Search

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long-term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long-term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long-term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long-term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long-term graft survival., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The use of an antibody induction agent in kidney transplantation lowers the risk of an acute rejection episode and may improve graft outcomes. Antithymocyte globulin (ATG) is the most commonly used antibody induction agent for kidney transplantation in the United States, despite its significant side effect profile and cost compared to the interleukin-2 receptor antagonists (IL2-RA). Our review suggests the IL2-RA are safe and well tolerated, and provide equal clinical benefit to ATG at a lower cost. We propose that there is insufficient evidence to justify the use of ATG induction in kidney transplantation.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

To address the results of calcineurin inhibitor (CNI) withdrawal after alemtuzumab induction relative to CNI continuation, we performed a pilot randomized clinical trial in renal allograft recipients on CNI, a mycophenolic acid derivative and steroids after the first 2 months posttransplantation. Forty patients were randomized to taper off CNI or to maintain it, and followed for at least 1 year. Four patients in the withdrawal group were treated for acute rejection while no patient received antirejection treatment in the control group. Two control patients withdrew CNI due to nephrotoxicity. Estimated GFR was similar in both groups after 1 year. Flow cytometry of CD4(+)CD25(+)CTLA-4(+)FoxP3(+) regulatory T cells (Treg) demonstrated a significant increase in Treg percentages in the peripheral blood of alemtuzumab-treated patients on CNI early postransplant. Furthermore, the increased Treg percentages in the withdrawal cohort were unchanged at month 6 postenrollment, whereas they decreased significantly in those patients maintained on CNI. Patients withdrawn from CNI after alemtuzumab trend toward a higher rejection rate, but most patients can be weaned from a CNI using this regimen. With the exception of maintaining increased Treg levels, the benefits are not appreciable in this short follow-up, and a larger randomized trial is justified.

The optimal use of kidneys from small pediatric deceased donors remains undetermined. Using data from the Scientific Registry of Transplant Recipients, 2886 small (< 21 kg) pediatric donors between 1993 and 2002 were identified. Donor factors predictive of kidney recovery and transplantation (1343 en bloc; 1600 single) were identified by logistic regression. Multivariable Cox regression was used to assess the risk of graft loss. The rate of kidney recovery from small pediatric donors was significantly higher with increasing age, weight and height. The odds of transplant of recovered small donor kidneys were significantly higher with increasing age, weight, height and en bloc recovery (adjusted odds ratio = 65.8 vs. single; p < 0.0001), and significantly lower with increasing creatinine. Compared to en bloc, solitary transplants had a 78% higher risk of graft loss (p < 0.0001). En bloc transplants had a similar graft survival to ideal donors (p = 0.45) while solitary transplants had an increased risk of graft loss (p < 0.0001). En bloc recovery of kidneys from small pediatric donors may result in the highest probability of transplantation. Although limited by the retrospective nature of the study, kidneys transplanted en bloc had a similar graft survival to ideal donors but may not maximize the number of successfully transplanted recipients.

Different strain combinations of rat are available to study immunological and transplant-related problems in kidney transplant models. Although numerous modifications of surgical techniques for ureteric reconstruction have been evaluated in order to reduce complications and to extend long-term survival, ureteric complications still occur frequently, especially when there is a disproportion in the diameter of donor and host ureters. Instead of using the current nonsplinted ureteroureterostomy, a versatile and rapid technical modification was developed to perform reconstruct the ureters of disproportionate diameter. The overall incidence of ureteric complications was 80% (8/10) using the former method, whereas this rate was significantly reduced to 15% (3/20) using the new method (P < .001). Our modification shows the feasibility of a nonsplinted ureteroureterostomy for the technical, highly demanding rat model of kidney transplantation with an acceptable rate of ureteric complications considering disproportionate differences in diameter between the host and the donor ureter.

The best available method currently for achieving steady normoglycemia in individuals with type 1 diabetes mellitus (DM) is replacing the pancreas, e.g. whole pancreas transplantation. Pancreatic transplantation, as either simultaneous pancreas-kidney (SPK) or solitary pancreas transplantation alone (PTA), has moved beyond simple metabolic or quality-of-life goals. It is now an effective treatment to reverse or minimize metabolic abnormalities and complications of type 1 DM as well as potentially extend the life span of those afflicted by type 1 DM and its many co-morbid complications. Candidates for SPK and PTA transplantation need to meet various criteria even to undergo the transplant procedure and receive a pancreatic allograft that is deemed suitable. SPK and PTA recipients, though free from insulin use, still may encounter common post-transplant medical complications, e.g. cardiovascular disease, high blood pressure, as well as complications unique to SPK and PTA transplantation. The advantages of PTA and SPK transplantation are frankly now more obvious as improvements in surgical technique and new immunosuppression have made an increasing number of PTA and SPK transplants viable and functional long-term. The idea of pancreas transplantation can be touted as a therapeutic advance for type 1 DM. It can improve survival and limit many diabetic-related complications, while improving quality of life, especially in those individuals also afflicted with diabetic-related kidney disease.

We report an experience with 71 simultaneous kidney-pancreas transplant (SKPT) recipients receiving daclizumab induction in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The mean follow-up time was 5.9+/-2.5 (SD) months (range 0.5-11 months). The study population included 47 males (65%) and 24 females (35%) with a mean age of 40+/-8 years. The mean pretransplant duration of diabetes and dialysis were 25+/-8 and 1.5+/-0.9 years (34 hemodialysis, 16 peritoneal dialysis), respectively. Mean HLA match was 1.2+/-1.5, with one patient receiving a second transplant. The mean cold ischemic times for the kidney and the pancreas were 15+/-5 and 16+/-4 hr, respectively. Six-month patient, kidney, and pancreas graft survival and rejection rates were 97, 96, 93, and 35%, respectively. There were two deaths, one due to fungal infection and the other due to a cardiac event. There were three kidney graft losses, two immunological, and one death with function. Of the five pancreas graft losses, two were due to infection, one immunological, one thrombosis, and one death with function. The patient population was then stratified according to the number of daclizumab doses: 4-5 doses (n=45) or 1-3 doses (n=26). There were no differences in patient and kidney graft survival rates, 98 vs. 96%, and 92 vs. 92%, respectively. However, there was a trend toward improved pancreas graft survival in the group receiving 4-5 doses (96%) compared with 1-3 doses (85%), P=0.07. Although more patients receiving 1-3 doses had rejection (54%) than patients receiving 4-5 doses (24%), there was no dose response relationship between the total number of doses or the adjusted total mg/kg dose and time to rejection. All patients with functioning grafts have good renal and pancreas allograft function at 6 and 12 months. The overall incidence of major infection was 27% and there were no differences in the incidence of infection between the two groups. No major adverse events were attributed to daclizumab use. In conclusion, excellent short-term outcomes were noted in this retrospective, multicenter survey of initial experience with daclizumab induction in combination with TAC, MMF, and steroids in SKPT recipients. Optimal dosing strategies for SKPT recipients remain to be determined.

