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 The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P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.     

Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil.

The management of liver transplant recipients with renal function impairment remains controversial because cyclosporine withdrawal from triple immunosuppression regimens may be followed by graft rejection. A nonnephrotoxic and powerful immunosuppressant such as mycophenolate mofetil (MMF) could allow a reduction of cyclosporine dosage or its withdrawal and an improvement in renal function in these patients. Eleven patients with serum creatinine levels greater than 1.5 mg/dL, normal graft function, and a rejection-free period of at least 1 year started MMF at a dose of 2000 mg/d (reduced in case of adverse events) while cyclosporine dosage was slowly reduced. At last follow-up (63 +/- 5 weeks), 7 patients remained free of cyclosporine (6 of those patients are also free of steroids), 2 patients reduced their cyclosporine dose, and 2 patients developed mild acute rejection that responded to a switch to tacrolimus therapy. Serum creatinine and urea levels in the 7 patients free of cyclosporine decreased from 2.22 +/- 0.13 to 1.90 +/- 0.19 mg/dL (P =.05) and 0.95 +/- 0.10 to 0.60 +/- 0.10 g/L (P <.001), respectively. Creatinine clearance increased from 38.16 +/- 5.60 to 47.01 +/- 6. 76 mL/min (P =.005). Control of arterial hypertension also improved. Tolerance to MMF was good, but 6 patients required dose reductions, mainly because of asymptomatic anemia. In conclusion, in liver transplant recipients with stable graft function, MMF may allow cyclosporine dose reduction or discontinuation, thus improving renal function and the control of arterial hypertension. This change of treatment must be carefully monitored because of the frequent need for MMF dose reduction and the risk for rejection.     

Single-center, open, prospective, randomized pilot study comparing cyclosporine versus tacrolimus in simultaneous pancreas-kidney transplantation

BACKGROUND: Although tacrolimus (Prograf) is the calcineurin inhibitor usually employed in simultaneous pancreas-kidney transplantation (SPKTx), no prospective randomized studies have compared its efficacy to cyclosporine (Neoral), when either drug is used in combination with mycophenolate mofetil (MMF) and the pancreas is drained into the portal vein. METHODS: Between May 2001 and June 2003, 16 SPKTx recipients were randomized to be prescribed Neoral and 17 Prograf in addition to basiliximab, steroids, and MMF. All pancreata were drained into the portal vein. RESULTS: After a median follow-up of 15.6 months, six kidney acute rejection episodes were observed with Prograf (36.5%; one steroid-resistant) and one Neoral (n = 1, 6.2%; P =.04). No pancreas rejection episode was recorded. Two infections occurred in two recipients from each group. No major adverse events were noted other than a severe hematological toxicity (Prograf). Metabolic parameters were equivalent in the two groups, save for higher total cholesterol (212 +/- 39 mg/dL vs 173 +/- 23 mg/dL; P =.008), LDL (129 +/- 33 mg/dL vs 101 +/- 21 mg/dL; P =.029), and triglyceride (191 +/- 86 mg/dL vs 126 +/- 40 mg/dL; P =.028), values with Neoral, although the same differences were already present at baseline. One recipient (Neoral) died with functioning grafts. Patient, pancreas, and kidney survival rates were all 94% for Neoral versus 100% for Prograf. CONCLUSIONS: Although a larger series and a longer follow-up are needed, Neoral and Prograf used in combination with MMF seem to achieve equivalent success rates among primary SPKTx when the pancreas is drained into the portal vein.     

Renal function in patients with cadaveric kidney transplants treated with tacrolimus or cyclosporine

INTRODUCTION: Renal function predicts graft survival in kidney transplant patients. This study compared the 2-year evolution of renal function in patients treated with cyclosporine or tacrolimus in combination with mycophenolate mofetil (MMF) and prednisone. METHODS: We studied 1558 cadaveric renal transplant recipients from 14 Spanish hospitals between January 2000 and December 2002. Of these, 1168 were treated with tacrolimus and 390 with cyclosporine. The primary efficacy endpoint was long-term renal function. Renal function was measured by serum creatinine and glomerular filtration rate (GFR) by creatinine clearance calculated from the Cockcroft-Gault formula. This report summarizes the 2-year results. RESULTS: At 24 months the tacrolimus group showed significantly better serum creatinine (1.5 +/- 0.7 vs 1.8 +/- 0.8 mg/dL, P < .001) and GFR (60.5 +/- 20.9 mL/min vs 47.9 +/- 10.0, P < .001) than the cyclosporine group. Additionally, recipients with ideal graft donors (23.5 +/- 2.8 vs 24.0 +/- 2.9 years) had a better serum creatinine at 2 years (1.23 +/- 0.2 vs 1.5 +/- 0.4 mg/dL, P < .05). Multivariate analysis showed that tacrolimus was an independent factor associated with better renal function: odds ratio 1.6, 95% confidence interval (1.2 to 2.2), P < .001. CONCLUSIONS: Patients with a renal transplant treated with tacrolimus in combination with MMF and prednisone displayed better renal function at 2 years than those who received cyclosporine.     

