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Background: Chronic immunosuppression following pancreas transplantation carries significant risk, including posttransplant lymphoproliferative disease (PTLD). We sought to define the incidence, risk factors, and long-term outcomes of PTLD following pancreas transplantation at a single center., Methods: All adult pancreas transplants between February 1, 1983 and December 31, 2023 at the University of Minnesota were reviewed, including pancreas transplant alone (PTA), simultaneous pancreas-kidney transplants (SPK), and pancreas after kidney transplants (PAK)., Results: Among 2353 transplants, 110 cases of PTLD were identified, with an overall incidence of 4.8%. 17.3% were diagnosed within 1 year of transplant, 32.7% were diagnosed within 5 years, and 74 (67.3%) were diagnosed after 5 years. The overall 30-year incidence of PTLD did not differ by transplant type-7.4% for PTA, 14.2% for SPK, and 19.4% for PAK (p = 0.3). In multivariable analyses, older age and Epstein-Barr virus seronegativity were risk factors for PTLD, and PTLD was a risk factor for patient death. PTLD-specific mortality was 32.7%, although recipients with PTLD had similar median posttransplant survival compared to those without PTLD (14.9 year vs. 15.6 year, p = 0.9)., Conclusions: PTLD following pancreas transplantation is associated with significant mortality. Although the incidence of PTLD has decreased over time, a high index of suspicion for PTLD following PTx should remain in EBV-negative recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To describe the evolution of pancreas transplantation, including improved outcomes and factors associated with improved outcomes over the past 5 decades., Background: The world's first successful pancreas transplant was performed in December 1966 at the University of Minnesota. As new modalities for diabetes treatment mature, we must carefully assess the current state of pancreas transplantation to determine its ongoing role in patient care., Methods: A single-center retrospective review of 2500 pancreas transplants was performed over >50 years in bivariate and multivariable models. Transplants were divided into 6 eras; outcomes are presented for the entire cohort and by era., Results: All measures of patient and graft survival improved progressively through the 6 transplant eras. The overall death-censored pancreas graft half-lives were >35 years for simultaneous pancreas and kidney (SPK), 7.1 years for pancreas after kidney (PAK), and 3.3 years for pancreas transplants alone (PTA). The 10-year death-censored pancreas graft survival rate in the most recent era was 86.9% for SPK recipients, 58.2% for PAK recipients, and 47.6% for PTA. Overall, graft loss was most influenced by patient survival in SPK transplants, whereas graft loss in PAK and PTA recipients was more often due to graft failures. Predictors of improved pancreas graft survival were primary transplants, bladder drainage of exocrine secretions, younger donor age, and shorter preservation time., Conclusions: Pancreas outcomes have significantly improved over time through sequential, but overlapping, advances in surgical technique, immunosuppressive protocols, reduced preservation time, and the more recent reduction of immune-mediated graft loss., Competing Interests: The authors have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population but not individual risk., Methods: We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF = 20.4%) and investigated potential improvements., Results: We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable with that reported by Irish et al. For cohorts excluded by Irish: (a) in pump-perfused kidneys, the IC overestimated DGF risk; (b) in simultaneous pancreas kidney transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF-excluding those with single dialysis in the first 24 h posttransplant-we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC-predicted risk., Conclusions: The IC can be a useful population guide for predicting DGF in the population for which it was intended but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease., Competing Interests: R.B.M. was supported in part by the UAB-UCSD O’Brien Core Center for Acute Kidney Injury Research (NIH P30-DK079337) (5UO1DK115997) and Department of Veterans Affairs (5-IO1-BX003272). The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Major gaps remain in our understanding of antibody-mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long-term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean ± SD) 4.85 ± 1.86 years of follow-up. Time to AMR was 0.97 ± 1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel-reactive antibody >0%, positive T- or B-cell cross-match, and delayed graft function. Compared with no AMR, the adjusted time-dependent hazard ratio for death-censored graft failure is 10.1 (95% confidence interval, 6.5-15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90 days after transplant), and 24.0 (14.0-41.1) for late AMR (≥90 days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100 days or no improvement in estimated glomerular filtration rate by 42 days. Long-term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long-term allograft survival., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability., Methods: Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients' number of CYP3A5 loss-of-function alleles was assessed., Results: Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001)., Conclusion: CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Post-transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein-Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5-323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29-95 months) after PTLD diagnosis. After a median follow-up of 62.5 months (range 2-125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Predicting long-term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long-term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA-DR, ≥17 HLA-DQ) or low epitope-mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA-DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA-DQ locus nonadherent recipients with HLA-DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Hypertension (HTN) is common in pediatric recipients following kidney transplantation (KT). We retrospectively assessed the impact of HTN on long-term (>10-yr) outcomes in pediatric KT recipients (aged < 18 yr) at our center. Two hundred and ninety-three pediatric KT recipients (83% living donor [LD]) with graft survival (GS) for ≥5 yr were studied. HTN was defined by antihypertensive medication use at five yr post-KT. One hundred and sixty (55%) recipients did not have HTN, and 133 (45%) had HTN at five yr post-KT. There were no differences in actuarial patient survival between cohorts. Actuarial GS at 15 and 20 yr was 68% and 53% for recipients without HTN, and 53% and 33% for recipients with HTN (p = 0.006). Among LD recipients using one antihypertensive, GS at 15 yr was 100% for those using an angiotensin-converting enzyme inhibitor (ACEI) and 44% for those not using an ACEI (p = 0.04). Among these recipients, HTN treated with no ACEI was a significant risk factor for graft failure at >5 yr (hazard ratio [HR] = 2.5, p = 0.02), but HTN treated with an ACEI was not (HR = 0.6, p = 0.7). HTN at five yr post-KT is associated with poorer long-term GS in pediatric recipients, but ACEI therapy may enable better outcomes and should be studied further., (© 2013 John Wiley & Sons A/S.)