Background: Transplantation of donor-derived malignancies during organ transplantation fortunately is very rare. Discontinuation of immunosuppressive medications under these circumstances has previously resulted in complete tumor rejection. Ectopic adrenocorticotropic hormone (ACTH) production may result in Cushing syndrome and is not an uncommon paraneoplastic feature of small cell carcinoma of the lung. Theoretically, in the organ transplantation setting, the resulting high cortisol levels could suppress a tumor-rejection immune response. However, to the authors' knowledge, no such clinical scenario has been described in the literature published to date., Methods: A 25-year-old living related kidney transplant recipient presented with Cushing syndrome 32 months after transplantation. The donor had been diagnosed with small cell carcinoma of the lung 22 months earlier. On further evaluation, the kidney recipient was diagnosed with donor-derived small cell lung carcinoma of the transplanted kidney. She was found to have extensive disease involving the liver and retroperitoneum. Despite discontinuation of immunosuppressive medications, the disease progressed and cortisol levels remained elevated during 6 weeks of observation., Results: The patient received six cycles of cisplatin and etoposide, which resulted in resolution of her hypercortisolemia and a complete remission of her donor-derived small cell carcinoma. At last follow-up, she was 12 months from completing her therapy and continued in complete remission., Conclusions: Donor-derived small cell carcinoma and ectopic ACTH production can occur in a patient after kidney transplantation., (Copyright 2001 American Cancer Society.)

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.

Since 1984, we have performed 243 living-unrelated renal transplants at the University of Wisconsin. Rejection occurred in 47% of the patients. Graft loss occurred in 59 patients and 39 patients died. Graft survival in LURD transplants at 10 years is 54% and 43% at 15 years. Patient survival is 68% at 10 years and 54% at 15 years. These long-term results demonstrate that LURD is equivalent to haploidentical renal transplantation and superior to cadaveric transplantation. Husband-to-wife donation demonstrated improved graft survival when compared with wife-to-husband and nonspousal donation. Living-unrelated renal transplantation has been utilized successfully at the University of Wisconsin and may help to alleviate the donor shortage.

From January 1993 through June 1999, 18 simultaneous pancreas-kidney transplants (SPKs) were performed from controlled non-heart-beating donors (NHBDs) and 339 SPKs were performed from heart-beating donors (HBDs). No difference in donor characteristics was noted except for warm ischemic time, which was 14.8 min (range 4-46 min) for NHBDs. Following transplantation, no difference in pancreatic function was noted; however, a higher rate of enteric conversions was seen in pancreas transplants from NHBDs (32% vs. 13%; p < 0.01). Hemodialysis for acute tubular necrosis (ATN) was higher in kidney transplants from NHBDs (22.2% vs. 4.1%; p = 0.009) as was discharge serum creatinine (1.7 mg/dl vs. 1.5 mg/dl; p < 0.05). Also, the number of patients remaining rejection free was lower for NHBDs and approached significance (33.3% vs. 50.1%; p = 0.07). However, no difference in patient survival (100% vs. 95.4%) or pancreatic (87.4% vs. 86.5%) and renal (86.3% vs. 86.3%) allograft survival was noted during the study period. Our results indicate that SPK transplantation from controlled NHBDs is a viable method for increasing the number of pancreas and kidney transplants available for transplantation.

Background: In simultaneous kidney-pancreas (SPK) transplantation, manifestations of renal allograft rejection typically become evident before those of pancreatic rejection. This study compared mycophenolate mofetil (MMF) and azathioprine (AZA) in prevention of renal rejection after primary SPK transplantation., Methods: In an open-label, randomized, multicenter study, patients received MMF 1.5 g twice daily (n=74) or AZA 1-3 mg/kg daily (n=76) for 1 year after transplantation. The incidence of rejection was assessed at 6 months. Adverse events were tracked through 1 year. Survival data are reported through 2 years., Results: At 6 months, efficacy results for MMF vs. AZA patients, respectively, were the following: rejection (27% vs. 39%); rejection or death (34% vs. 42%); rejection, graft loss, death, or premature withdrawal (i.e., treatment failure; 41% vs. 55%). Six-month efficacy trends favored MMF, and time to rejection or treatment failure was significantly longer when compared with AZA (P=0.049). One-year efficacy results for MMF vs. AZA patients, respectively, were the following: treatment of renal rejection (35% vs. 47%); renal allograft loss or death (9% vs. 12%); pancreas allograft loss or death (15% vs. 14%). Five MMF patients (7%) and four (5%) in the AZA group died. More MMF than AZA patients developed opportunistic infections (54% vs. 38%), but the pathogens did not differ., Conclusions: Trends for most efficacy parameters favored MMF over AZA, and time to renal allograft rejection or treatment failure was statistically significantly longer for MMF. The use of MMF in the treatment of SPK recipients is a useful advance.