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.     

Rapid Discontinuation of Steroids in Living Donor Kidney Transplantation: A Pilot Study

Steroids are associated with significant postoperative complications (hypertension, cosmetic changes, bone loss, hyperlipidemia, diabetes, and cataracts). Most develop early; in addition, late post-transplant steroid withdrawal in kidney transplant recipients has been associated with increased acute rejection (AR). To obviate these problems, we studied outcome of a protocol of rapid discontinuation of prednisone (RDS) (steroids stopped on POD6). Between November 1, 1999 and October 31, 2000, 51 adult living donor (LD) first transplant recipients (2 HLA-id, 28 non-id relative, 21 LURD) were immunosuppressed with thymoglobulin (1.25 mg/kg intraoperatively and then qdx4); prednisone (P) (500 mg methylprednisolone intraoperatively, 1 mg/kg x 1 day, 0.5 mg/kg x 2 days, 0.25 mg/kg x 2 days, then d/c); MMF, 1 g b.i.d.; and CSA, 4 mg/kg b.i.d. adjusted to achieve levels of 150-200 ng/mL (by HPLC). Exclusion criteria were delayed graft function or primary disease requiring P. Minimum follow-up was 5.5 months (range 5.5 to 17.5 months). Outcome was compared vs. previous cohorts of LD recipients immunosuppressed with P/AZA/CSA (n = 171) or P/MMF/CSA (n = 43) (both without antibody induction). RESULTS: For the RDS group, average CSA level (+/- S.E.) at 3 and 6 months was 190 +/- 12 and 180 +/- 9; avg. MMF dose, 1.7 +/- 0.1 g and 1.7 +/- 0.1 g. There was no significant difference in 6- and 12-month actuarial patient survival, graft survival and rejection-free graft survival between recipients on the RDS protocol vs. historical controls. For RDS recipients, actuarial 6- and 12-month rejection-free graft survival was 87%. Of the 51 RDS recipients, five (10%) have had AR (at 20 days, 1 month, 3 months, 3 months, and 3.5 months post-transplant). After treatment, all five were maintained on 5 mg P; there have been no second AR episodes. Two additional recipients were started on 5 mg P due to low white blood count (WBC) and low/no MMF. Of the 51 grafts, one has failed (death with function). Average serum Cr level (+/- S.E.) at 3 and 6 months for RDS recipients was 1.7 +/- 0.5 (NS vs. historical controls). CONCLUSION: For low-risk LD recipients, a kidney transplant with an RDS protocol does not increase risk of AR or graft loss. Future studies will need to be done to assess AR rates with an RDS protocol in cadaver transplant recipients and in recipients with delayed graft function.     

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.     

Improvement of impaired renal function in heart transplant recipients treated with mycophenolate mofetil and low-dose cyclosporine

BACKGROUND: Cyclosporine (CsA) nephrotoxicity is a common problem after cardiac transplantation. We have studied the impact of CsA dose reduction in association with mycophenolate mofetil (MMF) treatment on renal function in heart transplant recipients with suspected CsA nephrotoxicity (serum creatinine level >2 mg/dl). METHODS: Twelve heart transplant recipients (11 men, 1 woman; 111 to 1813 days after transplantation) with CsA-based immunosuppression (plus azathioprine and/or steroids) and a serum creatinine level >2.0 mg/dl were started on a daily dose of 2000 mg of MMF. Dilated cardiomyopathy was the underlying disease in nine patients, ischemic cardiomyopathy in three patients. Mean patient age was 57 years (range 44-69 years). Azathioprine was discontinued and CsA slowly tapered. Creatinine clearance, serum creatinine level, urea nitrogen, and uric acid were monitored. CsA levels were measured, and CsA dose was adjusted for whole blood levels of 70-120 microg/L. Ten patients still had endomyocardial biopsies, whereas one had echocardiographic controls only. RESULTS: One grade 1B rejection episode according to ISHLT (International Society for Heart and Lung Transplantation) was observed until 1 year after the switch to MMF. One patient was excluded due to gastrointestinal side effects. CONCLUSIONS: Conversion from azathioprine to MMF with consecutive reduction of CsA in heart transplant recipients with CsA-impaired renal function improves renal function as evidenced by lower serum creatinine, urea nitrogen, uric acid, and higher creatinine clearance.     