There have been many reports showing significant associations between recipient genetic variants and allograft outcomes, including acute rejection and graft failure, but less is known about the contribution of the donor genotype. We analyzed 37 single-nucleotide polymorphisms (SNPs) within the toll-like receptor 4 (TLR4) gene from deceased donor liver allografts transplanted into 738 recipients to determine their effects on liver graft failure (LGF). Two SNPs exhibited a significant association with LGF after adjustments for donor race and recipient race and corrections for multiple test comparisons: rs11536865 [hazard ratio (HR) = 2.5, P = 0.0003] and rs5030717 (HR = 1.67, P = 0.0008). An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR = 1.62, P = 0.0006), and 2 SNPs exhibited a suggestive association in African American donors: rs11536865 (HR = 2.45, P = 0.002) and rs5030717 (HR = 2.32, P = 0.002). Additionally, the liver donor risk index (HR = 2.56, 95% confidence interval = 1.54-4.26, P = 0.0003) and the recipient hepatitis C virus (HCV) status (HR = 1.53, 95% confidence interval = 1.04-2.24, P = 0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusted for recipient race. Donor polymorphisms in TLR4 could be important factors in modulating TLR4 activity and, therefore, affect the risk of graft loss. Additionally, there is a suggestion of an interaction between polymorphisms within TLR4 and the HCV status., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background and Objectives: Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein., Design, Setting, Participants, & Measurements: Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied., Results: Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P<0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups., Conclusions: Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Assessment of kidney transplant biopsies relies on nonspecific inflammatory lesions: Interstitial infiltrates (i), tubulitis (t) and intimal arteritis (v). We studied the relationship between inflammation and prognosis in biopsies for clinical indications from 314 patients (median follow-up 25 months). We used a modified Banff classification, separately assessing inflammation (i-) in nonscarred (i-Banff), scarred (i-IFTA) and whole cortex (i-total), plus tubulitis and intimal arteritis. In early biopsies (<1 year), i- and t-lesions had no association with graft survival. In late (>1 year) biopsies, all i-scores correlated with progression to failure, due to the association of these infiltrates with progressive diseases: antibody-mediated rejection (ABMR) and glomerulonephritis. Tubulitis in nonscarred areas had no impact on survival. Severe tubulitis including scarred areas (tis3) was associated with worse survival, but reflected polyoma virus nephropathy or ABMR, not T-cell-mediated rejection. Intimal arteritis (v-lesions) had no association with allograft loss in early or late biopsies. In multivariate analysis, outcome was better predicted by the presence of progressive disease than by inflammation. Thus inflammation in late kidney transplants has no inherent prognostic impact, but predicts reduced survival because inflammation indicates actively progressing diseases. The most important predictor of outcome is the diagnosis of a progressive disease., (©2011 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We studied the impact of a first post-transplant cytomegalovirus (CMV) infection greater than one year after primary kidney transplantation. Risk factors for developing late CMV were acute rejection and donor-recipient CMV status. Of those developing late CMV, 35% were donor (D) positive, recipient (R) negative; however, 23% were D+R+, 22% D-R+, and 15% D-R-. Late CMV was associated with significantly decreased patient and graft survival., (© 2010 John Wiley & Sons A/S.)