Background: Diabetic renal disease continues to be the most significant cause of end-stage renal disease (ESRD) in the United States. Renal transplantation improves diabetic ESRD patient survival; however, the diabetic state remains associated with poor patient survival. Simultaneous pancreas-kidney (SPK) transplantation can restore normoglycemia and thus may improve outcomes., Methods: We assessed the impact of SPK on age-range-matched type 1 diabetic patients who underwent renal transplantation at a single center. The observed/expected life span and annual mortality rates (AMRs) were used as measures of survival. A Cox proportional hazards analysis was used to analyze the impact of potential variables on mortality in SPK recipients., Results: SPK transplantation (N = 335) increased the observed/expected life span compared with diabetic cadaveric (DM-Cad, N = 147) and live-donor (DM-Live, N = 160) transplant recipients (P = 0.004) and significantly reduced the AMRs (SPK, 1. 5%; DM-Cad, 6.27%; DM-Live, 3.65%, P = 0.008, SPK vs. other DM). Moreover, the SPK observed/expected life span and AMR were not significantly different from that of age-range-matched nondiabetic transplant recipients (N = 492). The only variable that was significantly associated with patient survival was discharge serum creatinine (relative risk 1.16, P < or = 0.0154)., Conclusion: These data demonstrate that SPK improves the ability for type 1 diabetic patients to live more of their expected life span. This suggests that glycemic control, even as a late intervention in a diabetic patient's lifetime, may beneficially affect survival.

Background: Registry analyses and single-center studies have demonstrated that hypertension significantly increases the risk for chronic graft loss. The graft itself may contribute to posttransplant hypertension, and intragraft vasoactive hormones therefore, may be dysregulated in posttransplant hypertension., Methods: We used the reverse-transcription polymerase chain reaction to assess the intragraft regulation of renin-angiotensin system transcripts in biopsy samples from 42 stable renal transplant patients with posttransplant hypertension. We also examined mRNA expression of inducible nitric oxide synthase, transforming growth factor-beta (TGF-beta), select cytokines, and metalloproteinase transcripts in biopsy tissue. Polymerase chain reaction products were quantitated using high performance liquid chromatography and normalized to beta-actin mRNA expression. Serum creatinine, glomerular filtration rate or creatinine clearance and tubular atrophy on biopsy were concurrently assessed., Results: Renin and select Thl cytokine mRNA expression correlated with blood pressure. Type 1 angiotensin II receptor mRNA expression significantly correlated with glomerular filtration rate or creatinine clearance (P = 0.034) and inversely correlated with Th1 cytokines, inducible nitric oxide synthase, and cyclooxygenase-1 mRNA expression (P< or =0.013 for each). Type 1 angiotensin II receptor mRNA also approached a significant inverse correlation with TGF-beta mRNA expression (P = 0.09). Conversely, angiotensin-converting enzyme mRNA expression directly correlated with Thl cytokine (P< or =0.008 for each) and TGF-beta mRNA expression (P = 0.006). Type 1 angiotensin II receptor mRNA expression also correlated with matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and tissue inhibitor of matrix metalloproteinase-3 mRNA expression. Notably, matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-3 inversely correlated with TGF-beta mRNA expression (P< or =0.0027 for each). Type 1 angiotensin II receptor mRNA expression at biopsy directly correlated with glomerular filtration rate at 2 year's follow-up. However, angiotensin-converting enzyme mRNA expression at biopsy inversely correlated with glomerular filtration rate at 2 year's follow-up., Conclusions: These data suggest that allograft-level RAS gene expression may be predictive of future graft function in the setting of diastolic hypertension.

The effectiveness of therapy for a chronic disease can be assessed by evaluating the length of time that a patient survives after receiving treatment. We used a novel means for measuring the effectiveness of renal replacement therapy for patients with end-stage renal disease (ESRD): the ratio of observed life span divided by expected life span. This ratio incorporated observed life span for patients from the time of ESRD and expected life span based on state-specific life-table analyses. A total of 3,782 individuals with ESRD were analyzed (average follow-up, 14.2 +/- 4.9 years); 3, 192 patients in that group received a kidney transplant at some point during their course of ESRD. For each patient, we determined a curve of observed/expected life span. Separate patient groups were analyzed to determine the median population observed/expected life span or the percentage of patients who reached 0.5 observed/expected life span. Younger transplant recipients (<21 years) had a median observed/expected life span of 67%, significantly greater than the median observed/expected life span for those aged 21 to 40 years (49%; P = 0.01) and 41 to 60 years (47%; P = 0.01). Surprisingly, 57% of the patients aged older than 60 years reached their median observed/expected life span (P = 0.02 versus <21 years; P = not significant against all others). A Cox proportional hazards model identified era of immunosuppression (hazards ratio, 0.32) and atherosclerotic vascular disease-related ESRD (hazards ratio, 2.07) as significant variables influencing patient survival and observed/expected life span. This simple ratio is easy to use and may be a helpful tool for assessing the survival benefits of risk-factor modifications and therapeutic advances in transplantation and ESRD care.

Objective: To compare the outcome of simultaneous pancreas-kidney transplantation (SPK) and living related donor renal transplantation (LRD) in patients with diabetes., Summary Background Data: It remains unanswered whether diabetic patients with end-stage renal failure are better served by LRD or SPK., Methods: Using a longitudinal database, data from all diabetic patients receiving LRD or cadaveric renal transplants or SPKs from January 1986 through January 1996 were analyzed. Patient and graft survival, early graft function, and the cause of patient and graft loss were compared for 43 HLA-identical LRDs, 87 haplotype-identical LRDs, 379 SPKs, and 296 cadaveric renal transplants., Results: The demographic composition of the SPK and LRD groups were similar, but because of less strict selection criteria in the cadaveric transplant group, patients were 10 years older, more patients received dialysis, and patients had been receiving dialysis longer before transplantation. Patient survival was similar for the SPK and LRD groups but was significantly lower for the cadaveric renal transplant group. Similarly, there was no difference in graft survival between SPK and LRD recipients, but it was significantly lower for recipients in the cadaveric renal transplant group. Delayed graft function was significantly more common in the cadaveric renal transplant group. Discharge creatinine, the strongest predictor of patient and graft survival, was highest in the SPK group and lowest in the HLA-identical LRD group. The rate of rejection within the first year was greatest in SPK patients (77%), intermediate in the haplotype-identical LRD and cadaveric transplant groups (57% and 48%, respectively), and lowest (16%) in the HLA-identical LRD group. Cardiovascular disease was the primary cause of death for all groups. Acute rejection, chronic rejection, and death with a functioning graft were the predominant causes of graft loss., Conclusions: This study demonstrates that there was no difference in patient or graft survival in diabetic patients receiving LRD or SPK transplants. However, graft and patient survival rates in diabetic recipients of cadaveric renal transplants were significantly lower than in the other groups.