Mycophenolat Mofetil und niedrigdosiertes Cyclosporin A verbessern die eingeschr?nkte Nierenfunktion von Herzempf?ngern

Zusammenfassung Cyclosporin (CSA) Nephrotoxizität ist ein häufiges Problem nach Herztransplantation. Wir untersuchten den Effekt einer CSA-Dosisreduktion in Verbindung mit einer Mycophenolat Mofetil (MMF) Behandlung auf die Nierenfunktion von Herzempfängern mit CSA-Nephrotoxizität (Serum-Kreatinin >2mg/dl).¶ Methoden: 14 herztransplantierte Patienten (12 Männer, 2 Frauen; 111 bis 1813 Tage nach HTX) mit CSA-basierter Immunsuppression (plus Azathioprin und/oder Steroide) und einem Serum Kreatinin >2mg/dl wurden mit einer Tagesdosis von 2000mg MMF behandelt. Eine dilatative Kardiomyopathie war bei 10 Patienten die Grunderkrankung, eine ischämische Kardiomyopathie bei 4. Das mittlere Patientenalter betrug 57 Jahre (44-69 Jahre). Azathioprin wurde abgesetzt und CSA langsam reduziert. Kreatinin-Clearance, Serum Kreatinin, Harnstoff-N und Harnsäure wurden kontrolliert. Cyclosporin-Spiegel wurden gemessen und die Dosis auf Zielspiegel von 70-1207g/l eingestellt. 12 Patienten hatten Endomyokardbiopsien, 2 nur noch echokardiographische Kontrollen. ¶ Ergebnisse: Zwei Abstoßungen Grad 1B nach ISHLT wurden beobachtet innerhalb von einem Jahr nach Wechsel zu MMF. ¶ Parameter Ausgangswert (N=14) Langzeit-Verlauf (N=14) P¶ Serum Kreatinin (mg/dl) 2,5 - 0,8 1,8 - 0,6 0,001 Harnstoff-N (mg(dl) 51 - 18 41 - 17 0,008 Harnsäure (mg/dl) 9,9 - 2,1 8,1 - 2,3 0,005 Kreatinin-Clearance (ml/min) 45 - 20 60 - 36 0,01 CSA-Spiegel (7g/l) 177 - 54 106 - 28 <0,001 Schlußfolgerungen: Die Umstellung von Azathioprin auf MMF mit konsekutiver Reduktion von CSA bei Herztransplantierten mit CSA-induzierter Nephropathie verbessert die Nierenfunktion belegt durch niedrigeres Serum-Kreatinin, Harnstoff-N, Harnsäure und höhere Kreatinin-Clearance. Summary Cyclosporin A (CSA) nephrotoxicity is a common problem after cardiac transplantation. We have studied the impact of CSA dose reduction in association with mycophenolate mofetil (MMF) treatment on renal function in heart transplant recipients with suspected CSA nephrotoxicity (serum creatinine >2mg/dl). Methods: 14 heart transplant recipients (12 men, 2 women; 111 to 1813 d post transplant) with CSA-based immunosuppression (plus azathioprine and/or steroids) and a serum creatinine >2mg/dl were started on a daily dose of MMF of 2000mg. Dilated cardiomyopathy was the underlying disease in 10 pts, ischemic cardiomyopathy in 4. Mean patient age was 57 yrs (range 44-69 yrs). Azathioprine was discontinued and CSA slowly tapered. Creatinine clearance, serum creatinine, urea nitrogen, and uric acid were monitored. Cyclosporine levels were measured and CSA dose adjusted for whole blood levels of 70-1207g/l. 12 pts still had endomyocardial biopsies while 2 had echocardiographic controls only.¶ Results: Two rejection episodes grade 1B acc. to ISHLT were observed until one year after switch to MMF. Results: Two rejection episodes grade 1B acc. to ISHLT were observed until one year after switch to MMF. ¶ Parameter Baseline¶(N=14) Late Follow-Up (N=14) P¶ Serum creatinine (mg/dl) 2.5 - 0.8 1.8 - 0.6 0.001 Blood urea nitrogen (mg/dl) 51 - 18 41 - 17 0.008 Uric acid (mg/dl) 9.9 - 2.1 8.1 - 2.3 0.005 Creatinine clearance (ml/min) 45 - 20 60 - 36 0.01 Whole blood CSA level (7g/l) 177 - 54 106 - 28 <0.001 Conclusions: Conversion from azathioprine to MMF with consecutive reduction of CSA in heart transplant recipients with CSA-induced renal impiarment improves renal function as evidenced by lower serum creatinine, urea nitrogen, uric acid, and higher creatinine clearance.     