In this single-institution study, we compared outcomes in diabetic recipients of living donor (LD) kidney transplants that did vs. did not undergo a subsequent pancreas transplant. Of 307 diabetic recipients who underwent LD kidney transplants from January 1, 1995, through December 31, 2003, a total of 175 underwent a subsequent pancreas after kidney (PAK) transplant; 75 were deemed eligible (E) for, but did not receive (for personal or financial reasons), a PAK, and thus had a kidney transplant alone (KTA); and 57 deemed ineligible (I) for a PAK because of comorbidity also had just a KTA. We analyzed the three groups (PAK, KTA-E, KTA-I) for differences in patient characteristics, glycemic control, renal function, patient and kidney graft survival rates, and causes of death. Kidney graft survival rates (actuarial) were similar in the PAK vs. KTA-E groups at one, five, and 10 yr post-transplant: 98%, 82%, and 67% (PAK) vs. 100%, 84%, and 62% (KTA-E) (p = 0.9). The long-term (greater than four yr post-transplant) estimated glomerular filtration rate (GFR) was higher in the PAK than in the KTA-E group: 53 +/- 20 mL/min (PAK) vs. 43 +/- 16 mL/min (KTA-E) (p = 0.016). The patient survival rates were also similar for the PAK and KTA-E groups. We conclude that the subsequent transplant of a pancreas after an LD kidney transplant does not adversely affect patient or kidney graft survival rates; in fact, it is associated with better long-term kidney graft function.

Protocols incorporating rapid discontinuation of prednisone (RDP) after kidney transplantation have been associated with good short-term results. However, concern remains that RDP will be associated with decreased long-term graft survival rates. We compared kidney transplant half-life (t1/2) for recipients treated with antibody induction, calcineurin inhibitor, antimetabolite, and RDP versus historical controls treated with antibody induction, calcineurin inhibitor, antimetabolite, and maintenance prednisone. For both living and deceased donor recipients, we found no difference between groups. We also found no differences in rate of graft loss to acute rejection or to tubular atrophy and interstitial fibrosis. Our study suggests that long-term graft outcome is not decreased when using RDP protocols versus chronic maintenance prednisone.

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function >10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common: >40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years), >10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and >30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.

Background: To induce accommodation in the hamster-to-rat cardiac transplantation model, in addition to cyclosporin A (CSA) to inhibit T-cell-mediated graft rejection, cobra venom factor (CVF) is often used to prevent complement-mediated graft rejection. Although it is generally assumed that CVF makes accommodation possible because it inactivates the complement membrane attack complex (MAC), it is not known which complement components must be inactivated and whether complement activation products generated by CVF are also involved in the induction of accommodation. Therefore, to investigate mechanisms by which CVF contributes to accommodation, we studied induction of accommodation of hamster hearts grafted into rats with complement deficiencies of C6; these rats cannot assemble the MAC but, in contrast to CVF, retain in their native state all complement proteins that precede the MAC., Methods: Golden Syrian hamster hearts were transplanted heterotopically into the abdomen of normocomplementemic and C6-deficient (C6D) PVG rats. Graft rejection was determined by cessation of palpable cardiac contractions. CSA, 10 mg/kg, was administered daily to all rats. Graft survival was compared in rats given CVF (60 U/kg 1-day pre-transplant and 20 U/kg/day for the next 9 days), C6D rats given no CVF, normocomplementemic rats given anti-C6 IgG or non-immune IgG but no CVF, and C6D rats reconstituted with normocomplementemic rat serum. Total complement and C6 serum levels were measured using hemolytic assays in rat peripheral blood., Results: We found that hamster hearts transplanted into C6D rats receiving CSA but no CVF survived long-term, with histology typical of an accommodated heart. The accommodated hamster heart did not reconstitute C6 levels of the C6D recipient rats. Moreover, in normocomplementemic rats given anti-C6 antibodies (abs) to induce partial C6 deficiency, accommodation also developed without administration of CVF. Accommodation of the hamster heart failed to develop in C6D rats whose complement was reconstituted by administration of normocomplementemic rat serum given before and following transplantation., Conclusions: These studies demonstrate that, in this model, inhibition of MAC-mediated graft rejection is sufficient to allow the development of accommodation. Inactivation of C3 or other complement proteins of the alternate pathway, or the presence of complement-derived biologically active fragments, is not needed for development of accommodation.