The recognition of allo-MHC and associated peptides on the surface of graft-derived APC by host T cells (direct pathway allorecognition) plays an important role in acute rejection after organ transplantation. However, the status of the direct pathway T cells in stable long term transplants remains unclear. To detect alloreactive T cell clones in PBL and the allograft during the transplant tolerance, we utilized RT-PCR instead of functional assays, which tend to underestimate their in vivo frequencies. We established alloreactive CD4+ and CD8+ T cell clones from peripheral blood sampled during the stable tolerance phase of a patient whose graft maintained good function for 9 years, 7 without immunosuppression. We analyzed the sequence of TCR Vbeta and Valpha genes and made clonotype-specific probes that allowed us to detect each clone in peripheral blood or biopsy specimens obtained during a 1-year period before and after the rapid onset of chronic rejection. We found an unexpectedly high level of donor HLA-specific T cell clonotype mRNA in peripheral blood during the late tolerance phase. Strong signals for two CD4+ clonotypes were detected in association with focal T cell infiltrates in the biopsy. Chronic rejection was associated with a reduction in direct pathway T cell clonotype mRNA in peripheral blood and the graft. Our data are inconsistent with the hypothesis that direct pathway T cells are involved only in early acute rejection events and suggest the possibility that some such T cells may contribute to the maintenance of peripheral tolerance to an allograft.

Background: Chronic rejection (CR) remains idiopathic, difficult to prospectively identify, and once detected, unresponsive to increased immunosuppression. We hypothesized that clinically stable human renal allografts have ongoing evidence of injury and immune activity, and that this correlates with the worsening of allograft function characteristic of CR., Methods: The allografts of 40 stable renal allograft recipients were biopsied 2-3 years after transplantation. Biopsies were processed for histology and RNA extraction. RNA was evaluated by semi-quantitative RT-polymerase chain reaction for CD3y mRNA (a marker of T cell receptor turnover), and mRNA from cytokine genes previously shown to be transcribed during acute rejection: tumor necrosis factor-alpha, interferon-gamma, interleukin- (IL) 1beta, IL-2, IL-4, IL-6, and IL-8. Clinical parameters including urine protein and glomerular filtration rate were measured the day of biopsy. Findings were then compared with clinical outcome to establish associations between subclinical inflammation and graft dysfunction. Allograft function was measured again 2 years after biopsy and correlated with findings at the time of biopsy., Results: Cytokine transcripts and histological evidence of injury were detected in more than two-thirds of stable grafts. The degree of the lymphocytic infiltrate correlated with the degree of proteinuria (P=0.034) and histological fibrosis (P=0.005). Similarly, the degree of intragraft CD3y transcription correlated with increasing proteinuria (P=0.043). IL-6 and IL-8 transcripts were also correlated with evidence of graft injury. After 2 years, those biopsies originally found to have evidence of fibrosis, tubular atrophy, or CD3gamma transcription had worsening graft function as determined by creatinine and glomerular filtration rate., Conclusions: These data demonstrate that significant injury and immune activity can be detected in patients who are stable on clinical grounds. Undetected subclinical graft injury may be a cause of chronic allograft rejection.

Background: Renal transplant artery stenosis (RTAS) continues to be a problematic, but potentially correctable, cause of post-transplant hypertension and graft dysfunction. Older transplant recipients, prone to peripheral vascular disease (PVD), may have pseudoRTAS with PVD involving their iliac system., Methods: We retrospectively analyzed 819 patients who underwent kidney transplantation between 1993 and 1997 to determine the contribution of pseudoRTAS to renal transplant renovascular disease. Univariate analyses were performed for donor and recipient variables, including age, weight, gender, race, renal disease, cholesterol and creatinine values, human leukocyte antigen (HLA) matching, cytomegalovirus (CMV) infection, and immunosuppressive medications. Significant variables were then analyzed by a Cox proportional hazards model., Results: Ninety-two patients (11.2%) underwent renal transplant arteriogram (Agram) or magnetic resonance angiography (MRA) for suspected RTAS. RTAS or pseudoRTAS, defined as one or more hemodynamically significant lesions in the transplant artery or iliac system, was evident in 44 patients (5.4%). Variables significantly associated with RTAS by univariate analysis were weight at the time of transplant (p = 0.0258), male gender (p = 0.034), discharge serum creatinine > 2 mg/dL (p = 0.0041), and donor age (p = 0.0062). Variables significantly associated with pseudoRTAS by univariate analysis were weight at the time of transplant (p = 0.0285), recipient age (p = 0.0049), insulin-dependent diabetes mellitus (IDDM; p = 0.0042), panel reactive antibody (PRA) at transplant (p = 0.018), and body mass index (p = 0.04). Weight at transplant and donor age remained significantly associated with an increased risk for RTAS in a multivariate stepwise Cox proportional hazards model. IDDM, transplant PRA, weight at transplant, and donor age were significantly associated with an increased risk for pseudoRTAS in a multivariate stepwise Cox proportional hazards model. Importantly, both RTAS and pseudoRTAS were associated with poorer graft survival (p < 0.007 for each)., Conclusions: Renal transplant renovascular disease encompasses pre-existing PVD acting as pseudoRTAS, as well as classical RTAS. Efforts to identify and correct renal transplant renovascular disease of either nature are important, given its negative impact on graft survival.

