New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Acute cellular and antibody-mediated rejection of the pancreas allograft: incidence, risk factors and outcomes.

Antibody-mediated rejection (AMR) after pancreas transplantation is a recently identified entity. We describe the incidence of, risk factors for, and outcomes after AMR, and the correlation of C4d immunostaining and donor-specific antibody (DSA) in the diagnosis of AMR. We retrospectively analyzed 162 pancreas transplants in 159 patients who underwent 94 pancreas allograft biopsies between 2006 and 2009. Univariate and multivariate analyses were performed to evaluate risk factors for pancreas graft AMR. One-year rejection rates and survival after rejection were calculated by Kaplan-Meier methods. AMR occurred in 10% of patients by 1-year posttransplant. Multivariate risk factors identified for AMR include nonprimary simultaneous pancreas-kidney (SPK) transplant, primary solitary pancreas (PAN) transplant and race mismatch. After pancreas rejection, patient survival was 100% but 20% (8 of 41) of pancreas grafts failed within 1 year. Graft survival after acute cellular rejection (ACR), AMR and mixed rejection was similar. Of biopsies that stained >5% C4d, 80% were associated with increased Class I DSA. In summary, AMR occurs at a measurable rate after pancreas transplantation, and the diagnosis should be actively sought using C4d staining and DSA levels in patients with graft dysfunction, especially after nonprimary SPK and primary PAN transplantation.

Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation.

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

A comparison of alemtuzumab with basiliximab induction in simultaneous pancreas-kidney transplantation.

Alemtuzumab is a humanized, rat monoclonal antibody directed against the CD52 antigen. After binding, alemtuzumab causes profound and durable depletion and has been successfully used as immune induction therapy for organ transplantation. This was a single center, retrospective review of patients who underwent simultaneous pancreas-kidney transplantation at the University of Wisconsin using alemtuzumab induction therapy compared with historical controls that received induction with basiliximab. There were no differences in donor or recipient demographics, rates of patient survival, renal or pancreas allograft survival, renal allograft delayed graft function, EBV infection, BKV infection, PTLD or sepsis. There was a statistically significant increase in the incidence of cytomegalovirus (CMV) infection in the alemtuzumab-treated group. Given the significantly higher incidence of CMV infections, we have since altered our induction protocol to consist of a single 30 mg dose of alemtuzumab instead of two doses. The long-term effects of this change remain to be seen. Due to the results seen in this study, the low initial cost of the drug and the absence of any severe, short-term side effects, alemtuzumab has been selected as the induction drug of choice at our center for patients undergoing SPK.

The impact of donor variables on the outcome of orthotopic liver transplantation for hepatitis C.

Morphologic characteristics of the graft have been proposed as a major contributor to the long-term outcomes in orthotopic liver transplantation (OLT). Our objective was to determine the impact of donor variables, including donor age, donor-recipient HLA match, and type of donation (DCD vs donation after brain death [DBD]), on the outcome of OLT in 192 patients with hepatitis C virus (HCV). Fourteen patients underwent OLT from donation after cardiac death (DCD) donors and 188 from DBD donors. Mean donor age, warm ischemia time at recovery, and cold ischemia time were similar between the groups. Overall graft survival rate at 1 year (55% DCD vs 85% DBD) and 5 years (46% DCD vs 78% DBD) was significantly lower in the DCD group (P = .0003). Similarly, patient survival rate at 1 year (62% DCD vs 93% DBD) and 5 years (62% DCD vs 82% DBD) was significantly lower in the DCD group (P = .0295). Incidences of hepatic artery thrombosis, portal vein thrombosis, and primary nonfunction were similar between the DCD and DBD groups. The incidence of liver abscess with ischemic-type biliary stricture was higher in recipients from DCD as compared with DBD (42% vs 2%). A trend toward lower graft survival was noted in recipients from donors older than 60 years of age in the HCV population (P = .07), with statistically lower patient survival (P = .02). Donor- recipient HLA matching did not appear to correlate with OLT outcome in patients with HCV. DCD donors and donors older than 60 years of age significantly impact patient and graft survival. Lower graft and patient survival in recipients from DCD donors does not appear to be related to early disease recurrence.

