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The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Living kidney donors make a significant contribution to alleviating the organ shortage. The aim of this article is to provide an overview of mid- and long-term (≥12 mo) living donor psychosocial outcomes and highlight areas that have been understudied and should be immediately addressed in both research and clinical practice. We conducted a narrative review by searching 3 databases. A total of 206 articles were included. Living donors can be divided into those who donate to an emotionally or genetically related person, the so-called directed donors, or to an emotionally or genetically unrelated recipient, the so-called nondirected donors. The most commonly investigated (bio)psychosocial outcome after living donation was health-related quality of life. Other generic (bio)psychological outcomes include specific aspects of mental health such as depression, and fatigue and pain. Social outcomes include financial and employment burdens and problems with insurance. Donation-specific psychosocial outcomes include regret, satisfaction, feelings of abandonment and unmet needs, and benefits of living kidney donation. The experience of living donation is complex and multifaceted, reflected in the co-occurrence of both benefits and burden after donation. Noticeably, no interventions have been developed to improve mid- or long-term psychosocial outcomes among living donors. We highlight areas for methodological improvement and identified 3 areas requiring immediate attention from the transplant community in both research and clinical care: (1) recognizing and providing care for the minority of donors who have poorer long-term psychosocial outcomes after donation, (2) minimizing donation-related financial burden, and (3) studying interventions to minimize long-term psychosocial problems., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kidney donors have increased risk of postdonation gestational hypertension (gHTN) and preeclampsia. In the general population, pregnancy complications are associated with long-term maternal risk. However, little data exist on whether donors with postdonation pregnancy-related complications have similar increased long-term risks. We studied whether postdonation gHTN, preeclampsia/eclampsia, or gestational diabetes (gDM) was associated with increased risk of developing hypertension, DM, cardiovascular disease, or estimated glomerular filtration rate <45 mL/min/1.73 m 2 ., Methods: Postdonation pregnancies with complications were matched to pregnancies without complications based on time from donation. Incidence of outcomes was compared using sequential Cox regression with robust standard errors. Donors with predonation pregnancy complications were excluded. Models were adjusted for age at pregnancy, gravidity, year of donation, and family history of hypertension, DM, and heart disease., Results: Of the 384 donors with postdonation pregnancies (median [quartiles] follow-up of 27.0 [14.2-36.2] y after donation), 39 experienced preeclampsia/eclampsia, 29 gHTN without preeclampsia, and 17 gDM. Median interval from donation to first pregnancy with preeclampsia was 5.1 (2.9-8.6) y; for gHTN, 3.7 (1.9-7.8) y; and for gDM, 7.3 (3.7-10.3) y. Preeclampsia/eclampsia (hazard ratio [HR] 2.70; 95% confidence interval [CI], 1.53-4.77) and gHTN (HR 2.39; 95% CI, 1.24-4.60) were associated with development of hypertension. Preeclampsia/eclampsia (HR 2.15; 95% CI, 1.11-4.16) and gDM (HR 5.60; 95% CI, 1.41-22.15) were associated with development of DM. Pregnancy-related complications were not associated with increased risk of cardiovascular disease or estimated glomerular filtration rate <45 mL/min/1.73 m 2 ., Conclusions: In our single-center study, postdonation preeclampsia, gHTN, or gDM was associated with long-term risk of hypertension or DM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ideally, when deciding whether to donate, kidney donor candidates would understand their long-term risks. Using single-center data (N = 4055; median [quartiles] follow-up: 18 [9-28] y), we developed a calculator for postdonation hypertension and validated it using long-term data from an external single-center cohort (N = 1189, median [quartiles] follow-up: 9 [5-17] y)., Methods: Risk factors considered were routinely obtained at evaluation from donor candidates. Two modeling approaches were evaluated: Cox proportional hazards and random survival forest models. Cross-validation prediction error and Harrell's concordance-index were used to compare accuracy for model development. Top-performing models were assessed in the validation cohort using the concordance-index and net reclassification improvement., Results: In the development cohort, 34% reported hypertension at a median (quartiles) of 16 (8-24) y postdonation; and in the validation cohort, 29% reported hypertension after 17 (10-22) y postdonation. The most accurate model was a Cox proportional hazards model with age, sex, race, estimated glomerular filtration rate, systolic and diastolic blood pressure, body mass index, glucose, smoking history, family history of hypertension, relationship with recipient, and hyperlipidemia (concordance-index, 0.72 in the development cohort and 0.82 in the validation cohort)., Conclusions: A postdonation hypertension calculator was developed and validated; it provides kidney donor candidates, their family, and care team a long-term projection of hypertension risk that can be incorporated into the informed consent process., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hypertension and diabetes are contraindications for living kidney donation in young candidates. However, little is known about the long-term outcomes of women who had these pregnancy-related complications and subsequently became donors. In the general population, gestational hypertension (GHtn), preeclampsia/eclampsia, and gestational diabetes (GDM) are associated with long-term risks., Methods: Donors with the specified predonation complication were matched to contemporary control donors with pregnancies without the complication using nearest neighbor propensity score matching. Propensity scores were estimated using logistic regression with covariates for gravidity, blood pressure, glucose, body mass index, age, and creatinine at donation, donation year, race, relationship with recipient, and family history of disease. Long-term incidence of hypertension, diabetes, cardiovascular disease, and reduced renal function (estimated glomerular filtration rate [eGFR] <30, eGFR <45 mL/min/1.73 m 2 ) were compared between groups using proportional hazards models., Results: Of 1862 donors with predonation pregnancies, 48 had preeclampsia/eclampsia, 49 had GHtn without preeclampsia, and 43 had GDM. Donors had a long interval between first pregnancy and donation (median, 18.5 y; interquartile range, 10.6-27.5) and a long postdonation follow-up time (median, 18.0; interquartile range, 9.2-27.7 y). GHtn was associated with the development of hypertension (hazard ratio, 1.89; 95% confidence interval, 1.26-2.83); GDM was associated with diabetes (hazard ratio, 3.04; 95% confidence interval, 1.33-6.99). Pregnancy complications were not associated with eGFR <30 or eGFR <45 mL/min/1.73 m 2 ., Conclusions: Our data suggest that women with predonation pregnancy-related complications have long-term risks even with a normal donor evaluation. Donor candidates with a history of pregnancy-related complications should be counseled about these risks., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 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.)