Background: Hypoalbuminemia is associated with poorer outcomes in renal transplantation. Diabetes can compound hypoalbuminemia's detrimental effects. Kidney-pancreas transplantation alters the diabetic milieu; yet, some patients continue to be hypoalbuminemic., Methods: We retrospectively analyzed 232 patients who underwent simultaneous kidney-pancreas transplantation (SPK) between 1993 and 1997 to determine the incidence and clinical correlates of hypoalbuminemia in SPK recipients. Post-SPK hypoalbuminemia was defined as a serum albumin level < or =3.5 g/dl. Univariate analyses were performed to determine whether post-SPK hypoalbuminemia was associated with pre-SPK variables. The effect of albumin level and hypoalbuminemia on the risk of post-SPK events (cardiac events, cytomegalovirus [CMV] infection, rejection, readmission, kidney and pancreas graft failure, and death) was examined with a Cox proportional hazards model., Results: The study population consisted of 149 men and 83 women. Average follow-up was 2.0+/-1.3 years. Hypoalbuminemia (serum albumin level < or =3.5 g/dL) was most common early after SPK (3 months: 44% of evaluable patients were hypoalbuminemic; 12 months: 15.3%; 36 months: 8.3%). Acute rejection episodes and readmission were the most common adverse events after SPK transplantation. There were 24 episodes of renal allograft loss and only 5 cardiac events. Ten SPK recipients died during the study time period. SPK-related hypoalbuminemia was associated with an increased risk for CMV infection (risk ratio [RR] 2.5; P<0.02), renal graft failure (RR 2.41; P=0.05), pancreas graft failure (RR 3.66; P=0.01), and a trend toward an increased risk for death (RR 2.8; P=0.19)., Conclusions: Post-SPK hypoalbuminemia resolves over time in many patients. Persistent post-SPK hypoalbuminemia is associated with an increased risk for CMV infection, graft loss, and a trend toward decreased survival. Efforts to improve nutrition, as it may affect hypoalbuminemia in SPK recipients, may be one strategy for improving SPK outcomes.

Based on the University of Wisconsin experience with 653 cadaver pancreas transplant performed since 1985, we noted that: 1. The overall 5- and 10-year patient survival rates were 87% and 80%, respectively. The 5- and 10-year pancreas graft survival rates were 70% and 60%, respectively, and the 5- and 10-year kidney graft survival rates were 80% and 60%, respectively. 2. An immunosuppressive regimen including TAC and MMF in both solitary pancreas and SPK transplants was very effective in reducing the rate of acute rejection and improving graft survival. 3. Pancreas graft survival in recipients of solitary pancreas transplants was equivalent to that in SPK recipients in the TAC-MMF era. 4. Anti-IL2 receptor monoclonal antibodies were safe and effective in solitary pancreas and SPK transplants. 5. Excellent short-term graft survival can be achieved in solitary pancreas transplants using enteric drainage.

Background: Although bladder drainage of the pancreas remains the most common site for drainage of exocrine secretions, enteric drainage is becoming more common in the United States. The most common cause of morbidity after pancreas transplantation is infection, particularly recurrent urinary tract infection., Methods: We examined the incidence of infectious complications for enteric-drained (ED) versus bladder-drained (BD) simultaneous pancreas-kidney transplants (PTx) to determine the incidence of post-transplant infection. The patient cohort included simultaneous pancreas-kidney PTx recipients from June 1995 through August 1997 using a similar induction protocol with antithymocyte globulin, mycophenolate mofetil, prednisone, and Neoral. During this time period, 48 BD PTx and 78 ED PTx were performed. Demographic data including age of transplant, gender, race, and duration of initial hospital stay were similar. However, mean follow-up for the BD PTx was 1.9 years vs. 0.9 years for ED PTx. Rejection, infection, and graft and patient survival rates were estimated by the method of Kaplan and Meier., Results: For the entire cohort, 1-year patient survival was 98%, kidney survival 94%, and pancreas survival 93%. There was no difference in survival between ED or BD PTx. At 6 months, kidney transplant rejection had occurred in 38% of BD PTx vs. 30% of ED PTx. Steroid resistant rejection was similar (BD 19%, ED 17%). Postoperative pancreatic leak occurred in 12% BD PTx and 5% ED PTx (P=0.06). There was no significant difference in time to first infection or first abdominal infection between groups. Opportunistic infections were much less likely to occur in ED recipients by 1 year (12% vs. 31%, P=0.002). Both cytomegalovirus infection rates (BD 21% vs. ED 8%, P=0.04) and fungal infection rates (BD 17% vs. ED 4%, P=0.04) were lower in ED PTx. The rate of first urinary tract infection was dramatically decreased with ED. At 1 year, only 20% of ED PTx developed a urinary tract infection vs. 63% of BD PTx (P=0.0001)., Conclusion: Enteric drainage of the pancreas is more physiologic, has similar results to bladder drainage, but has less infectious complications, particularly urinary tract infections.

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.

Background: During pregnancy and nursing, a baby's developing immune system is intimately exposed to the mother's antigens. To determine whether this exposure is of clinical benefit to patients who later receive an allograft as an adult, we analyzed the outcome of primary renal transplantations from sibling donors., Methods: We retrospectively studied graft survival and rejection episodes in 205 patients who had received renal transplants at nine centers between 1966 and 1996 from sibling donors bearing maternal or paternal HLA antigens not inherited by the recipient. The sibling donors were categorized by analysis of family HLA-typing data., Results: In the multicenter analysis, graft survival was higher at 5 years and at 10 years after transplantation in recipients of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient than in recipients of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient (86 percent vs. 67 percent at 5 years and 77 percent vs. 49 percent at 10 years, P=0.006 for both). Paradoxically, there was a higher incidence of early rejection in the former group, suggesting that fetal and neonatal exposure to maternal antigens results in immunologic priming. Pretransplantation transfusions of donor blood reduced the incidence of acute rejection while preserving the beneficial effect of tolerance to noninherited maternal antigens on graft survival. Since 1986, new immunosuppressive drugs have lessened the short-term, but not the long-term, survival advantage of grafts expressing maternal HLA antigens not inherited by the recipient., Conclusions: In the transplantation of a kidney from a sibling donor who is mismatched with the recipient for one HLA haplotype, graft survival is higher when the donor has maternal HLA antigens not inherited by the recipient than when the donor has paternal HLA antigens not inherited by the recipient.