Background: Determining factors associated with negative slope of inverse creatinine vs. time (1/Cr vs. t) may help prevent a decline in renal allograft function., Methods: A total of 1389 adult recipients of primary renal transplants were divided into quartiles based on the slope of 1/Cr vs. t calculated from 6 and 12 months post transplant. A multivariate analysis of risk factors for being in the worst vs. best quartile employed these variables: donor source, HLA mismatch, recipient age, donor age, panel-reactive antibody (PRA), acute rejection (AR), 3-month cyclosporin A (CsA) level, 1-yr CsA level and acute tubular necrosis. Two separate analyses compared risk factors in patients with 1 and 3 yr survival, respectively., Results: In recipients with > or = 1 yr graft survival, high PRA and AR were associated with negative slopes of 1/Cr vs. t. For those with > or = 3 yr graft survival, both AR and 3-month CsA level > 150 ng/mL were significant risk factors, using both 6- and 12-month slopes. Stratification of AR showed 1 AR episode > or = 6 months and multiple AR episodes carried significant risk for negative slopes., Conclusion: Optimization of allograft function invokes a conundrum between the needs to avoid both AR and high early CsA levels. We support a policy of carefully balancing these two risks.

Background: Individuals with end-stage renal disease (ESRD) must weigh the benefits and risks of dialysis vs. a transplant. However, if the patient has extrarenal morbidity, survival may be limited. We have recommended that, when possible, recipients have a living donor (LD) transplant. However, it could be argued that for recipients with extrarenal morbidity, the potential benefit does not justify the donor risks and that, therefore, recipients with increased risks should be denied an LD transplant., Materials and Methods: We studied the outcome of LD vs. deceased donor (DD) transplants in recipients with extrarenal morbidity. For recipients with extrarenal morbidity, patient survival (p < 0.01) and graft survival (p < 0.01) rates were significantly better for LD (vs. DD) transplant recipients. We found no difference in death-censored graft survival rates., Conclusion: Kidney transplant recipients with extrarenal morbidity benefit from an LD transplant. Both donor and recipient informed consent is important.

Although long-term survival after kidney transplantation is critically dependent on maintaining stable allograft function, few studies have examined renal allograft function over time. Using pooled data from 10 278 consecutive transplants at five centers, we calculated slopes of estimated glomerular filtration rates (eGFR) measured after 1, 6 and 12 months in 9515, 8861 and 7359 patients surviving > or =1, > or =6 and > or =12 months, respectively. Slopes of eGFR progressively diminished for patients transplanted during 1984-1989, 1990-1993, 1994-1998 and 1999-2002 (analysis of variance p < 0.0001 and p = 0.1245 for slopes measured after 1 and 6 months, respectively). Slopes measured after 12 months were less in the most recent era: -2.2 +/- 7.2 mL/min/1.73 m(2)/year, -2.3 +/- 6.6 mL/min/1.73 m(2)/year, -2.4 +/- 7.4 mL/min/1.73 m(2)/year and -1.4 +/- 10.9 mL/min/1.73 m(2)/year, respectively, p = 0.0058. Slopes measured after 1, 6 and 12 months each were less for transplantations during 1999-2002, after adjusting for multiple transplantation characteristics (p < 0.0001). Similarly, in Cox proportional hazards analysis, the risk (95% CI) for a 25% reduction in eGFR was 0.92 (0.85-1.01), p = 0.0736 during 1990-1994; 0.94 (0.82-1.08), p = 0.4111 during 1995-1998 and 0.78 (0.64-0.95), p = 0.0110 during 1999-2002 (compared to 1984-1989). We conclude that the rate of decline in allograft function after kidney transplantation has improved, suggesting that stable, long-term function may be achievable.

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine-mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8-12 ng/mL)-low-level sirolimus (SRL) (3-7 ng/mL) (n = 72); or low-level TAC (3-7 ng/mL)-high-level SRL (8-12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.

Historically, late steroid withdrawal after kidney transplants has been associated with an increased rejection rate. Recently, low rejection rates have been reported for recipients treated with complete avoidance or rapid elimination of steroids. However, follow-up has been short. We herein report on 3-year outcome in recipients whose prednisone was rapidly eliminated and who were maintained on a steroid-free regimen. From 10/1/1999 through 5/1/2003, 349 recipients (254 LD, 95 CAD; 319 in first 30 s) were immunosuppressed with polyclonal antibody (Thymoglobulin), a calcineurin inhibitor, either mycophenolate mofetil or sirolimus, and rapid discontinuation of prednisone. Actuarial 3-year patient survival was 95%; graft survival, 93%. Acute rejection-free graft survival at 1 year was 94%; at 3 years, 92%. There was no difference between LD and CAD. At 2 years, the mean (+/- SE) serum creatinine level for LDs was 1.6 +/- 0.5 mg/dL; for CAD, 1.6 +/- 0.4 mg/dL. We have no new cases of PTLD or avascular necrosis; 22 recipients (6%) developed CMV. Currently, 84% of recipients remain prednisone-free. We conclude that excellent 3-year patient and graft survival can be achieved without maintenance prednisone. With such a protocol, steroid-related side-effects are minimal.