Background: Many kidney donor candidates with impaired fasting glucose (IFG) and all candidates with diabetes are currently excluded from kidney donation, fearing the development of an accelerated course of diabetic kidney disease in the remaining kidney., Methods: We studied mortality, proteinuria, and end-stage kidney disease (ESKD) in 8280 donors who donated between 1963 and 2007 according to donation fasting plasma glucose (FPG): <100 mg/dL (n = 6204), 100-125 mg/dL (n = 1826), and ≥126 mg/dL (n = 250)., Results: Donors with IFG and those with FPG ≥126 mg/dL were older, less likely to be non-Hispanic White, had a higher body mass index, and were more likely to be related to their recipient. After 15.7 ± 10.5 y from donation to study close, 4.4% died, 29.4% developed hypertension, 13.8% developed proteinuria, and 41 (0.5%) developed ESKD. In both the logistic and Cox models, IFG was associated with a higher diabetes risk (adjusted hazard ratio [aHR], 1.65; 95% confidence interval [CI], 1.18-2.30) and hypertension (aHR, 1.35; 95% CI, 1.10-1.65; P = 0.003 for both), but not higher risk of proteinuria or ESKD. The multivariable risk of mortality in donors with ≥126 mg/dL was higher than the 2 other groups, but risks of proteinuria, cardiovascular disease, and reduced estimated glomerular filtration rate were similar to those with FPG <126 mg/dL. Three cases of ESKD developed in the 250 donors with FPG ≥126 mg/dL at 18.6 ± 10.3 y after donation (aHR, 5.36; 95% CI, 1.0-27.01; P = 0.04)., Conclusions: Donors with IFG and the majority of donors with ≥126 mg/dL do well and perhaps should not be routinely excluded from donation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Glomerular size in renal allografts is impacted by donor-recipient factors and response to injury. In serial biopsies of patients with well-functioning grafts, increased glomerular size correlates with better survival. However, no previous study has addressed the association of glomerular size at the time of a for-cause biopsy and clinical/histopathologic markers of injury, or effect on long-term graft outcome., Methods: Two cohorts of kidney transplant recipients enrolled in the Deterioration of Kidney Allograft Function study were evaluated. The prospective cohort (PC, n = 581): patients undergoing first for-cause kidney biopsy 1.7 ± 1.4 (mean ± SD) y posttransplant; and the cross-sectional cohort (CSC, n = 446): patients developing new-onset renal function deterioration 7.7 ± 5.6 y posttransplant. Glomerular planar surface area and diameter were measured on all glomeruli containing a vascular pole. Kidney biopsy was read centrally in a blinded fashion according to the Banff criteria., Results: Glomerular area was significantly higher in the CSC than the PC; time from transplant to indication biopsy was associated with glomerular area in both cohorts (P values ≤ 0.001). Glomerular area was associated with indices of microvascular inflammation (glomerulitis, peritubular capillary infiltrates; P values ≤ 0.001) and segmental glomerulosclerosis (P value < 0.0001). In the CSC, higher glomerular area was associated with higher estimated glomerular filtration rate (P value ≤ 0.001) and increased graft survival after accounting for microvascular inflammation (adjusted hazard ratio = 0.967; 95% confidence interval: 0.948-0.986; hazard ratio in biopsies without evidence of diabetes or antibody mediated rejection = 0.919, 95% confidence interval: 0.856-0.987)., Conclusions: Glomerular size is associated with histopathologic features present at the time of indication biopsy and with increased graft survival in the CSC., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: About half of late kidney allograft losses are attributed to death with function (DWF), a poorly characterized outcome. An ongoing question is whether DWF is a consequence of chronic allograft dysfunction. Using the prospective Long-term Deterioration of Kidney Allograft Function study database, we sought to better define the impact, phenotype, and clinical course of DWF in the current era., Methods: Three thousand five hundred eighty-seven kidney recipients with functional grafts at 90 days post-transplant were followed prospectively for a median of 5.2 years., Results: Characteristics at transplantation in those with DWF (N = 350, 9.8%) differed from those who otherwise lost their grafts (death-censored graft failure [DC-GF], N = 295, 8.2%) or maintained function (N = 2942, 82.0%); DWF patients were older, sicker, and had been on dialysis longer, with more preexisting cardiovascular disease, whereas DC-GF patients experienced more early rejection, more acute rejection after 90 days, and a clinically significant decrease in kidney function before graft failure. In contrast, the clinical course after transplantation in DWF patients did not differ before death from those who maintained function throughout., Conclusions: DWF and DC-GF in kidney transplant recipients represent differing clinical phenotypes occurring in distinct patient populations. Reducing the impact of DWF requires better definition of causes and clinical course and then trials of therapies to improve outcomes. Composite endpoints in clinical trials that group DWF and DC-GF together may obscure important clinical findings.