The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression

BACKGROUND: We performed a sequential study to determine the efficacy and side effects of low-dose (1 g) mycophenolate mofetil (MMF) in a CNI drug avoidance regimen including sirolimus/steroids. METHODS: A total of 260 kidney-only recipients were given basiliximab (232) or thymoglobulin (28) induction, and sirolimus/steroids. In addition, 160 recipients were begun on standard MMF 1 g twice daily (2-g group), while 100 recipients were begun on low-dose MMF 500 mg twice daily (1-g group). The 1-g recipients were concentration controlled to keep mycophenolic acid (MPA) C0 levels at 1.8-4 microg/ml. RESULTS: There were no statistically significant differences in demographics between the groups. At 6 months there were no significant differences between the 2-g and 1-g MMF groups in patient survival (96.8% vs. 96%), graft survival (92.5% vs. 95%), biopsy-confirmed and treated acute rejection (8.8% vs. 13%), or mean creatinine mg/dL (1.41+/-0.52 vs. 1.47+/-0.67), respectively. Mean MPA C0 levels microg/ml were (4.7 vs. 2.3) at 1 month, (4.1 vs. 3.1) at 3 months, and (3.9 vs. 2.4) at 6 months. There were no significant differences at 1, 3, or 6 months in mean WBC, HgB, or platelets, or wound complications. There were significant reductions in the number of patients reporting nausea-vomiting-dyspepsia (20.6% vs. 8%, P=0.007), diarrhea (34.3% vs. 20%, P=0.01), and abdominal pains (10.6% vs. 4%, P=0.05), between the 2-g and 1-g MMF groups, respectively. CONCLUSIONS: The use of concentration-controlled 1-g MMF results in comparable transplant outcomes with less GI toxicity during the first 6 months posttransplant in a CNI drug-free sirolimus based immunosuppressive regimen.     

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.     

Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure

BACKGROUND: Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function. METHODS AND RESULTS: Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.     

Beneficial effects of fluvastatin on progressive renal allograft dysfunction

To assess the time-dependent changes in renal function in relation to antioxidant and lipid-lowering effects of fluvastatin in hyperlipidemic renal transplant recipients, 20 patients were treated with fluvastatin 40 mg/d for 12 months, after failure of a dietary program. Plasma malondialdehyde (MDA) levels and lipid profiles were evaluated in relation to serum creatinine and calculated creatinine clearances 18 months before and during the fluvastatin treatment. Mean baseline lipid values were: total cholesterol 318 mg/dL, triglycerides 212 mg/dL, LDL cholesterol 219 mg/dL, HDL cholesterol 58 mg/dL, apolipoprotein A 176 mg/dL, and apolipoprotein B 145 mg/dL. During 12 months of treatment, fluvastatin produced consistent and significant reductions in total and LDL cholesterol (-18.4% and -24.1%), triglycerides (-17.7%), and apolipoprotein B (-22.7%) as well as an increase in HDL cholesterol (12.3%) and apolipoprotein A (9.2%). Plasma MDA levels decreased by 41.8% (from 3.5 +/- 0.3 to 1.8 +/- 0.1 nmol/mL, P =.00002). Creatinine clearance, which had been declining at a rate of 0.32 mL/min/month during the previous 18 months before treatment, progressively improved during treatment, giving a positive slope of the creatinine clearance, which increased by 0.35 mL/min/month, (P =.016; 53.3 +/- 4.2 mL/min vs 49.8 +/- 4.1 mL/min pretreatment). Multiple linear regression analysis revealed that MDA was the parameter most closely associated with the variability in creatinine clearance. In conclusion, renal transplant patients with lipid abnormalities display renoprotective activity of fluvastatin, possibly due to its lipid-lowering and antioxidant effects.     