Background: Living unrelated renal donation (LURD) has the potential to reduce the current waiting list significantly for kidney transplantation. The purpose of this study was to examine the long-term results of 150 LURDs performed at our center during a 16-year period., Methods: From Dec 23, 1981, to Feb 13, 1998, 150 LURDs, 219 human leukocyte antigen (HLA)-identical, 577 haploidentical, and 1789 cadaveric kidney transplant procedures were performed. Surgical complications, rejection episodes, infectious complications, and the cause of graft loss and death were examined. Ten-year patient and graft survival rates between groups were compared., Results: Fourteen surgical complications including lymphocele (n = 7), ureteral stricture (n = 4), and ureteral leak (n = 3) were seen. Seventy-eight patients (52%) had 123 rejection episodes and 66 patients (44%) had 1 or more infections. Thirty-six allografts were lost and 25 deaths occurred. Patient survival rates at 10 years for HLA-identical, haploidentical, LURD, and cadaveric transplant procedures were 86%, 82%, 63%, and 64%, respectively. Allograft survival rates at 10 years for HLA-identical, haploidentical, LURD, and cadaver transplant procedures were 75%, 59%, 56%, and 44%, respectively., Conclusions: Long-term LURD allograft survival rates are lower than those for HLA-identical but equivalent to those of haploidentical and better than those of cadaveric kidney transplantations. Spousal and nonspousal LURDs should be actively encouraged to help alleviate the current donor kidney shortage.

Methods: From December 1985 to October 1997, 500 simultaneous pancreas-kidney transplants (SPKs) were performed at the University of Wisconsin. Bladder drainage (BD) was used in 388 and enteric drainage (ED) in 112. All pancreas transplants were preserved in UW solution., Results: Patient survival at 1, 5, and 10 years was 96.4%, 88.6%, and 76.3%; kidney function, 88.6%, 80.3%, and 66.6%; and pancreas function, 87.5%, 78.1%, and 67.2%. Thrombosis of the pancreas occurred in three to four (0.6% to 0.8%) and primary nonfunction in one (0.2%). There was a 4.2% acute tubular necrosis rate for the kidney. Conversion from BD to ED was required in 24% of cases. Primary indications for enteric conversion (EC) were leak (14%), urethritis and extravasation (7%), and chronic hematuria (3%). No graft was lost as a result of EC. There was no difference in 1-year graft survival between ED and BD. Leading causes of pancreas loss were rejection in 45 patients and death with a functioning graft in 27 patients. Since June 1995, mycophenolate mofetil was used for immunosuppression (n = 109). One-year survival rates with mycophenolate mofetil are patient, 98.1 %; kidney, 94.2%; and pancreas, 93.1%. Steroid-resistant rejections decreased from 48% to 15%., Conclusions: This series represents the world's largest experience with SPK, including the longest follow-up for BD pancreatic transplants. Ten-year graft survival rates exceed those of all other transplants, with the exception of HLA-identical living-related grafts. This series confirms that SPK is a highly successful procedure for selected diabetic patients with renal failure.

In this study, we demonstrated that Px grafts from donors older than 45 years are associated with an increased risk of developing poor glycemic control and premature loss of Px function. Previous studies corroborate our finding that age of the donor is the principal donor characteristic impacting postoperative Px survival. Whereas prior studies also implicated hyperamylasemia as a factor which contributes adversely to outcome, we were unable to demonstrate a significant influence of donor hyperamylasemia on long-term graft survival, although it did correlate with the degree of immediate postoperative pancreatitis and with the need for oral hypoglycemic agents. Similarly, elevated blood glucoses in the donor, which can be a result of many other factors unrelated to the quality of the graft, did not predict a poor outcome in the recipient. NHB donor pancreata did as well as HB pancreata with regards to all postoperative functional parameters. A marginally increased risk of developing major complications was associated with older donors. Despite the frequent use of non-ideal donors, including older and NHB donors, excellent overall Px graft survival can be achieved. Although the quality of the pancreas graft was not directly addressed in this study, we believe irrespective of hyperglycemia or hyperamylasemia, subjective assessment of organ quality by an experienced transplant surgeon is the most important determinant of suitability.

Objectives: To identify the incidence and the success of endourologic therapy for symptomatic bladder-related calculi in simultaneous kidney-pancreas (SPK) transplant patients with bladder drainage., Methods: A retrospective review of 300 SPK transplant patients with bladder drainage, treated at the University of Wisconsin, Madison from December 1985 to November 1995, is presented. A 3% incidence of bladder calculi was identified. All patients underwent cystolitholapaxy using electrohydraulic lithotripsy and endoscopic suture removal. Follow-up ranged from 15 to 86 months., Results: A 100% stone-free rate was achieved after cystolitholapaxy and endoscopic suture removal. Two patients (22%) developed postprocedural urinary tract infections. No pancreaticoduodenocystotomy leaks or further complications were identified., Conclusions: SPK transplant patients with nonabsorbable sutures used for the duodenocystotomy anastomosis are at an increased risk for bladder calculi. Cystolitholapaxy with electrohydraulic lithotripsy is a safe and effective treatment for these suture-related stones.

Background: Diastolic hypertension after renal transplantation leads to significant chronic morbidity and mortality. Recently, calcineurin phosphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transforming growth factor-beta (TGF-beta) and resultant endothelin-mediated renal arteriolar vasospasm., Methods: To investigate this hypothesis in humans, the allografts of 40 stable renal allograft recipients were biopsied 2 to 3 years after transplantation. Both cyclosporine and tacrolimus patients were included. Biopsies were divided and processed for histology and RNA extraction. RNA was then converted to cDNA and evaluated by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography-quantitated) for TGF-beta, endothelin, and renin transcription. Inflammatory cytokine gene transcription was also evaluated. Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank correlation coefficient (rs) analysis., Results: Diastolic hypertension was prevalent in the study population, with 40% of individuals having diastolic pressure >90 mmHg. TGF-beta and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detected in 91%. Intragraft transcription of TGF-beta (rs=0.61, P=0.0003) and endothelin (rs=0.43, P=0.0188) was strongly correlated with increasing transcription intragraft renin. In turn, renin transcription was strongly correlated with increasing diastolic blood pressure (rs=0.55, P=0.0015). Histological correlation of fibrosis score did not predict the degree of hypertension, nor did it correlate with TGF-beta transcription. Inflammatory cytokine transcription was not related to renin transcription or diastolic hypertension but was correlated with histological evidence of immune graft injury., Conclusions: These data support the hypothesis that posttransplant diastolic hypertension is a result of TGF-beta-induced, endothelin-mediated arteriolar vasoconstriction and subsequent activation of the renin-angiotensin pathway. These effects are independent of immune-mediated graft injury.