Kidney function after solitary pancreas transplantation.

Preserving kidney function in patients after solitary pancreas transplantation (SPTx) is an important consideration, yet various factors may negatively impact long-term function of the native kidneys or kidney allograft. To determine changes in kidney function over time in a series of patients receiving SPTx, we conducted a retrospective analysis and tracked changes in serum creatinine (SCr) and calculated glomerular filtration rate (GFR) from baseline to 6 months, 1 year, or 3 years after SPTx in a series of pancreas after kidney transplants PAK; (n = 61) and pancreas transplants alone PTA; (n = 27) performed at our institution. The mean follow-up for the PAK and PTA groups was 3.4 and 2.7 years, respectively. In this series, 8% of patients after SPTx developed significant kidney failure, defined by either initiation of dialysis or receiving a kidney transplant (PAK-6, PTA-1). Twenty seven percent of SPTx patients with a baseline GFR < 60 suffered either an elevated SCr > 2.2, dialysis, or kidney transplant, whereas no patients with a baseline GFR > 60 developed significant kidney dysfunction. In the PAK group, the GFR did not show significant deterioration over time. In contrast to relatively stable kidney function in PAK patients, PTA patients experienced overall significantly greater rates of decline over time. GFR in PTA patients decreased from 78 +/- 19 (40 to 114) mL/min/1.73 m2 at baseline to 65 +/- 20 at 1 year (P = .006), while SCr increased from 1.03 +/- 0.25 mg/dL to 1.28 +/- 0.43 over the same time period (P = .012). These data show that kidney function may deteriorate after SPTx and proper patient selection may reduce the frequency of this complication.

Predictors and outcomes of candiduria in renal transplant recipients.

BACKGROUND: The epidemiology of candiduria in renal transplantation is unknown. METHODS: We performed a nested case-control study to evaluate the epidemiology of candiduria in renal transplant recipients at the University of Wisconsin (Madison) over an 8-year period. RESULTS: Renal transplantations were performed on 1738 patients during this period, 192 of whom had 276 episodes of candiduria. Candida glabrata, which was recovered from 98 (51%) of 192 case patients, was the most common pathogen identified. Most case patients were asymptomatic. Independent predictors of candiduria were female sex (odds ratio [OR], 12.5; 95% confidence interval [CI], 6.7-23.0), intensive care unit admission (OR, 8.8; 95% CI, 2.3-35.0), antibiotic use during the month before candiduria (OR, 3.8; 95% CI, 1.7-8.3), presence of an indwelling bladder catheter (OR, 4.4; 95% CI, 2.1-9.4), diabetes (OR, 2.2; 95% CI, 1.3-3.9), neurogenic bladder (OR, 7.6; 95% CI, 2.1-27), and malnutrition (OR, 2.4; 95% CI, 1.3-4.4). Log-rank testing of Kaplan-Meier curves revealed that 60-day, 90-day, and cumulative survival rates were significantly different between case and control patients; there was no difference in the survival rate during the first 30 days after transplantation. A variety of regimens were used for treatment; 119 case patients (62%) underwent removal of the indwelling bladder catheter within 1 week after diagnosis of candiduria. Candiduria cleared in 148 case patients (77%). Treatment of candiduria was not associated with an improved survival rate. CONCLUSIONS: Candiduria occurs commonly in renal transplant recipients. Risk factors for candiduria in such persons are similar to those in hospitalized patients who have not received a transplant. Candiduria is associated with reduced survival rates among persons who have undergone renal transplantation; this is likely a marker for severity of illness. Treatment of asymptomatic candiduria in renal transplant recipients does not appear to result in improved outcome.

OKT3 rescue therapy in pancreas-allograft rejection.