New immunosuppressive treatment in kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has been successfully introduced into clinical practice with evident benefits for renal transplant recipients. SUBJECTS AND METHODS: To evaluate some clinical results of MMF introduction, two groups of subjects underwent cadaveric renal transplants over the last 3 years and were retrospectively investigated. The first group (AZA group) contained 40 subjects (26 males and 14 females) on triple-drug therapy with steroids, cyclosporine and azathioprine (AZA). The second group (MMF group) contained 25 patients ( 19 males and 6 females) on the same regime with steroids and cyclosporine but MMF was administered as a third drug instead of AZA. The AZA group received renal transplant after a mean dialytic time of 32 +/- 19 months and the AZA group's dialytic time was 39.9 +/- 17 months. Clinical data, collected after a minimum 12 months observational period included a crude mortality rate and survival analysis recognized by Kaplan-Meyer curve, creatinine, creatinine clearance, rejection episodes and major clinical events such as infections and acute tubular necrosis. RESULTS: One subject died in each group. For kidney graft survival, Kaplan Meyer survival analysis showed a mean survival time of 1170.04 days in the AZA group vs 845 in the MMF group without statistical significance. Graft survival demonstrated 5:40 (12.5%) graft losses in the AZA group vs no kidney transplant loss in the MMF group (the only deceased patient had a well functioning kidney). The curve of graft cumulative proportion survival analysis demonstrated a more improved survival in the MMF group, but this difference did not reach a statistical significance (p = 0.07). Acute rejection episodes in the AZA group were 37.5% vs. 20% in the MMF group. In both groups, CMV infection was successfully treated with specific antiviral agents. CONCLUSIONS: MMF represents an important step towards induction and maintenance of immunosuppression. Our experience in a relatively small cohort investigated in a single center, demonstrates encouraging results regarding graft survival in comparison to those detected in conventional triple drug therapy. Surprisingly, in spite of stronger immunosuppressive treatment, the prevalence of CMV infections was not statistically different in the MMF versus the AZA group.     

HLA-identical renal transplants: impact of cyclosporine on intermediate-term survival and renal function

Seventy-two and 34 consecutive HLA-identical sibling renal transplant recipients were treated with azathioprine/prednisone (AZA; follow-up, 5.0 years) and cyclosporine/prednisone (CSA; mean follow-up, 2.9 years), respectively. Both groups were similar in age, sex, race, and number of transplants, but there were more diabetics in the CSA group (34% v 8%). Actual patient survival at 1 year and actuarial patient survival at 5 years were 100% and 96%, respectively in the CSA group compared with an actual patient survival of 91% and 82% at 1 and 5 years, respectively, in the AZA group. Actual graft survival at 1 year improved from 85% in the AZA group to 97% in the CSA-treated recipients (P less than 0.05). Mean serum creatinine at 5 years remained stable in the AZA group at a mean of 123 mumol/L (1.4 mg/dL) compared with a progressive increase in this parameter to a mean of 212 mumol/L (2.4 mg/dL) after the same time interval in the CSA patients. Furthermore, the slopes of the serum creatinine against time were significantly different between the two groups (P less than 0.01). Mean daily CSA dose averaged 4 mg/kg 12 months following transplantation, with a decrease to 2.4 mg/kg by the fifth year. Causes of death in the AZA group were cardiovascular (eight), sepsis (three), cancer (one); and in the CSA group, Kaposi's sarcoma (one). Causes of graft failure in the AZA group were immunological (six), sepsis (three), technical (two), recurrence of disease (one), and patient death with a functioning graft (five). Technical (one), noncompliance (two), recurrence of disease (one), and patient death with a functioning kidney (one) caused graft failure in the CSA group. No difference in posttransplantation serum cholesterol or incidence of new onset diabetes was observed between the two groups, but hypertension was significantly more frequent (51% v 21%, P less than 0.01) when CSA was used. In conclusion, intermediate-term results of CSA-treated HLA-identical transplant recipients showed improved patient and graft survival with less complications apart from hypertension. However, the slow, but relentless, increase in serum creatinine in the CSA-treated patients compared with those treated with AZA is of concern.     

