9 after conversion to AZA; p = 0.02). No allograft loss occurred as a result of conversion. These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.     

Anemia in the period immediately following renal transplantation

INTRODUCTION: Anemia remains frequent in the first month following renal transplantation and is a risk factor for cardiovascular accidents. The purpose of this study was to analyze the prevalence of anemia during this period notably among different immunosuppressive treatment groups. METHODS: In this study, we entered the patients who had received a renal allograft in our transplant unit from 1993 to 2003, including patients who had received azathioprine (AZA) from 1993 to 1996 and mycophenolate mofetil (MMF) from 1996 to 2003. No patient received rHu-erythropoietin after transplantation during that period. A mathematical model normalized the hemoglobin (Hb) threshold level at which blood transfusion was decided and Hb on admission. RESULTS: One hundred and eighty-eight patients on AZA and 223 on MMF were included in the analysis. The mean age +/- SD was 41 +/- 12 years in the AZA group, and 45 +/- 12 years in the MMF group (P < .006). Before the transplantation, Hb was higher in the MMF group (11.4 +/- 1.9 vs 10.2 +/- 2 g/dL, P < .0001). After normalization at a threshold level of transfusion of 7 g/dL, transfusions were more frequent among the MMF group (72% vs 48%, P < .0001). Double therapy with MMF (1500 mg/d) + steroids or therapy with MMF (750 mg/d) + tacrolimus + steroids increased the risk of transfusion compared to the AZA group. MMF (750 mg/d) + cyclosporine conferred a similar risk of transfusion compared with the AZA group. CONCLUSION: MMF alone or in association with tacrolimus is associated with an increased risk of anemia and transfusion in the immediate posttransplantation period.     

Cyclosporine levels at 2 hours after dose and body mass index in relation to graft function in renal transplant patients treated with azathioprine or mycophenolate mofetil

The aim of this study was to evaluate the effect of C(2) levels on renal graft function in relation to body mass index (BMI). This retrospective study of 95 renal transplant patients included 53 on AZA and 42 on MMF at 3.1 years after transplantation. The cohort was divided into groups according to their C(2) levels, namely <600 ng/mL, 600 to 900 ng/mL, or >900 ng/mL, and according to BMI (>26 kg/m(2)). In every group, we evaluated the percentage of patients with an increase in creatinine by 1 mg/dL or >/=50% from the first year posttransplant. There was no difference in age, gender, graft source, and dose of corticosteroids or CsA between the groups. Patients on AZA with C(2) 600 to 900 ng/mL showed a lower prevalence of renal dysfunction (3.4%) than those with C(2) levels <600 ng/mL (14.3%) or >900 ng/mL (20%). Seventeen percent of the patients on AZA and 11.9% on MMF had BMI >26 kg/m(2) (P = NS). An increased serum creatinine was present in 22.2% of patients with BMI >26 kg/m(2) in the AZA group vs 20% in the cohort MMF (P = NS). These findings suggest that long-standing renal recipients on AZA with C(2) levels of between 600 and 900 ng/mL show better preservation of renal function. We did not identify differences on the basis of C(2) levels in MMF-treated recipients. The influence of BMI on long-term graft function seemed to be independent of AZA or MMF therapy.     

Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease acute rejection episodes after kidney transplantation, and has been associated with better graft and patient survival vs azathioprine (AZA). Previous studies reported a higher risk of death due to infection in elderly recipients treated with MMF-based immunosuppression. METHODS: We analysed 5069 elderly ( > 65 years of age) primary renal allograft recipients treated with either MMF or AZA reported to the Scientific Registry of Transplant Recipients between 1988 and 2000, and compared rates of acute rejection, late acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft. RESULTS: In Cox proportional hazard models, MMF was associated with lower rates of late acute rejection with 12 (RR = 0.72, P = 0.11) and 24 months (RR = 0.50, P = 0.028) of continuous therapy. In univariate analysis (Kaplan-Meier), MMF was associated with improved patient (P = 0.0003) and graft (P<0.0001) survival vs AZA, and trends toward improved patient and graft survival in multivariate analyses. CONCLUSIONS: These findings demonstrate the efficacy of MMF-based immunosuppression in elderly transplant recipients and do not suggest an increased risk of death compared to treatment with AZA.     

Renin-angiotensin system blockade in biopsy-proven allograft nephropathy

Allograft nephropathy leads to progressive renal injury and ultimate graft loss. In native kidney disease, the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is beneficial in retarding the decline of renal function. We reviewed a cohort of renal transplant recipients who were prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy. Patients were followed from time of initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function, and rate of renal function decline pre- and post-ACEi/ARB. The 5-year allograft survival after biopsy was 83%. Mean serum creatinine was 2.2 +/- 1.1 mg/dL (range 1.0 to 4.3) at time of biopsy and 2.6 +/- 1.2 mg/dL (1.2 to 6.5) at last follow-up. The mean slope of the creatinine versus time (SD) was 2.43 (7.93) in the 12 months prior to therapy and 1.45 (3.66) following therapy, with the absolute difference in slope -3.38 (6.06) (P =.0004). We conclude that treatment with ACEi/ARB is beneficial in the management of allograft nephropathy.     

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.     

Spontaneous changes in the rate of decline in reciprocal serum creatinine: errors in predicting the progression of renal disease from extrapolation of the slope.

The slope of reciprocal serum creatinine (1/Pcr) versus time has been used to measure the rate of progression of chronic renal disease, predict the interval until onset of end-stage renal disease, and assess the effect of therapy. In order to determine the errors that might result from extrapolating the slope of 1/Pcr versus time beyond the interval of observation, we applied a method of linear regression analysis to search for spontaneous changes in slope in 21 patients from New England Medical Center and 56 patients in three published studies in whom the decline in 1/Pcr appeared constant (r greater than or equal to 0.84 for the correlation of 1/Pcr versus time). Significant changes in the slope (breakpoints) were identified in one third to one half of the 77 patients and appeared to be spontaneous. The second slope was less steep in 49 patients (6.1%); the mean value for serum creatinine at the time of the breakpoint was 5.3 mg/dL; the mean change in slope (absolute value) was 0.005 dL/mg/month (adults) and 0.017 dL/mg/month (children); and the mean error in prediction of the interval until the final value for serum creatinine was 27% of the actual interval. We conclude that spontaneous breakpoints in the slope of 1/Pcr versus time are very frequent, even among patients with an apparent constant rate of decline. Breakpoints may cause errors in extrapolating the slope to predict the interval until the onset of end-stage renal disease and to assess the effect of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)