Cyclosporine toxicity: the effect of combined therapy using cyclosporine, azathioprine, and prednisone

Forty-nine patients among 360 who received renal transplants under cyclosporine (CsA)/prednisone (Pred) immunosuppression required alteration of the immunosuppressive regimen because of intractable nephrotoxicity. Twenty-five patients, converted totally to azathioprine (Aza)/Pred, suffered intractable nephrotoxicity with no associated evidence suggesting ongoing rejection. The results with Aza/Pred conversion were disappointing because of an unacceptably high incidence of rejection and allograft loss. Twenty-four patients with intractable CsA nephrotoxicity were, therefore, treated using an alternative approach combining Aza with aggressive CsA dose reduction, and continued Pred therapy. All patients tolerated initiation of Aza without complication; allograft rejection was not common. Renal function improved for 23 of the 24 (96%) CsA/Aza/Pred patients with mean serum creatinine levels falling from 3.5 +/- 0.5 mg/dL to 2.2 +/- 0.4 mg/dL after a mean follow-up of 14 months (P less than .001). Among 18 patients observed at least 12 months, seven (39%) enjoyed serum creatinine values less than or equal to 2 mg/dL. Nine CsA/Aza/Pred-treated patients (37.5%) required hospitalization because of infectious complications, all of which resolved with temporary reduction of immunosuppression and specific antimicrobial therapy when indicated. One patient sustained acute allograft rejection as a result of patient noncompliance, and one patient on a seemingly appropriate CsA/Aza/Pred dose responded initially to steroid pulse antirejection therapy; however, renal function again worsened. Two patients developed progressive renal dysfunction due to chronic rejection, and returned to dialysis 13 and 17 months, respectively, following initiation of CsA/Aza/Pred. Overall, the actuarial graft survival for CsA/Aza/Pred-treated patients was 100% at 1 year, and 84% at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Sirolimus experience in heart transplantation

INTRODUCTION: Sirolimus is a potent, nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Recent data support the conversion in late renal failure secondary to calcineurin inhibitors (CNIs), with limited experience in de novo regimens in patients with predictive factors of postoperative renal impairment. OBJECTIVE: We evaluated our experience of sirolimus-based immunosuppression administered to 25 heart transplant recipients. METHODS: A retrospective analysis of 25 heart transplant recipients who received sirolimus included 17 conversions due to late CNI-related chronic renal dysfunction, six patients with a de novo regimen, and two patients who developed posttransplant pulmonary neoplasms. The conversion from CNI to sirolimus was started with 2 mg, with an average time after transplantation of 78 +/- 43 months and a mean baseline serum creatinine level of 2.1 +/- 0.45 mg/dL. The mean clinical follow-up was 17 +/- 9 months postconversion, and included echocardiography and laboratory studies. In the de novo group successive endomyocardial biopsies were performed during the first semester. RESULTS: Serum creatinine fell from 2.1 +/- 0.45 mg/dL to 1.8 +/- 0.51 mg/dL (P = .012). Mean sirolimus levels were 15 +/- 9 ng/mL (doses 2.2 +/- 0.4 mg). This improvement continued until 3 months (creatinine 1.5 +/- 0.35 P < .01)/sirolimus levels 11.7 +/- 5 ng/mL [1.9 +/- 0.7 mg]), with maintenance at 6 months (1.58 +/- 0.3 mg/dL/14 +/- 4 ng/mL [1.85 +/- 0.7 mg]) and 1-year postconversion (1.53 +/- 0.39 mg/dL; P = .019/10.7 +/- 2.5 ng/mL [1.5 +/- 0.7 mg]). De novo, after a mean follow-up of 13 months (range 3 to 35), sirolimus appeared to increase the incidence of a moderate histological grade of rejection without hemodynamic compromise. Side effects were common (63%), including peripheral edema, skin eruptions, and pericardial effusion. Only one patient discontinued treatment, due to intestinal intolerance. Four patients died during follow-up: two because of lung neoplasms and two because of progressive graft vessel disease. CONCLUSION: Sirolimus improved late CNI-related chronic renal dysfunction. Kidney function was preserved using a de novo CNI-free immunosuppressive regimen for recent cardiac transplant recipients.     