Randomized trial of tacrolimus versus cyclosporine in steroid withdrawal in living donor renal transplant recipients

The introduction of new immunosuppressants has prompted trials of steroid withdrawal. However, several groups have reported a higher incidence of rejection. We conducted a randomized two-arm, parallel-group, open-label, prospective study to compare steroid withdrawal (at 6 months posttransplant) from the regimens of tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine + MMF (CSA group). The entry criteria were recipients of first living donor transplants with no diabetes mellitus (DM), congestive heart failure, chronic liver disease, or acute rejection within 6 months posttransplant. The primary endpoint was a biopsy-proven acute rejection episode or treatment failure within 1 year posttransplant. While 87 recipients were assigned to FK (n = 43) and CSA groups (n = 44) before transplantation, 76 recipients (FK 39, CSA 37) could be tapered off steroids at 6 months posttransplant, since 11 were excluded due to acute rejection within 6 months posttransplant (FK two, CSA three) or protocol violations (FK two, CSA four). After steroid withdrawal, the incidence of acute rejection episodes was 0% in the FK group and 13.5% in the CSA group (P < .05). Other results at 12 months posttransplantation were comparable: the incidences of DM 7.8% versus 0% (FK group vs CSA group), hypercholesterolemia 41.0% versus 59.5%, hypertensives 48.7% versus 59.6% as well as the levels of plasma creatinine 1.21 +/- 0.24 versus 1.31 +/- 0.50 mg/dL (P > .05 in every variable). These data suggest that steroid withdrawal is successful in first living donor renal transplant recipients. Tacrolimus may be significantly more effective than cyclosporine to prevent acute rejection after steroid withdrawal.     

A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year

BACKGROUND: This is the 1-year report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. METHODS: Prior to transplantation, recipients were randomized to receive tacrolimus plus corticosteroids with either sirolimus (n=185) or MMF (n=176). The incidence of biopsy-confirmed acute rejection at 6 months was the primary endpoint of the study. Patient and graft survival, renal function, study drug dosing and discontinuations were evaluated at 1 year. RESULTS: At 1 year, there was no difference in patient survival (95.7% sirolimus vs. 97.2% MMF; P=0.45) or graft survival (90.8% sirolimus vs. 94.3% MMF; P=0.22). Patients without delayed graft function (DGF) receiving MMF had significantly better graft survival (99% vs. 93%; P=0.01). Patients receiving a transplant from a live donor had a trend towards better graft survival with MMF as compared to sirolimus (98% vs. 91%; P=0.07). Patients receiving sirolimus had a significantly higher incidence of study drug discontinuation (26.5% vs. 14.8% MMF; P=0.006). Patients receiving MMF had significantly better renal function as shown by median serum creatinine levels (1.3 mg/dL vs. 1.5 mg/dL; P=0.03) and a trend towards higher calculated creatinine clearance (CrCl), (58.4 ml/min vs. 54.3 ml/min; P=0.06). More patients in the sirolimus group had a serum creatinine >2.0 mg/dL, (20.4% vs. 11.0%; P=0.02). CONCLUSIONS: Tacrolimus is safe and effective in live and deceased donor kidney transplantation when given in combination with sirolimus or MMF. Patient and graft survival were excellent in both arms. Renal function is superior for patients treated with tacrolimus + MMF combination.     

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.     

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.     

Vascular complication and Doppler ultrasonographic finding after renal transplantation

OBJECTIVES: Vascular complications are common after renal transplantation. In this study we correlated Doppler sonographic indices and transplant kidney function. METHODS: We reviewed data on 244 renal transplant patients. Doppler ultrasonographic evaluation was performed during the first 2 weeks after renal transplantation. We determined resistive index (RI) and pulsatility index (PI) in the interlobar arteries and thrombosis of renal and lower limb veins. Serum creatinine (Cr) and cyclosporine levels were evaluated prior to sonographic assessment. RESULTS: The mean age of the 142 male and 102 female patients was 36.31 +/- 3.30 years. Prevalence of real artery stenosis was 9.5%. In these patients the mean serum Cr level (2.21 +/- 1.83 mg/dL) was significantly higher than among patients with patent renovascular tributary (1.49 +/- 1.00 mg/dL; P=.03). RI and PI were also significantly correlated with serum Cr(P=.05 and .001, respectively). There was no relationship between cyclosporine level or panel-reactive antibody with RI and PI. Retransplant patients showed higher RI than first renal allograft recipients (0.72 +/- 0.16 vs 0.63 +/- 0.11; P=.006). Serum Cr level was higher among renal allograft recipients with Doppler evidence of thrombosis of the lower limb veins (3.1 +/- 0.98 mg/dL versus 1.56 +/- 1.13 mg/dL; P=.04). CONCLUSIONS: RI and PI are two valuable Doppler ultrasonographic markers to determine renal allograft function and related vascular complications.