Background: As short-term transplant results improve, it has become difficult to use patient or graft survival or acute rejection as clinical trial endpoints, except in large, multicenter studies. Despite better outcomes, graft failure continues over time., Methods: We studied 6- and 12-month creatinine (Cr) level and change in creatinine (deltaCr) level (3-12 months, 6-12 months) as predictors of graft survival for 1,389 primary kidney transplants (minimum graft survival 1 year). Determining the prognostic value of Cr level (6 or 12 months), the subgroups were as follows: less than 1, 1 to 1.4, 1.5 to 1.9, 2.0 to 2.4, 2.5 to 2.9, and greater than or equal to 3 mg/dL. For deltaCr level, the subgroups were as follows: less than 0, 0, 0.01 to 0.2, and greater than 0.2. Subgroup actuarial graft survival was determined. Cox regression analyses were performed with forward, stepwise selection., Results: After 12-month Cr level entered the model, no other variable was significant. Repeating this with continuous variables, 12-month Cr level was again the best predictor. Five-year graft survival for 12-month Cr level less than 1 (n=38) was 95%; for 1.0 to 1.4 (n=454), 87%; for 1.5 to 1.9 (n=463), 86%; for 2.0 to 2.4 (n=166), 78%; for 2.5 to 2.9 (n=54), 60%; for greater than or equal to 3 (n=45), 41%. A major breakpoint for outcome is 1-year Cr level=2.0. A power analysis was performed for the combined endpoint of graft loss and 1-year Cr level greater than 2, reached by 30% of patients. To avoid missing a reduction to 20% (actual decrease 33%) (alpha=0.05; power=0.8), 313 patients would be required per group. For a reduction to 15% (actual decrease 50%), 133 patients would be required., Conclusions: Twelve-month Cr level is an accurate surrogate for long-term outcome. The use of a combined endpoint (graft loss and 12-month Cr level) allows trials to be performed without exorbitant numbers.

Background: Transplant candidates frequently ask whether they should, based on information available at the time, accept a cadaver kidney or wait for a potentially better one., Methods: We analyzed 937 first and second cadaver transplants done between January 1, 1984 and December 31, 1997 to determine if information available at the time an offer is made could be used to predict long-term graft survival., Results: By Cox regression, risk factors for worse long-term graft survival were older donor age, cardiovascular or cerebrovascular cause of donor death, and delayed graft function (DGF). HLA-ABDR mismatch was marginally significant. Whether DGF will occur is not known at the time of an offer, but risk factors can be determined; we found these to be older donor age and > 10% panel-reactive antibodies (PRA) at transplantation (by Cox regression). Using these variables (PRA, ABDR mismatch, donor age, and donor cause of death) known at the time of an offer, we calculated the relative risk of worse long-term graft survival for each subgroup (Table 3 in manuscript). In general, older age and donor death from cardiovascular or cerebrovascular disease were associated with worse outcome. Kidneys from donors of < 50 yr had the best outcome, irrespective of match., Conclusion: The data provided can be used to help guide patients as to whether they are better off accepting an offered kidney or waiting for a potentially better one. If an offer is declined, the next kidney may have a potentially worse outcome.

Background: There is a debate about the relative contribution of immunologic (rejection) and nonimmunologic (limited nephron mass) factors in long-term graft survival., Methods: Using multivariate analysis, we studied the association of the following variables with outcome: delayed graft function (DGF), acute rejection, recipient race (black vs. nonblack), donor age (<50 vs. > or =50), donor race, and donor and recipient gender. Because of the association between DGF and rejection, recipients were grouped as follows: DGF, rejection; DGF, no rejection; no DGF, rejection; no DGF, no rejection. Data were analyzed on 1199 first kidney transplants in adults (752 living donor, 447 cadaver donor) done between January 1, 1985 and December 31, 1996. Two analyses were done: first, all transplants; second, only those with > or =1 year survival. For both, there was no difference in risk factors if death with function was or was not censored., Results: For all cadaver transplant recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age > or =50. For living donor recipients, only acute rejection was a risk factor. When only 1-year graft survivors were considered, risk factors were the same: for cadaver recipients, risk factors were acute rejection, DGF plus rejection, black recipient race, and donor age > or =50; for living donor recipients the risk factor was rejection., Conclusion: We found immunologic factors (rejection with or without DGF) to be significant in both living donor and cadaver donor transplants. Nonim. munologic factors (donor age, recipient race) were significant only in cadaver donor transplants.