The effect of sirolimus in the development of chronic allograft nephropathy

PURPOSE: The effect of sirolimus (SRL) in renal function was studied in renal transplant recipients. PATIENTS AND METHODS: We studied 20 patients who underwent live related kidney transplantation 1 to 2 years prior under cyclosporine (CsA) treatment and displayed serum creatinine values between 2 and 3 mg/dL. The patients were randomized into 2 groups prospectively. The calcineurin inhibitors (CNI) group continued taking CsA; the SRL group underwent a switch from CsA to SRL. Biopsies were performed to assess chronic allograft nephropathy (CAN) findings and TGFbeta1 in the transplanted kidneys at the beginning and the end of the study. Creatinine clearance, serum creatinine, and proteinuria values were detected in the beginning as well as at 1, 3, 6, and 12 months later. RESULTS: At the beginning of the study, the creatinine clearance and serum creatinine levels were 52.21 mL/min and 2.05 mg/dL in the CNI group and 47.76 mL/min and 2.13 mg/dL in the SRL group, respectively. At 12 months, these values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Creatinine clearance values between the 2 groups at 12 months were statistically different. Although it was not significant, there was a tendency toward decreases inflammatory infiltration and TGFbeta1 levels in the SRL group compared with the CNI group on the second biopsies. CONCLUSION: Pathologic findings of CAN development, serum creatinine, and creatinine clearance values were ameliorated in the SRL group. We concluded that SRL positively affected long-term graft survival.     

Safety of Low-Dose Cyclosporine Therapy Before Transplantation in Kidney Allograft Recipients

Introduction

Graft dysfunction immediately posttransplantation can vary from subtle slowing of the expected decrease in creatinine concentration to frank oliguria requiring dialysis therapy for days to weeks. Risk factors for slow and delayed graft function include prolonged preservation, older donor age, and high plasma renin activity in the recipient. Cyclosporine (CsA) nephrotoxicity is another cause of early kidney allograft dysfunction.

Objective

To evaluate early kidney allograft function in patients who received low-dose CsA therapy for 48 hours before transplant surgery for comparison with that in recipients who received CsA therapy after improvement in allograft function.

Patients and Methods

In a case-control comparative study, 66 kidney recipients were divided into 2 groups on the basis of time of initiation of CsA therapy. In group 1, patients received CsA, 100 mg twice a day, for 48 hours before surgery, and in group 2, patients received CsA therapy after surgery when allograft function had improved (serum creatinine concentration ≤3 mg/dL). Other immunosuppression medications were the same in both groups. Statistical analysis was performed to compare kidney allograft function in the first month posttransplantation.

Results

In group 1 vs group 2, at day 1 posttransplantation, mean (SD) blood urea concentration was 73.72 (31.00) mg/dL vs 87.52 (29.82) mg/dL, serum creatinine concentration was 5.11 (1.83) mg/dL vs 6.42 (3.64) mg/dL, and urine volume in 24 hours was 11,052 (4290) mL vs 9629 (45.30) mL. At the end of the study, blood urea concentration was 49.61 (12.18) mg/dL vs 69.11 (33.76) mg/dL, serum creatinine concentration was 1.22 (0.28) mg/dL vs 1.47 (0.79) mg/dL, and urine volume in 24 hours was 3202 (986) mL vs 3095 (726) mL. No significant difference was noted between the 2 groups for age, sex, and immunosuppression medications.

Conclusion

Low-dose CsA therapy before transplant surgery preserves early allograft function without deleterious effects.     

Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.     

Mycophenolate mofetil for renal dysfunction after pediatric liver transplantation

BACKGROUND: Cyclosporine A (CsA) and tacrolimus (Tac) provide effective immunosuppression after orthotopic liver transplantation (OLT) but can cause renal dysfunction that may progress to end-stage renal failure (ESRF). Mycophenolate mofetil (MMF) is a newer immunosuppressant that does not affect renal function. Its long-term use in children with renal dysfunction after OLT has not yet been fully evaluated. METHODS: A retrospective analysis was performed of all children begun on MMF for renal dysfunction and followed up for at least 1 year. Renal dysfunction was defined as calculated glomerular filtration rate (cGFR) of less than 65 mL/min/1.73 m2. cGFR and liver function were measured before and after transfer. Data were analyzed using the Wilcoxon signed rank test. RESULTS: Forty-eight children (23 males) began MMF at a median age of 11.1 (0.9-18.1) years and at a median of 4.0 (0.3-12.4) years postOLT. Median baseline cGFR was 54 (range 29-65) mL/min/1.73 m2. Immunosuppression after transfer was MMF monotherapy in 36, MMF with steroids, in 4 and MMF with low-dose CsA or Tac in 8. In 44 (92%) patients, there was a statistically significant increase to a median cGFR of 69 (28-114) mL/min/1.73 m2 by 1 month and a further increase to a median cGFR of 77 (24-105) mL/min/1.73 m2 by 2 months of MMF treatment, after which time cGFR was maintained. Children aged less than 3 years at OLT or who were less than 5 years postOLT when MMF was begun demonstrated greater increases in cGFR. Four children with a median baseline cGFR of 34 (range 31-49) mL/min/1.73 m2 did not respond and progressed to ESRF. Mild side effects occurred in seven (15%) and gastrointestinal bleeding requiring discontinuation of MMF in one (2%). Liver function abnormalities occurred in seven (15%): transient transaminitis in three, acute rejection in two, and chronic rejection in two, of whom one required retransplantation. CONCLUSIONS: In 92% children with renal dysfunction after OLT, MMF treatment provided safe and effective immunosuppression and allowed CsA or Tac to be discontinued or reduced, leading to improvement of renal function. The improvement was greatest in younger children and those who began MMF early postOLT. Side effects were uncommon. Additional steroid cover during the transfer to MMF should be considered to prevent liver-allograft rejection.     

