Renal transplantations in African Americans: a single-center experience of outcomes and innovations to improve access and results.

OBJECTIVE: To report a single-center 10-year experience of outcomes of kidney transplantation in African Americans (AAs) vs Caucasian Americans (CA) and to propose ways in which to improve kidney transplant outcomes in AAs, increased access to kidney transplantation, prevention of kidney disease, and acceptance of organ donor registration rates in AAs. METHODS: We compared outcomes of deceased donor (DD) and living donor (LD) renal transplantation in AAs vs CAs in 772 recipients of first allografts at our transplant center from January 1995 to March 2004. For DD and LD transplants, no significant differences in gender, age, body mass index, or transplant panel reactive antibody (PRA) existed between AA and CA recipients. RESULTS: Primary diagnosis of hypertension was more common in AA, DD, and LD recipients. Significant differences for DD transplants included Medicaid insurance in 23% AA compared with 7.0% CA (P<.0001) and more frequent diabetes mellitus type 2 in AAs (15% vs 4.1%, P=.0009). Eighty-three percent of AAs had received hemodialysis compared with 72% of CAs (P=.02). AAs endured significantly longer pretransplant dialysis (911±618 vs 682±526 days CA, P=.0006) and greater time on the waiting list (972±575 vs 637±466 days CA, P<0001). In DD renal transplants, AAs had more human leukocyte antigen (HLA) mismatches than CAs (4.1±1.4 vs 2.7±2.1, P<.0001). Mean follow-up for survivors was 7.1±2.5 years. Among LD transplants, graft survival and graft function were comparable for AAs and CAs; however, among DD transplants, graft function and survival were substantially worse for AAs (P=.0003). In both LD and DD transplants, patient survival was similar for AAs and CAs. CONCLUSION: Our data show that AAs receiving allografts from LDs have equivalent short- and long-term outcomes to CAs, but AAs have worse short- and long-term outcomes after DD transplantation. As such, we conclude that AAs should be educated about prevention of kidney disease, the importance of organ donor registration, the merits of LD over DD, and encouraged to seek LD options.

A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients.

BACKGROUND: Wound healing problems and lymphoceles have been reported with greater frequency in kidney recipients given de novo sirolimus. This problem has led to increased patient morbidity and cost; and has been an impediment to the completion of randomized controlled trials in which wound problems have necessitated premature discontinuation of mammalian target of rapamycin inhibitors. METHODS: We developed a systematic program to reduce these problems based on patient selection (body mass index [BMI] <32 kg/m2), the use of closed suction drains, modifications of surgical technique, and avoidance of a loading dose of sirolimus. Consecutive series of adult kidney-only recipients given antibody induction followed by de novo sirolimus, mycophenolate mofetil, and steroids were compared; group 1: 204 patients transplanted with few restrictions and group 2: 103 patients transplanted using the above program. RESULTS: This approach resulted in a significant reduction (group 2 vs. group 1) in cumulative wound complications (7.8% vs. 19.6%, P=0.007), and nonoperative wound complications (2.9% vs. 14.2%, P=0.001). In addition, the incidence of lymphoceles detected (22.3% vs. 47.1%, P<0.0001), treated (4.8% vs. 24.5%, P<0.0001), or needing surgical intervention (1.9% vs. 14.2%, P=0.001) was significantly reduced. Multivariate analysis demonstrated that a BMI more than 30 to 32 kg/m2 was the most significant variable related to delayed wound healing (odds ratio [OR] 3.01, 0.02) or surgical repair (OR 8.05, P=0.0001), whereas BMI (OR 1.54, P=0.038) and acute rejections (OR 1.34, P=0.03) were most associated with lymphocele treatment. CONCLUSIONS: A systematic program of wound care using de novo sirolimus can produce wound healing complications comparable with that reported with other agents.

Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.

BACKGROUND: We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function. METHODS: Sixty-one patients were randomized to either sirolimus (n=31) or cyclosporine (n=30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10-12 ng/mL for at least 6 months. RESULTS: After 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs. 90%, P=0.681), acute rejection rates (12.9 vs. 23.3%, P=0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P=0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P=0.72), and overall medical and surgical morbidity (P=NS). Although unadjusted patient survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P=0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P=0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P=NS). CONCLUSIONS: This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elimination should be subjected to controlled trials.

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.

The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation.

PURPOSE: We compared the incidence of lymphocele formation and treatment in kidney transplant recipients given 3 immunosuppressive drug regimens. MATERIALS AND METHODS: Consecutive series of adult kidney only recipients, including group 1-152 who received sirolimus/mycophenolate mofetil (MMF)/prednisone (P), group 2-168 who received cyclosporine/MMF/P and group 3-193 who received cyclosporine/azathioprine/P, were analyzed for post-transplantation lymphocele formation. All available records and imaging studies were reviewed, such as ultrasound, computerized tomography, magnetic resonance imaging etc, for peritransplant fluid collections greater than 2.5 cm. Demographic characteristics and the risk factors for lymphocele were compared in these 513 recipients using univariate and multivariate analysis. RESULTS: The overall incidence of lymphocele formation was 174 of 513 cases (33.9%) and the incidence of treated lymphoceles was 81 of 513 (15.7%). In groups 1 to 3 the incidence was 45.5%, 33.9% and 24.7%, respectively. These differences were significantly higher in group 1 vs groups 2 or 3 (p = 0.014) but they were not significantly different between groups 2 and 3. Similarly the incidence of treated lymphoceles was 23%, 12.5% and 12.9%, respectively. Findings were again statistically higher in group 1 vs groups 2 and 3 (p = 0.003) but not statistically significant between groups 2 and 3. A greater number of group 1 patients required surgical interventions compared with those in groups 2 and 3 (13.8% vs 4.7% and 4.8%, respectively, p = 0.019). In addition, acute rejection (p = 0.001) and body mass index greater than 32 (p = 0.02) were significant risk factors on multivariate analysis. CONCLUSIONS: The combination of sirolimus/MMF/P, obesity with a body mass index of greater than 30 kg/m and acute rejection are independent risk factors for lymphocele formation and treatment after kidney transplantation. Patients should be counseled and consideration should be given to prophylactic measures in this higher risk renal transplant population.