Background: Hyperacute rejection of porcine organs transplanted into primate recipients is initiated by the binding of preformed xenoreactive natural antibodies to the vascular endothelium of the graft and activation of the classical complement pathway. Several small animal models are currently employed to study various aspects of xenograft rejection; however, none has been shown to manifest hyperacute rejection mediated by the classical pathway of complement activation., Methods: We performed heterotopic mouse heart transplants into weanling rabbits, adult rabbits, and C6-deficient rabbits. The recipients received no immunosuppression. Rejected grafts were subjected to histologic analysis and immunofluorescence staining for rabbit IgG, IgM, and C3. Levels of preexisting cytotoxic antibodies as well as classical and alternative complement pathway activities were determined in rabbit serum using mouse red cells as targets., Results: Mean graft survival was 37+/-9.6 min for mouse-to-weanling rabbit transplants (n=10), and 40+/-11.1 min for mouse-to-adult rabbit transplants (n=5). Rejected grafts showed diffuse interstitial hemorrhage, endothelial cell damage, myocyte necrosis, moderate diffuse deposition of rabbit IgG, and dense deposition of rabbit IgM and C3 on the vascular endothelium of the graft, consistent with hyperacute rejection. One mouse-to-C6-deficient rabbit transplant was rejected at 21 hr with severe interstitial hemorrhage, cellular necrosis and a moderate cellular infiltrate consisting primarily of neutrophils and some mononuclear cells. A second transplant in a C6-deficient rabbit was functioning when the recipient died at 6.5 hr as a result of complications of surgery; the graft had normal myocytes and vasculature with minimal spotty interstitial hemorrhage. Both weanling and adult rabbit serum were found to have high titers of cytotoxic IgM anti-mouse antibodies and strong classical complement pathway activity with minimal alternative pathway activity towards mouse red cells., Conclusions: The mouse-to-rabbit species combination manifests hyperacute xenograft rejection. In vitro studies suggest that this process is mediated by IgM anti-mouse natural antibodies and activation of the classical pathway of complement.

Cadaver renal allografts with immediate excellent function have good long-term outcomes, while grafts with delayed function have been associated with an increased incidence of acute rejection (AR) and subsequent poor long-term graft survival. There is, however, an intermediate group with initial slow function whose outcome is not well defined. This group was examined by reviewing 510 patients that received primary cadaver transplants between 1/85 and 8/95. Recipients were grouped by initial function into: 1) those with immediate graft function (IGF), defined by serum creatinine (Cr) level < 3 mg/dl on post-operative day (POD) 5 (n = 237); 2) those with slow graft function (SGF), defined by serum Cr > 3 mg/dl on POD 5 but no need for dialysis (n = 160); and 3) those with delayed graft function (DGF), defined by the need for dialysis in the first week post-transplant (n = 113). Five-year graft survivals were determined for each group by Kaplan-Meier methods and compared by a generalized Wilcoxon test. The incidence of AR in the first 6 months was significantly higher in those with SGF (40%) vs. those with IGF (30%) (p < 0.05); both groups had a lower incidence than those with DGF (47%) (p < 0.05). In the absence of AR, 5-yr graft survival was similar between the 3 groups, 94%, 97% and 92% for IGF, SGF and DGF respectively. In the presence of AR, 5-yr graft survival was significantly reduced in all groups, but most notably in those with SGF (51%) or DGF (53%), as compared to those with IGF (80%), (p < 0.001). We conclude that recipients with SGF, but no AR, have excellent outcomes, comparable to those with IGF. However, there is an increased incidence of early AR associated with SGF. In recipients with SGF or DGF, AR has a more profound detrimental effect on long-term graft survival than in the IGF group. Thus, recipients with SGF are at increased risk for AR with resultant poor long-term graft survival, and may need modified immunosuppressive protocols.