Rapamycin at six years can exhibit normal renal function without proteinuria or neoplasia after renal transplantation. A single-center experience

Currently, long-term experience with Rapamune (RAPA) after renal transplantation is scarce. We present our experience with RAPA in patients who were included in clinical trials. Between 1996 and 1999, 27 renal transplant patients received RAPA alone or in combination with cyclosporine (CyA). We study 15 of them (9 males, 6 females; mean age 36 years) who are currently functioning with a mean follow-up of 6 years (range, 5.2-8 years). The presence of delayed graft function was 40% and acute rejection 26.6%, all of them controlled with steroids. Notably, no patients experienced an acute rejection episode after the first year. Among 15 patients, 12 received steroids, RAPA and CyA; and 3 received steroids, RAPA, azathioprine (AZA) or mycophenolate mofetil (MMF) for immunosuppression. At the end of follow-up, the situation was the opposite: 12 patients received steroids (2.5-5 mg/d) and RAPA associated with or without AZA/MMF, and 3 were maintained with steroids, RAPA and CyA. Renal function was excellent in the entire group: mean SCr 1.1 mg/dL (range, 0.7-1.8) with mean RAPA blood levels (HPLC) of 11 ng/dL (range 8-16). Hyperlipidemia was universal with all patients (100%) receiving statins maintaining acceptable levels of cholesterol (mean 209 +/- 28 mg/dL) and tryglycerides (mean 154 +/- 76 mg/dL). Arterial hypertension present in 12 of 15 (80%) patients was controlled with a mean of 1.5 drugs. Notably, no patient presented with proteinuria, neoplasia, posttransplant diabetes, or cardiovascular events. In conclusion, these single-center results suggest that Rapamune may be useful in the long-run after renal transplantation. The presence of normal renal function and the absence of proteinuria and neoplasia in these renal transplant patients may have important clinical implications.     

Cyclosporine withdrawal in post-renal transplant thrombotic microangiopathy

INTRODUCTION: Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)-treated renal transplantation but optimum treatment strategies are not clearly defined. PATIENTS AND METHODS: All patients transplanted between January 1996 and December 2001 at our center who had biopsy-proven TMA and in whom CsA was withdrawn were studied retrospectively. RESULTS: The TMA was found in nine of 688 patients (1.3%). All except one donor were living related. HLA matching was one haplotype in all except one where both haplotypes were different. There were five males and four females and the mean age was 24.9 +/- 9 yr. All of them developed TMA within 3 months of transplant. Five of nine had evidence of microangiopathic hemolysis on peripheral film. Serum creatinine at the time of diagnosis of TMA was 3.1 +/- 1.3 mg/dL. Cyclosporine was discontinued in all and mycophenolate mofetil was substituted for azathioprine. No episode of acute rejection occurred after CsA withdrawal. Graft function did not improve in four who eventually became dialysis-dependent after a mean duration of 12.6 +/- 8.3 months. Remaining patients showed stabilization or improvement in function and all had serum creatinine below 2 mg/dL after a mean follow up of 24 months. CONCLUSION: The CsA withdrawal in cases with TMA at a stage when significant functional deterioration has not taken place can salvage the graft.     

Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

BACKGROUND: Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. METHODS: CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. RESULTS: In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. CONCLUSIONS: Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.     