OKT3 has emerged as a highly effective antirejection therapy, but its efficacy in pancreas transplantation remains to be determined. During a 26-mo period, 46 vascularized pancreas transplants were performed with pancreaticoduodenocystostomy. Twenty-one patients (45.7%) were treated with OKT3. Indications for OKT3 use included steroid- and/or antilymphoblast globulin-resistant rejection in isolated-pancreas transplant (n = 8) or simultaneous pancreas-kidney-transplant (n = 13) recipients. A total of 46 rejection episodes occurred (mean 2.2). OKT3 was administered for a 14-day course concomitant with pulsed corticosteroids, azathioprine, and cyclosporin. OKT3 rescue therapy was successful in 13 cases (61.9%). The mean time to rejection reversal was 8.8 days (range 5-14 days). In isolated-pancreas transplants, OKT3 reversed only 1 episode of rejection (12.5%). In contrast, 12 episodes (92.3%) of allograft rejection were responsive to OKT3 in simultaneous pancreas-kidney recipients (P less than .05). Graft loss from rejection occurred at a mean 5.5 mo posttransplantation. OKT3 therapy was more successful in the setting of early rejection, rejection in combined pancreas-kidney transplants, and rejection not associated with hyperglycemia. No graft loss due to infection or patient death has occurred after OKT3 therapy. After a mean follow-up of 17.3 mo, patient survival was 89.1%, and allograft survival was 26.3% in isolated-pancreas and 85.2% in simultaneous pancreas-kidney transplants (P less than .05). Salvage therapy with OKT3 is a safe and effective means of reversing rejection in pancreas-allograft recipients. OKT3 is more effective in simultaneous pancreas-kidney recipients due to the earlier diagnosis of rejection.

Early detection of rejection in pancreas transplantation.

A major dilemma in pancreas transplantation is the lack of reliable methods for the early detection of allograft rejection. Over a 26-mo period, 70 rejection episodes occurred in 36 patients (13 isolated-pancreas, 23 simultaneous pancreas-kidney recipients) with pancreaticoduodenocystostomy. A total of 300 radionuclide pancreas examinations were performed (mean 8.3/patient) utilizing 99mTc-labeled DTPA. Computer analysis generated a quantitative measure of blood flow to the allograft (technetium index, TI). Rejection episodes were defined as isolated pancreas, isolated kidney, or combined pancreas-kidney. Mean urinary amylase (UA) levels and TI during normal allograft function were 30,256 U/L and 0.57%, respectively, whereas levels heralding rejection were 6873 U/L and 0.39% (P less than .05). The treatment of rejection based on kidney dysfunction or combined pancreas-kidney dysfunction resulted in significantly higher graft salvage and a lower incidence of hyperglycemia compared with isolated-pancreas-allograft rejection. After therapy, a TI greater than 0.3% was associated with 95.9% graft survival, whereas levels less than 0.3% resulted in a 72.7% rate of graft loss (P less than .001). Similarly, pancreas allografts with a UA greater than 10,000 U/L had 92.2% functional survival, whereas levels less than 10,000 U/L resulted in a 53.3% rate of graft loss (P less than 0.001). Overall, reversal of rejection occurred in 80% of cases, with 10 pancreas and 2 kidney allografts lost due to rejection. Monitoring pancreas-allograft function by UA, TI, and renal function in simultaneous transplants allows for the timely diagnosis and successful treatment of pancreas-allograft rejection.

Use of UW solution in pancreas transplantation.

We have recently reported successful 72-h preservation of the canine pancreas with a new cold-storage solution developed at the University of Wisconsin (UW solution). Over 10 mo, we performed 11 combined pancreas-kidney and 4 isolated-pancreas transplants with this solution. In situ cooling of the donor pancreas was performed with 1000 ml of UW solution followed by ex vivo perfusion with an additional 250-500 ml. Graft preservation times ranged from 3 to 19 h (mean 10.2 h). Pancreas transplants were vascularized whole-organ grafts with pancreaticoduodenocystostomy. Early graft function was excellent as assessed by immediate insulin independence, high urinary amylase and low serum amylase levels, and a technetium perfusion index indicating good pancreatic blood flow. There were no episodes of primary nonfunction, graft pancreatitis, or vascular thrombosis. Actuarial patient and graft survival at 1 mo was 92.9%. We conclude that UW solution provides excellent early graft function for up to 19 h of cold storage. Based on previously reported data on its efficacy in liver and kidney preservation, UW solution seems ideally suited as a universal intra-aortic flush and cold-storage solution.

Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

Radiation therapy for renal transplant rejection refractory to pulse steroids and OKT3.

PURPOSE: To determine the response rate and kidney graft survival following local irradiation to the transplanted renal graft undergoing persistent rejection after medical management including pulse steroids and OKT3. The role of radiation for renal transplant rejection after failure of OKT3 has not been previously reported. METHODS AND MATERIALS: From July 1, 1988 to July 1, 1994, 72 consecutive patients with kidney graft rejection were treated with local irradiation to the transplanted renal graft following failure of medical management. All patients received pulse steroids and OKT3, an anti-CD3 immunosuppressant. Patients who failed to respond to methylprednisolone and OKT3 therapy were referred for radiation therapy. The median time from the diagnosis of rejection to irradiation was 8 days. All kidney grafts received local graft irradiation to a total of 8 Gy delivered in four daily fractions. RESULTS: Sixty (83%) patients initially responded to radiotherapy at 7 days after completion of radiotherapy, as defined by a decrease in serum creatinine. Thirty-five responding patients have not experienced a second episode of graft rejection. Overall, 43 (60%) patients have renal graft survival, with a median follow-up of 16 months (range of 6-73 months)> CONCLUSION: It is concluded that there is a subgroup of kidney graft patients undergoing graft rejection who are refractory to pulse steroids and OKT3 therapy where irradiation may be an effective modality with high rates of response and a moderate rate of graft survival. However, a prospective, randomized trial in these medically refractory patients is needed to ascertain whether these results are clinically significant.

Cytomegalovirus infection and posttransplant lymphoproliferative disease in renal transplant recipients: results of the U.S. multicenter FK506 Kidney Transplant Study Group.

BACKGROUND: The recent U.S. multicenter randomized trial of FK506 versus cyclosporine (CsA) demonstrated equivalent patient and graft survival in patients treated with FK506 and statistically fewer rejection episodes in the first year posttransplant. METHODS: To determine if more effective posttransplant immunosuppression was associated with an increased risk of cytomegalovirus (CMV) or posttransplant lymphoproliferative disease (PTLD), we examined the incidence of these two opportunistic infections during 3 years of follow-up. RESULTS: CMV infection occurred in 40 (19.5%) FK506 and 40 (19.3%) CsA-treated patients. The incidence of CMV disease was 9.3% in FK506 and 6.8% in CsA-treated recipients; the most common site of CMV disease was the gastrointestinal tract. A multivariate analysis of several risk factors demonstrated that a CMV- recipient of a CMV+ donor was at greatest risk for CMV infection. The incidence of posttransplant lymphoproliferative disease was equal in the two treatment arms: six CsA- and five FK506-treated recipients. CONCLUSIONS: The results of this study suggest that the superior efficacy of FK506 in the prevention of acute rejection was not associated with an increased risk of CMV or posttransplant lymphoproliferative disease compared with CsA.

Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group.

BACKGROUND: Tacrolimus (FK506) is a safe and effective treatment for the prevention of rejection of renal allografts. Mycophenolate mofetil (MMF) has been used as adjunct immunosuppressive therapy with cyclosporine and corticosteroids for the same purpose. The objective of this study was to investigate the safety and efficacy of FK506 and MMF in renal transplant recipients. METHODS: After cadaveric renal transplant, patients were randomized to receive tacrolimus in combination with either azathioprine (AZA, n=59), MMF 1 g/day (n=59), or MMF 2 g/day group (n=58). Patients were followed for 1 yr posttransplant for the incidence of biopsy-confirmed acute rejection, patient and graft survival, and adverse events. RESULTS: Tacrolimus doses and trough concentrations were similar between treatment groups at all time points; 80% of patients were maintained within a range of 5.0-13.9 ng/ml at 12 months posttransplant. The mean dose of MMF decreased in the 2 g/day group to 1.5 g/day by 6 months posttransplant, primarily due to gastrointestinal GI-related disorders. The incidence of biopsy-confirmed acute rejection at 1 year was 32.2%, 32.2%, and 8.6% in the AZA, MMF 1 g/day, and MMF 2 g/day groups, respectively (P<0.01). The use of antilymphocyte antibodies for the treatment of rejection was comparable across treatment groups. The incidence of most adverse events was similar across treatment groups and comparable with previous reports. The overall incidence of posttransplant diabetes mellitus was 11.9%, with the lowest rate observed in the MMF 2 g/day group (4.7%), and was reversible in 40% of patients. The incidence of malignancies and opportunistic infections was low and not different across treatment groups. CONCLUSION: Tacrolimus in combination with an initial dose of MMF 2 g/day is a very effective and safe regimen in cadaveric kidney transplant recipients.