Infants are thought to be more immunoreactive and at a greater risk for developing irreversible rejection compared with older children. We investigated this by analyzing patient and graft survival rates, incidence of acute rejection, reversibility of acute rejection, development of a subsequent acute rejection, and incidence of graft loss due to rejection in 154 children (< 18 years of age) after primary renal transplantation. Most patients (n = 139) were treated with quadruple immunosuppression (antibody, azathioprine, prednisone, cyclosporine). Treatment of the first acute rejection episode (ARE) consisted of antibody and increased prednisone (68%) or increased prednisone alone (30%), and was not significantly different between the age groups. Transplants were from living donors (LRD) in 80% of cases. Patients were followed for at least 1 year (mean 58 +/- 30 months); 68% (105/154) of recipients experienced 1 or more ARE. The incidence of ARE was significantly lower in patients < 2 years of age (45%) compared with patients 2-5 (76%, P = 0.01), 6-12 (78%, P = 0.005), and 13-17 (76%, P = 0.009) years of age. There was no significant difference in the 1-, 2- and 5-year patient or graft survival rates, the development of a subsequent acute rejection, or the incidence of graft loss due to acute rejection when analyzed by age group. These data suggest that the impact of an ARE is similar for younger and older children in our population receiving predominantly LRD transplants and quadruple immuno-suppression.

Unlabelled: We analyzed 420 kidney retransplants at the University of Minnesota, 87 of which did and 333 which did not share HLA mismatches with the previous transplant. There was no difference in outcome. We conclude that exceptions to routine HLA matching policies do not have to be made for kidney retransplants., Objective: To determine if the kidney graft functional survival rate for retransplants is influenced by presence of HLA mismatches in common with the previous (failed) transplant., Summary Background Data: Kidney retransplants have a lower function rate than primary grafts. An anamnestic response to HLA antigens shared with the previous donor could be one factor responsible, but reports in the literature are conflicting., Methods: Of 420 kidney retransplants with HLA information done at the University of Minnesota, 87 shared > or = 1 HLA antigens specifically mismatched with the previous donor (63 cadaver and 24 living donor retransplants), while 333 did not (247 cadaver, 86 living donor). Patient and graft survival rates were calculated by life-table analysis for recipients with vs. without repeat mismatches, with the significance of differences determined by the Lee-Desu statistic., Results: Patient and kidney graft retransplant survival rate curves were not significantly different (p > or = 0.41) for those exposed or not exposed to the same HLA mismatches as before. At 2 years, 70% vs. 61%, respectively, of cadaver grafts and 71% vs. 78%, respectively, of living donor grafts were functioning., Conclusions: The probability of a successful outcome with a kidney retransplant is no different for patients who do than for those who do not receive an organ sharing HLA mismatches with the previous donor. Exceptions to routine HLA matching policies do not need to be made for kidney retransplants.

Although their relative importance and interaction are unclear, donor antigen(Ag)*-specific hyporeactivity and allogeneic microchimerism have been associated with improved long-term graft outcome and a lower incidence of chronic rejection in solid organ transplant recipients. We have postulated that a critical level of donor antigen, for a critical time period, is necessary to develop and maintain donor antigen-specific hyporeactivity; both the level and the time may differ by organ transplanted. In our current study, we tested donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in liver and kidney recipients and compared these values with our previous findings in lung recipients. We tested 25 liver recipients at 12 to 29 months posttransplant: 10 (40%) had developed donor antigen-specific hyporeactivity; 5 (20%), peripheral blood allogeneic microchimerism. For all but 1 of the chimeric and hyporeactive recipients, the level of donor cells was very low (< 1:20,000). Five hyporeactive recipients and all 15 donor antigen-responsive recipients did not have detectable levels of peripheral blood microchimerism. No chronic rejection has developed in any of these recipients to date--however, a lower incidence of acute rejection was observed for those recipients with donor antigen-specific hyporeactivity (30% versus 60% without) or with peripheral blood allogeneic microchimerism (20% versus 55% without) (P = ns). These results differ from our previous findings in 19 lung recipients: at 12 to 18 months posttransplant, 35% of them had developed donor antigen-specific hyporeactivity; 47%, peripheral blood allogeneic microchimerism. All donor antigen-specific hyporeactivity recipients as well as some donor antigen-responsive recipients had peripheral blood allogeneic microchimerism. We expanded our current study to include 26 recipients and a quantitative estimate of the level of allogeneic microchimerism. We observed that the hyporesponsive recipients tended to have higher levels of donor cells in their peripheral blood (> 1:6,000) than did the responsive recipients. We previously reported that 22% of kidney recipients had developed donor antigen-specific hyporeactivity at 12 to 18 months posttransplant. In our current study of 33 kidney recipients, we observed peripheral blood allogeneic microchimerism in 7 (21%) at 12 to 18 months posttransplant. The level of donor cells was very low (approximately 1:75,000), with no correlation between donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism at the time point tested. These studies emphasize the organ-specific nature of the development of donor antigen-specific hyporeactivity and the persistence of peripheral blood allogeneic microchimerism. Donor antigen-specific hyporeactivity correlates with very low levels of donor cells in liver recipients, while a higher critical level of donor cells is important in lung recipients. Additional sequential early posttransplant studies are necessary to further define the possible interrelationship between donor antigen and the development and maintenance of donor antigen-specific hyporeactivity.