The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients.

BACKGROUND: The aim of this study was to determine whether there has been an increase in the incidence or severity of wound-healing complications that can be attributed to the introduction of newer immunosuppressive drugs. METHODS: Consecutive series of adult kidney-only transplant recipients were selected from our Unified Transplant Database backward from September 2002. There were 513 patients divided into groups on the basis of their maintenance immunosuppression given for at least the first 30 days posttransplant. Group I (152) was given sirolimus, mycophenolate mofetil, and prednisone (SRL/MMF/P) between March 2000 and September 2002; group II (168) was given cyclosporine A (CsA)/MMF/P between January 1999 and July 2002; and group III (193) was given azathioprine (AzA)/CsA/P between January 1993 and December 1997. A classification system for wound-healing problems was developed, and each of the three groups was analyzed by univariate and multivariate analysis. RESULTS: From groups III to II to I, there was a significant increase in mean age (42.4 vs. 49 years), percent of patients diabetic (17% vs. 29%), mean body mass index (BMI) (24.2 vs. 27.1 kg/m2), and percent BMI greater than 30 (13.5% vs. 27%). The cumulative percentage of all wound-healing problems between group I (19.7%) vs. group II (16.1%) and group III (15.6%) was not significantly different. The most significant risk factor was a recipient BMI greater than 30 (P=0.0012) and delayed graft function (P=0.0041). CONCLUSIONS: During a 10-year period marked by changing recipient demographics, the introduction of MMF and SRL did not result in a significant increase in transplant wound-healing complications. The most significant risk factor associated with transplant wound-healing complications remains body weight, which was the major influence for each of the immunosuppressive drug combinations described.

The effect of two different cyclosporine formulations on the long-term progression to chronic rejection in renal allograft recipients.

INTRODUCTION: The introduction of the microemulsion formulation of cyclosporine (CsA) (Neoral-NEO) has been shown to provide improved absorption and less intrapatient variability than the previous formulation (Sandimmune-SIM) in kidney transplant recipients. It has been suggested that the use of the microemulsion formulation results in less acute rejection, and therefore permits better long-term transplant outcomes. Our aim was to determine whether the microemulsion formulation of cyclosporine has reduced the long-term (5 yr or more) rates of chronic rejection (allograft nephropathy) in a renal transplant population. METHODS: The study population included 792 (508 cadaveric and 284 living donor) transplants performed in 786 patients at the Cleveland Clinic Foundation and its affiliate hospitals between July 1, 1987 and July 1, 1998. Patients who were less than 18-yr-old or had less than 12 months of graft function were excluded from the analysis. Over 90% of the cadaveric and 11% of the live donor recipients were given an induction antibody. A total of 591 patients were given the SIM formulation and 201 the NEO formulation of cyclosporine. Additional maintenance therapy included either azathioprine or mycophenolate mofetil, and steroids. All patients were followed to graft loss, death, or return to dialysis. The NEO group was followed until December 2001. The diagnosis of acute rejection was biopsy confirmed in >92% of cases. Chronic rejection was identified by clinical and biopsy criteria. Demographic and clinical data was collected from medical records, interviews, and phone contact with patients and treating physicians. RESULTS: The mean follow-up was 84 +/- 31 months for the SIM group, and 54 +/- 14 months for the NEO group. At 70 months there was no significant difference (p = 0.17) - actuarial patient survival between the SIM (90.7%) vs. the NEO (93%) treated patients. In addition, at 70 months there was no significant difference (p = 0.55) in death censored actuarial graft survival between the SIM (84.3%) and the NEO treated (85.7%) patients. The acute rejection-free rate was 10% higher for the NEO vs. the SIM patients (79 vs. 69%, p = 0.0004). Chronic rejection was diagnosed in 141 of 591 (24%) of the SIM patients and in 56 of 201 (28%) of the NEO patients (p = ns). At 5 yr the mean serum creatinine (mg/dL) was 2.07 +/- 1.69 for the SIM and 2.15 +/- 1.61 for the NEO patients (p = ns). CONCLUSIONS: The use of the microemulsion formulation of CsA has led to the improved delivery of the parent drug, and a decrease in the number of acute rejection episodes post-transplant. However, patient and graft survival, renal function, and progression to chronic allograft nephropathy at 5 yr were no different. The advantages of greater drug exposure from the microemulsion formulation may be counterbalanced by increased drug induced nephrotoxicity over time.

Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine.

BACKGROUND: Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. METHODS: We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. RESULTS: Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. CONCLUSIONS: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.