This study examines whether changes in beta 2-microglobulin (B2M) serum levels are useful in the early detection of post-transplant lymphoproliferative disease (PTLD). Serum B2M is monitored daily post-transplant at our center as a marker of change in lymphocyte activation. We identified 16 cases (16/1359; 1.2%) of PTLD from among 1359 kidney and kidney-pancreas transplants. Those with CNS lymphoma (two patients) and titer change only (one) were not included in this review. Thirteen patients had serum titer and clinical evidence of EBV activity; 12 of these patients had histological evidence of PTLD (lymph node 6, kidney 3, and generalized disease 3). Three patients died with disseminated PTLD infection. Nine are alive but only two have the original transplant kidney. All patients received quadruple immunosuppression for induction, and 11 were subsequently treated with OKT3 or ALG for rejection. The mean number of days of induction ALG therapy was 14.8 d (20 mg/kg/d). The mean number of days of OKT3 therapy for rejection was 14.4 d (5 mg/d). During rejection the highest mean creatinine level was 6.8 mg/dL, and the highest mean B2M level was 16.4. With PTLD, the highest mean creatinine level was 7.0 mg/dL and the highest mean B2M level was 32.3 mg/L. The difference in creatinine levels was not significant, but the difference in B2M levels was significant (p < 0.01). We conclude that B2M levels are useful markers in differentiating rejection from PTLD.

Between 1980 and 1995, 13 patients with end-stage renal disease due to Wegener's granulomatosis received 14 renal transplants (10 cadaveric, 4 living related). The mean follow-up in the 13 successfully transplanted patients was 50 months (4-107 months). One patient had primary nonfunction and received another graft 4 months later. Three episodes of acute rejection occurred in two patients, and one of these patients lost her graft due to severe vascular rejection 4 months after transplantation. Two patients died with well-functioning grafts (one of metastatic cancer and one of sepsis). One patient presented with perisinusitis and had a mild recurrence of Wegener's disease. None of the patients developed recurrent disease in the transplanted organ. At the last follow-up, the mean creatinine (+/-SD) in the 12 patients with functioning grafts was 1.6 +/- 0.6 mgdl. We conclude that renal transplantation is an excellent treatment for renal failure due to Wegener's granulomatosis. Recurrence of the disease is uncommon in patients under immunosuppression, but careful monitoring is extremely important.

Background: Exposure to hepatitis C virus (HCV) and subsequent infection after renal transplantation lead to significant clinical hepatitis in approximately 50% of graft recipients., Methods: One hundred thirty-two consecutive renal allotransplant patients, who underwent transplantation of kidneys from HCV-positive cadaveric donors, were studied to investigate the relationship between donor and recipient HLA type and the risk of developing clinical hepatitis. Specific attention was directed toward the DR3 and DR4 alleles, as these had previously been associated with worse prognoses in autoimmune and viral hepatitis., Results: Overall, 42% of patients receiving kidneys from donors seropositive for HCV developed clinical hepatitis. This was unrelated to preoperative recipient HCV serum reactivity (P=0.65). Patients receiving kidneys from seropositive donors with HCV RNA as detected by PCR were more likely to develop hepatitis than those receiving kidneys from PCR-negative donors (56% vs. 11%; P=0.005). The presence of the DR3 allele was associated with a significant risk of clinical hepatitis (P=0.025); 80% of DR3-positive recipients (n=34) progressed to hepatitis compared with 42% of DR3-negative patients. No other recipient HLA type was significantly related to prognosis. All patients receiving a donated kidney that expressed the B41 allele developed hepatitis, compared with 55% of recipients of non-B41 grafts (P=0.039). No association between the development of clinical hepatitis and HLA compatibility was found., Conclusions: These results suggest that both HLA type and viral presence as assayed by polymerase chain reaction, influence the risk of disease progression after transplantation of HCV-positive kidneys. Application of these associations may decrease the relative risk of a recipient contracting HCV hepatitis after cadaveric renal transplantation.

Diabetic transplant recipients are at a high risk for foot pathology leading to amputation. This retrospective study from 1/85 to 2/95 examines the risk of foot complications in a population (n = 340) of diabetic renal and combined renal/pancreas transplant recipients. All groups suffered high lower extremity amputation and foot fracture rates. Patients with better circulation and protective sensation intact fared better. Smoking had a profoundly negative effect on the amputation rate as did an amputation prior to the transplant. Patients with pretransplant dialysis were at a higher risk for post-transplant amputation. Concomitant pancreas transplant did not in general significantly affect the risk of amputation or fracture. Females had almost twice the fracture rate of males.

Background: Since the advent of cyclosporine-based immunosuppression for cadaveric kidney transplants in 1983, several changes have been made in immunosuppressive management at the University of Wisconsin. Since 1986, OKT3 has been available to treat steroid-resistant rejection; since 1992, OKT3 has been used as an induction agent replacing antilymphocyte globulin; and since 1993, mycophenolate mofetil has been used in 104 patients., Methods: The impact of different immunosuppressive strategies on overall and immunologic graft survival (defined as graft loss caused by rejection) was evaluated in 1210 primary cadaveric renal transplants at the University of Wisconsin. Covariables, including degree of human leukocyte antigen matching, age, gender, cause of kidney failure, and early graft dysfunction, were evaluated. The series was subdivided into four eras according to immunosuppressive regimen, and the results were analyzed by era., Results: Our principal findings are that immunologic graft survival has improved significantly during this series whereas overall graft survival has not. Mycophenolate was associated with a significant decrease in acute rejection. For a given patient, graft loss from rejection becomes less likely over time. Late rejection poses a greater risk than early rejection for graft loss., Conclusions: Improving outcomes may be related to improving immunosuppressive treatment, increasing degree of human leukocyte antigen matching, and better early graft function.