We assessed the efficacy of 5 dose levels of oral rapamycin for prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels.

Background: T cells that receive T-cell antigen receptor signals but do not undergo mitosis become unresponsive to subsequent antigenic stimulation. This can be achieved by antigen presentation to T cells in the absence of critical costimulatory signals from antigen-presenting cells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes, which do not provide costimulatory signals to T cells in vitro, leads to T-cell unresponsiveness in vivo and specifically prolongs the survival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to determine whether in vivo infusion of adherent APC-depleted donor peripheral blood mononuclear cells (PBMC), with or without rapamycin, induces prolonged kidney allograft survival in a large animal model., Methods: MHC homozygous inbred miniature swine (SLAcc) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 x 10(8) cells) from MHC disparate SLAdd donors, with and without three peritransfusion infections of rapamycin (0.25 mg/kg/day intramuscularly) the day before, the day of, and the day after the transfusion. SLAcc recipients received an SLAdd kidney transplant 6 days later. No posttransplant immunosuppression was given., Results: In contrast to donor-specific whole blood transfusions, which uniformly resulted in sensitization and hyperacute rejection (less than 1 day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 +/- 4.5 days) to untreated controls (mean, 7.8 +/- 5.0 days). Pretransplant rapamycin alone also had no effect on survival (mean, 7.7 +/- 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, however, increased survival significantly (mean, 27.3 +/- 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBMC; p = 0.03 versus recipients of rapamycin alone)., Conclusions: Pretransplant transfusion with costimulator-deficient donor PBMC plus peritransfusion rapamycin treatment, but neither alone, prolongs renal allograft survival in pigs without posttransplant immunosuppression. This strategy, once optimized, may be applicable to human transplant tolerance.

Recipient selection criteria for pancreas (Px) transplantation differ among centers, based on perceived recipient risk factors, and their validity has not been determined. At the University of Minnesota we have been very liberal in accepting patients for Tx, some of whom have risk factors cited as exclusion criteria by other centers, giving us the opportunity to determine, retrospectively, the impact of their presence on outcome. Between July 1986 and March 1993, we performed 319 bladder-drained cadaver Px Txs at the University of Minnesota, 166 simultaneous with a kidney (SPK), 68 after a kidney (PAK), and 85 alone (PTA). To determine which putative "risk factors" influence patient and graft survival, we used uni- and multivariate (Cox regression) analyses to assess the impact of recipient category, duration of diabetes, and age at onset and at Tx; presence of pre-Tx cardiac (CD) disease (myocardial infarction, bypass, angioplasty), peripheral vascular disease (PVD) (stroke, bypass, angioplasty, amputation); blindness, hypertension, and excess weight; and of Px re-Txs. The incidences of all risk factors except re-Tx were significantly higher in SPK than PTA recipients. Px re-Txs comprised 40% of PAK, 26% of PTA, and 10% of SPK cases (P < 0.0001). Duration of diabetes correlated (P < or = 0.01) with all risk factors but one (hypertension). Recipient age correlated (P < or = 0.01) with CD, blindness, duration of diabetes, and age at onset of diabetes; CD risk factors correlated (P < 0.015) with hypertension and PVD. Recipient age (> or = 45) influenced the technical failure rate only in SPK recipients, with a relative risk (RR) of 2.13 (P = 0.08). Recipient age influenced Px graft and patient survival rates in both SPK and PAK recipients; for those > or = 45, the RR of graft loss was 1.73 and 1.76, respectively (P < or = 0.25), and the RR for ultimately dying was 3.07 in PAK (P = 0.02) and 5.86 in SPK (P = 0.17) recipients. SPK recipients with CD factors were at higher risk to ultimately die (RR = 3.78, P = 0.009), independent of age. Px re-Txs were not at higher risk to fail in PTA, but were in PAK recipients (RR = 1.86, P = 0.09); the risk for technical failure was higher for re-Txs only in SPK recipients (RR = 2.11, P = 0.24). Blindness, hypertension, PVD, and duration of diabetes did not negatively influence patient and graft outcome in any recipient category.(ABSTRACT TRUNCATED AT 400 WORDS)