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose (n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 +/- 0.36 versus 1.58 +/- 0.33 mg/dL, P < .001) and BUN (39.2 +/- 11.8 versus 29.9 +/- 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 +/- 10.8 versus 61.6 +/- 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 +/- 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 +/- 19 versus 130 +/- 14 mm Hg, P < .01) and diastolic (82 +/- 9 to 74 +/- 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 +/- 25.9 versus 25.2 +/- 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.     

Rapamycin rescue therapy in patients after kidney transplantation: first clinical experience

This study was aimed at analysing rapamycin (RAPA) rescue therapy with calcineurin inhibitor (CNI) withdrawal in renal transplant patients primarily presenting with CNI-nephrotoxicity (CNI-Neph), chronic allograft nephropathy (CAN) without [CAN(a)] and with histological changes suggestive of chronic rejection [CAN(b)]. In 36 patient with CNI-Neph (n = 6), CAN(b) (n = 21), CAN(a) (n = 7), and others (n = 2) RAPA therapy was started 4.4-115 months (median 30.6 months) after renal transplantation. During a follow up of 3-33 months (median 19 months) parameters of kidney function were recorded. Three patients on haemodialysis did not show any recovery of graft function. Of the remaining 33 patients renal function improved in 22 (66.7%), was stable in three (9%) but deteriorated in eight (24%) patients, of whom seven (21%) required haemodialysis thereafter. Success rate of RAPA therapy differed with respect to the histological diagnosis: 70% in CAN(b), 80% in CNI-Neph and 33% in CAN(a). Furthermore, in patients with creatinine levels above 400 mum (n = 6) graft function rarely improved (n = 2, 33%). The RAPA rescue therapy with CNI withdrawal appears promising in a special cohort of patients with chronic renal allograft dysfunction even late after transplantation.     

Conversion from cyclosporine A to tacrolimus in pediatric kidney transplant recipients with chronic rejection: changes in the immune responses

BACKGROUND: Tacrolimus (Tac) has immunosuppressant properties similar to those of cyclosporine A (CsA), but it is more potent. At present, however, its immunosuppressive activity in renal transplant recipients with ongoing chronic rejection has not been clarified. METHODS: We studied changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, cytotoxic antibodies, lymphocyte population, and cytokine response before and after the conversion from CsA to Tac in 14 pediatric renal transplant recipients with chronic rejection. CsA (5.9+/-0.2 mg/kg/d) was replaced by Tac (0.1+/-0.004 mg/kg/d). RESULTS: Serum creatinine decreased (2.3+/-0.2-1.9+/-0.2 mg/dL, P <0.005), creatinine clearance increased (36.8+/-2.5-46.1+/-4.4 mL/min/1.73 m, P <0.005), and urinary protein excretion decreased (0.4+/-0.01-0.2+/-0.04 g/24 hr, P <0.03) after 6 months, and these values were maintained after 2 years with Tac treatment. During Tac therapy, anti-donor and anti-control mixed lymphocyte culture decreased 38% and 31% (P <0.05), respectively. Cell-mediated lympholysis did not change. CD3 decreased from 87%+/-2% to 80%+/-2% (P <0.005), and CD8 decreased from 34%+/-3% to 27%+/-2% (P <0.005). The switch to Tac decreased the interferon-gamma production in vitro (P <0.05) and increased tumor necrosis factor-alpha levels (P <0.05). The release of interleukin-10 was strikingly augmented with CsA or Tac therapy (P <0.01), but transforming growth factor-beta secretion was similar. CONCLUSIONS: Our data indicate that conversion from CsA to Tac therapy leads to an improvement in renal function without altering key elements of the immunosuppression in children with ongoing chronic rejection.     

mTOR inhibitors: do they help preserve renal function?