A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation.

BACKGROUND: Mycophenolate mofetil (MMF; Cell-Cept) is a potent and selective inhibitor of B and T lymphocyte proliferation that has proven effective in reducing the incidence of acute rejection in cadaveric kidney transplant recipients in several randomized, blinded clinical studies. Because the frequency and characteristics of rejection episodes may be different and more severe after combined pancreas-kidney transplantation, we hypothesized that MMF would have a significant impact on pancreas-kidney rejection and graft outcome. Therefore, we compared the efficacy of MMF versus azathioprine (AZA) in cyclosporine-treated simultaneous pancreas-kidney transplantations. METHODS: A retrospective comparison of 358 consecutive primary SPK transplantations performed from 1990 to 1997 was conducted. Patients received either MMF (n=109, 3 g/day) or AZA (n=249, 2 mg/kg q.d.) in combination with cyclosporine-based immunosuppression. All patients received a quadruple-drug sequential induction protocol with either OKT3 or Atgam. Several outcome parameters, including patient and graft survival rates and frequency of rejection, were analyzed. RESULTS: MMF-treated patients demonstrated a markedly reduced rate of biopsy-proven kidney rejection (31 vs. 75% AZA, P=0.0001), clinically significant pancreas rejection (7 vs. 24% AZA; P=0.003), and steroid-refractory rejection (15 vs. 52% AZA; P=0.01). As a result, kidney and pancreas allograft survival was significantly better in MMF patients compared with AZA patients (2-year survival rates: kidney, 95 vs. 86%; and pancreas, 95 vs. 83%). Although surgical infections after transplantation were more frequent in MMF patients, MMF patients were more likely to have undergone enteric drainage. Importantly, we did not observe an increased incidence of any of the bacterial, fungal, or viral infections that typically plague immunosuppressed transplant recipients. CONCLUSIONS: This retrospective study demonstrates that MMF is a highly effective immunosuppressant in SPK transplantation. It is not associated with an increased risk of opportunistic infections when a balanced immunosuppressive management approach is used. MMF strikingly reduces the frequency of acute cellular and steroid-resistant rejection. As a result of this combined experience, it is not unexpected then that we observe significantly improved graft survival rates in MMF-treated SPK patients compared with patients receiving a more traditional immunosuppressive regimen.

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.

The influence of native nephrectomy on the incidence of recurrent disease following renal transplantation for primary glomerulonephritis.

Factors influencing the incidence of recurrent glomerulonephritis following renal transplantation are poorly understood. Bilateral pretransplant native nephrectomy has been advocated to reduce the likelihood of recurrence after renal transplant. However, there is significant morbidity of native nephrectomy in the uremic population. Therefore, we sought to determine the effect of pretransplant native nephrectomy on the incidence of recurrent primary glomerulonephritis and the attendant risk of graft failure due to recurrent disease. Three hundred sixty-four consecutive cadaveric (n = 214), living-related (n = 137), and living-unrelated (n = 13) renal transplants were performed in 319 patients with a diagnosis of primary glomerulonephritis. Specific diagnoses included were focal segmental glomerulosclerosis (FSGS), rapidly progressive glomerulonephritis/idiopathic crescentic glomerulonephritis (RPGN/ICG), IgA nephropathy (IgA), mesangioproliferative glomerulonephritis, type I and II (MPG), anti-glomerular basement membrane nephritis (anti-GBM), and membranous glomerulonephritis (MGN). Rates of recurrence and graft loss were compared between patients treated with bilateral native nephrectomy (n = 61) and those who were not (n = 303). Bilateral nephrectomy did not prevent or delay the onset of recurrent glomerulonephritis in the renal allograft. In fact, there was a significantly increased five- and ten-year risk of recurrence in patients undergoing pretransplant nephrectomy vs. no nephrectomy (25.2% and 42% vs. 13.9% and 19.4%, P < 0.02, respectively). The increased rate of recurrence was evident in the CAD/LUD recipients, but not in recipients of LRD transplants. Of the specific diseases, FSGS and MGN recurred more commonly (20.2% and 20.3%, respectively). A detrimental effect of pretransplant nephrectomy on recurrence rates and incidence of graft loss due to recurrent disease independent of other variables could be demonstrated only for FSGS patients. Based on these findings, we no longer recommend native nephrectomy in the prospective renal transplant recipient at high risk for developing recurrent glomerulonephritis.