Mycophenolate mofetil (MMF) is the first drug approved for the prevention of renal allograft rejection in the United States in the last 10 years. MMF is the morpholinoethyl ester of mycophenolic acid (MPA) and is a selective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that is critical for the production of guanine monophosphate. MPA is a potent inhibitor of IMPDH, particularly the type II isoform. Compared with other cell types, lymphocytes appear to be more sensitive to inhibition of the type II isoform of IMPDH. This decreases the metabolism of guanine nucleotides, which are necessary for cell function. MMF is rapidly converted to MPA, which is the pharmacologically active drug. MPA is highly bound to serum albumin, and recent evidence suggests that the pharmacologic activity of MPA is a function of the unbound drug. Recent studies in human clinical transplantation have demonstrated the efficacy of this compound in renal transplantation. A major clinical study with > 1,499 patients demonstrated a 50% reduction in the incidence of acute rejection when compared with azathioprine or placebo control. The primary side effects in these studies were leukopenia, gastrointestinal problems, and cytomegalovirus disease. MMF represents a major advance in immunosuppression for renal transplant recipients. Ongoing studies are being performed in other types of solid organ 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.

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.

Controversy exists regarding the risk factors for renal allograft loss in patients with systemic lupus erythematosus (SLE). This study is a retrospective evaluation of each of these independent risk factors in 80 renal transplants for ESRD secondary to SLE done at our institution between 1971 and 1994. Our entire non-diabetic cohort of 1,966 renal transplants is used as a comparison group. Our results showed equivalent graft survival rates between lupus patients and the cohort at 1, 5 and 10 years (P = 0.56). However, an analysis of cyclosporine-era cadaver grafts revealed that the lupus group had poorer 5-year graft survival than the cohort (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus graft survival showed significantly improved outcome in living-related lupus recipients over cadaver grafts at five years (89% vs. 41%, P = 0.003). The majority of grafts lost in the lupus cadaver recipients were due to chronic rejection. Rejection was increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated.

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.

After a decade of rapid development, simultaneous pancreas--kidney (SPK) transplantation has become routine at the University of Wisconsin (UW). Since developing the concept of direct drainage of pancreas allograft exocrine secretions into the urinary bladder at UW in 1982, we performed 381 SPK transplantations in this technique. Patient and graft survival following SPK transplantation has increased significantly from our early experience to the recent time. The one- and five-year patient survival rates for the entire series of 381 SPK transplantations were 96% and 88% respectively. The actuarial one- and five-year kidney allograft survival rates in these patients were 87% and 78%. The pancreas allograft survival rates were similar at 86% and 74%. Several changes are responsible for our current high level of success. UW preservation solution, improved surgical technique, advances in immunosuppression, and expeditious diagnosis and treatment of complications.

Objective: The objective of this study was to analyze a single center's 28-year experience with 1000 living donor transplants., Summary Background Data: The number of potential renal transplant recipients far exceeds the number of cadaveric donors. For this reason, living related donors (LRDs) and, more recently, living unrelated donors (LURDs) have been used to decrease the cadaveric donor shortage., Methods: From November 15, 1966, until August 5, 1994, 1000 living donor transplants were performed; 906 were living related and 94 were living unrelated transplants. Results were divided into precyclosporine (1966-1986, era I) and cyclosporine (1986-1994, era II) eras. Patient and graft survivals were compared between diabetic and nondiabetic recipients, between LRDs and LURDs, and according to human leukocyte antigen (HLA) matching. Donor mortality, morbidity, and postoperative renal function were also analyzed., Results: The 5-, 10-, and 20-year graft survivals were 78.8%, 64.8%, and 43.4%, respectively. Patient and graft survival improved in era II (patient = 87.0% vs. 81.7%, p = 0.03; graft = 72.9% vs. 67.7%, p = 0.04). Nondiabetic patient and graft survivals were better than diabetic patient survivals in both eras. However, diabetic patient survival improved in era II (78.0% vs. 66.9%, p = 0.04). In era II, HLA-identical recipients had better graft survival than haploidentical or mismatched recipients (91.7% vs. 67.3% and 66.1%, p = 0.01). No difference between haploidentical LRDs and LURDs was seen. One donor death occurred in 1970, and 17% of donors developed postoperative complications., Conclusion: Living related and unrelated renal donation continues to be an important source of kidneys for patients with end-stage renal disease.

Mycophenolate mofetil (MMF), a new immunosuppressant that selectively inhibits proliferation of T and B lymphocytes, may reduce the frequency and severity of acute graft rejection. Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation. The purpose of this randomized, double-blind, multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation. A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were randomized to receive MMF 1.0 g b.i.d. (MMF 2 g treatment group), MMF 1.5 g b.i.d. (MMF 3 g treatment group), or azathioprine 1-2 mg/kg/day. CsA, corticosteroids, and antithymocyte globulin (ATGAM) were administered as part of a quadruple sequential induction protocol. The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason) during the first 6 months after transplant. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. The 495 patients who received study drug were included in the safety and secondary efficacy analyses. Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6% of patients in the azathioprine group compared with 31.1% (P = 0.0015) and 31.3% (P = 0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine (P = 0.0036) and MMF 3 g versus azathioprine (P = 0.0006). First biopsy-proven rejection alone occurred in 38.0% of patients who received azathioprine compared with 19.8% and 17.5% of patients who received MMF 2 g and 3 g, respectively. Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups (44.5%, 24.8%, and 21.1%, respectively). The use of antilymphocyte agents to treat rejection was greater in the azathioprine group (20.1%) compared with the MMF 2 g group (10.3%) and the MMF 3 g group (5.4%). At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups.(ABSTRACT TRUNCATED AT 400 WORDS)