BACKGROUND: Renal function deterioration is one of the main problems facing heart transplant recipients. The mammalian target of rapamycin (mTOR) inhibitors, in combination with or replacing calcineurin inhibitors, may help preserve renal function. The aim of this study was to evaluate the progression of renal function after switching the immunosuppressive regimen. PATIENTS AND METHODS: We studied 23 heart transplant recipients (5.5 +/- 4.5 years since transplantation). An mTOR inhibitor was introduced to replace cyclosporine (everolimus, 65%; sirolimus, 35%). Patient clinical characteristics and renal function were studied after switching. The statistical analysis used Student t test for paired data. RESULTS: The reason for the transplantation was ischemic cardiopathy (52%), dilated myocardiopathy (39%), or other causes (9%). Mean age at time of transplantation was 52 +/- 9 years. Comorbidities were as follows hypertension (43%), insulin-dependent diabetes (22%), hypercholesterolemia (39%), and ex-smokers (70%). The reason for the switch was increased creatinine (65%), appearance of tumors (26%), or others (8%). Previous creatinine level was 1.89 +/- 0.6 mg/dL with clearance of 61.7 +/- 23 mL/min and at the end of follow-up (mean follow-up, 11 +/- 6 months) creatinine level was 2.0 +/- 1.45 mg/dL with clearance of 68.3 +/- 35 mL/min, namely, no significant difference (P = .49 and P = .57, respectively). In the subgroup of patients who switched treatment due to renal dysfunction, initial creatinine level was 2.38 +/- 0.4 mg/dL with clearance of 42.3 +/- 10 mL/min and at the end of follow-up it was 2.28 +/- 0.2 mg/dL and 43.6 +/- 11 mL/min, respectively (P = .68 for creatinine and clearance). CONCLUSIONS: The introduction of mTOR inhibitors to the immunosuppressant regimen may be useful to delay renal functional deterioration caused by calcineurin inhibitors.     

Immunosuppression With Low-Dose Daclizumab in Liver Transplant Recipients With Impaired Kidney Function: A Single-Center Experience

Background

Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function.

Methods

We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids.

Results

Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 ± 1.22 mg/dL and 19 ± 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 ± 0.3 mg/dL and 107 ± 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 ± 0.45 mg/dL and 86 ± 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]).

Conclusions

Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.     

C2 therapeutic drug monitoring of cyclosporine is a safe and feasible method in de novo heart transplant patients

BACKGROUND: The narrow therapeutic window of cyclosporine (CsA) requires close therapeutic drug monitoring (TDM). While C2-TDM has been established after renal and liver transplantations, clinical experience is limited for patients after de novo heart transplantation (HTX). PATIENTS AND METHODS: In a retrospective study, we investigated 40 patients undergoing HTX; 34 patients received induction therapy using antithymocyte globulin (ATG Mérieux). Immunosuppression was administered with CsA (Sandimmun-Optoral), with dosages adjusted according to C2 levels (800-1100 ng/mL during the first 6 months and reduced to 400-600 ng/mL from the beginning of the first year). At different times TI (months 1-3). TII (months 12-14) TIII (months 24-26), and TIV (months 34-36), we obtained measures of acute cellular rejections (ARs), cytomegalovirus (CMV) infections, creatinine, and safety laboratory parameters. RESULTS: The cumulative survival was 95% after 1 year, and 88% after 3.8 years. Eight ARs were diagnosed at a mean of 7.6 months after HTX in 7 patients. Twenty-four CMV infections/reactivations were verified. In 10 cases, treatment was started because of clinical symptoms. The mean creatinine values significantly rose in the early postoperative phase (TI: 1.23+/-0.47 mg/dL, TII: 1.49+/-0.41 mg/dL; P<.0001). Thereafter the creatinine values declined; however, this was not statistically significant (TIII: 1.38+/-0.57 mg/dL, TIV: 1.15+/-0.30 mg/dL). All other safety parameters showed no significant changes. CONCLUSIONS: C2 allows individualization of immunosuppression with reduced CsA toxicity, but without loss in safety among de novo patients after HTX. We obtained freedom from severe AR, a low number of CMV infections, and excellent patient survival.     

Alemtuzumab induction with tacrolimus monotherapy in de novo renal transplantation

OBJECTIVES: Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. METHODS: This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. RESULTS: At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 +/- 0.65 mg/dL at 3 months, 1.56 +/- 0.84 at 6 months, 1.45 +/- 0.37 at 12 months, and 1.74 +/- 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and >6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. CONCLUSION: Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.     

Conversion from tacrolimus to cyclosporine could improve control of posttransplant diabetes mellitus after renal transplantation

Posttransplant diabetes mellitus (PTDM) occurs in approximately 15% to 20% of renal transplant patients. It has important clinical implications for graft function and survival. Anticalcineurin drugs are associated with an increased risk of developing PTDM. There is a little evidence that conversion from tacrolimus to cyclosporine (CsA)-based immunosuppression improves glucose metabolism and reverses diabetes. This prospective study included nine renal transplant patients (mean age of 34 +/- 20) with PTDM under immunosuppression with tacrolimus. Five were switched directly to CsA and the other four (glycemia > 250 mg/dL) required insulin and were simultaneously switched to CsA. Basal blood levels of tacrolimus were 7.9 +/- 1.9 ng/dL. Conversion was associated with an early, significant improvement of glycemia and HbA1c blood levels (P < .01). At the end of the follow-up, the glycemia (105 +/- 20 mg/dL) and Hb1Ac (5.1 +/- 0.4 mg/dL) were normal. Insulin was discontinued between 3 and 6 months in all patients who required it at the beginning. Cholesterol did not change significantly and triglycerides decreased significantly (basal 210 +/- 85 mg/dL, at 12 months 125 +/- 29, P < .01). Graft function was stable with a mean serum creatinine of 1.7 +/- 0.2 mg/dL. CsA blood levels remained stable during all follow-up periods (P = NS). There were neither episodes of acute rejection nor secondary effects related to the medication. In summary, renal transplant patients receiving tacrolimus who develop PTDM may display better control of hyperglycemia by a switch to CsA.     