Determinants of graft survival after renal transplantation.

We studied multiple determinants of graft survival at a single center and the effects of nonimmunologic graft loss on transplant survival. This retrospective study examined the results of 589 cadaver donor transplants performed between 1986 and 1992. Graft survival rates were calculated using Kaplan-Meier estimates for both overall graft survival (all causes of graft loss) and immunologic graft survival (function lost due to acute or chronic rejection and noncompliance). Cadaver graft survival was significantly poorer with an increasing degree of DR mismatch (P=0.02). An analysis of pretransplant variables showed graft loss risk was highest with greater DR mismatches, two B-antigen mismatch, higher donor serum creatinine, and younger recipient age. After transplantation, acute rejection was the most significant factor associated with long-term graft survival. Our data demonstrate a significant advantage for zero DR and one DR mismatch cadaver donor transplants, with excellent immunologic graft survival. This study suggests that a combination of immediate graft function, prevention of acute rejection by appropriate early immunosuppressive therapy, and acceptable DR match enhances cadaveric graft survival.

Kidney retransplantation in the cyclosporine era.

The results of kidney retransplantation in the cyclosporine era remain to be determined. Over a 42-month period, 76 nonprimary renal transplants (66 second, 7 third, 3 fourth allografts) were performed in 73 recipients under cyclosporine immunosuppression. The patient population was predominantly white (90.4%) with a mean age of 32.3 years. Twenty-one recipients (28.8%) were diabetic, and 36 (49.3%) were highly sensitized (panel-reactive antibody [PRA] greater than 50%). Sixty-two patients received cadaver donor grafts while the remaining donations were living-related (12) or living-unrelated (2). A sequential antilymphocyte globulin/cyclosporine protocol was employed, with cyclosporine therapy delayed until adequate renal function occurred. Overall patient and graft survival is 92.1% and 60.5%, respectively, after a mean follow-up of 20.0 months. The mean serum creatinine is 1.64 mg/dl in the 46 functioning allografts. Graft survival is 63.6% for secondary grafts, 28.6% for tertiary grafts, and 66.7% for fourth kidney transplants. In second transplants, recipients of cadaver donor kidneys have a graft survival of 58.5%, while living-related donor graft survival is 84.6% (P = 0.07). In the cadaver retransplant population, duration of previous transplant function greater than one year and HLA-DR matching were associated with increased graft survival, while age over 39 and presence of diabetes mellitus with reduced graft survival. However, these trends were not significant. Peak PRA above 50% did demonstrate a significant negative impact on graft survival both in the univariate and multivariate analyses of risk factors. Acute rejection occurred in 50 patients (65.8%), and was successfully reversed 50% of the time. Of the 30 grafts lost, 25 (83.3%) occurred within four months of retransplantation. Transplant nephrectomy was performed in 20 patients. Cyclosporine was not administered in 21 (70%) of these early graft failures, negating any potential beneficial effect. Retransplantation can be performed safely, with living-donor graft survival superior to cadaver retransplant rates. Rejection and early graft loss are common, especially in the highly sensitized patient. The impact of cyclosporine immunosuppression in renal retransplantation is much less dramatic than in primary transplantation in a protocol that delays cyclosporine therapy until allograft function is demonstrated.