Combination therapy of mycophenolate mofetil and rapamycin in prevention of chronic renal allograft rejection in the rat

BACKGROUND: Chronic rejection is the leading cause of long-term allograft loss. Until now, no therapy has been recognized as being efficient in its prevention. In addition to their immunosuppressive activity, mycophenolate mofetil (MMF) and rapamycin (RAPA) show diverse properties against vascular smooth muscle cell activity, cell-adhesion molecule expression, and ischemia-reperfusion injury. The combination effect of MMF and RAPA was tested to prevent chronic renal allograft rejection in the rat in this study. METHODS: Nephrectomized Lewis recipients underwent orthotopic transplantation with Fisher (F344) kidneys (allograft groups) or Lewis kidneys (isograft control). The initial episode of acute rejection was controlled with a short course of cyclosporine A (CsA) (1.5 mg/kg/day for 10 days). From weeks 4 to 20, animals were thereafter treated every other day either with vehicle, MMF (20 mg/kg), RAPA (0.8 mg/kg), or MMF (20 mg/kg) plus RAPA (0.8 mg/kg) in combination. Animals were sequentially killed at serial intervals over a follow-up of 50 weeks, and histologic study was performed on harvested kidneys according to the Banff working classification for allograft pathology. RESULTS: Animals treated with MMF or RAPA alone showed a Banff sum score similar to the allograft control group (6.31+/-1.01 and 7.27+/-1.14 vs. 7.21+/-1.14, respectively; P>0.05). When the recipient rats were treated with MMF and RAPA in combination, it resulted in a clinically and statistically significant reduction of Banff sum score (4.21+/-0.79, P<0.01), with specific inhibition of vascular fibrous intimal thickening, allograft glomerulopathy, and interstitial fibrosis. CONCLUSION: Over a 50-week study, concomitant therapy of MMF and RAPA prevents chronic renal allograft rejection, probably through reduction of ischemic and cytotoxic degenerative changes. These results warrant further investigation in the combination of MMF and RAPA as anti-chronic rejection therapy in clinical transplantation.     

Is sirolimus a safe alternative to reduce or eliminate calcineurin inhibitors in chronic allograft nephropathy in kidney transplantation?

PURPOSE: We evaluate whether cyclosporine (CsA) or tacrolimus (FK) could be reduced or eliminated after sirolimus was added in chronic allograft nephropathy (CAN). By reducing doses of CsA or FK, we expected that renal function would improve. METHOD AND MATERIAL: Twenty-one patients with CAN had sirolimus added as an immunosuppressive agent. We evaluated the creatinine (Cr) level 3 months after addition. The doses of CsA and FK were decreased gradually and then eliminated over a course of 4 to 6 weeks. If the Cr level rose rapidly or other prominent signs of rejection occurred; low-dose CsA or FK would be added per protocol. We evaluated the duration of engraftment before sirolimus and the Cr level when it was added. RESULTS: Renal function improved in 13 of 21 cases. The improvement in Cr ranged from 12.5% maximally to 1.84% minimally. Seven of 13 cases still required low-dose CsA. The average duration of engraftment before sirolimus was 13.66 +/- 10.80 months. The average Cr level before sirolimus was 1.65 +/- 0.56 mg/dL. In the other eight cases, the Cr level kept rising from 5.1% to 20.4%. The average duration of engraftment was 88.38 +/- 42.21 months. The average Cr level before sirolimus was 2.85 +/- 0.54 mg/dL. Hyperuricemia was noted in 31.3% and hyperlipidemia in 68.8%. CONCLUSION: Sirolimus is a safe alternative to reduce or eliminate CsA or FK in CAN. In cases with a long duration of engraftment and high Cr level, sirolimus might have some effect as a substitute for CNI and thus prevent further nephrotoxicity.