Background: In response to calls for an increased focus on pretransplant outcomes and other patient-centered metrics in public reports of center outcomes, a mixed methods study evaluated how the content and presentation style of new information influences decision-making. The mixed methods design utilized qualitative and quantitative phases where the strengths of one method help address limitations of the other, and multiple methods facilitate comparing results., Methods: First, a series of organ-specific focus groups of kidney, liver, heart, and lung patients helped to develop and refine potential displays of center outcomes and understand patient perceptions. A subsequent randomized survey included adult internet users who viewed a single, randomly-selected variation of 6 potential online information displays. Multinomial regression evaluated the effects of graphical presentations of information on decision-making., Results: One hundred twenty-seven candidates and recipients joined 23 focus groups. Survey responses were analyzed from 975 adults. Qualitative feedback identified patient perceptions of uncertainty in outcome metrics, in particular pretransplant metrics, and suggested a need for clear guidance to interpret the most important metric for organ-specific patient mortality. In the randomized survey, only respondents who viewed a note indicating that transplant rate had the largest impact on survival chose the hospital with the best transplant rate over the hospital with the best posttransplant outcomes (marginal relative risk and 95% confidence interval, 1.161.501.95)., Conclusions: The presentation of public reports influenced decision-making behavior. The combination of qualitative and quantitative research helped to guide and enhance understanding of the impacts of proposed changes in reported metrics.

Background: Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism., Methods: In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans., Results: Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4., Conclusions: Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.

Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes., Methods: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes., Results: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified., Conclusions: These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

Background: Recent changes in policies guiding allocation of transplant kidneys are predicted to increase sharing between distant geographic regions. The potential exists for an increase in cold ischemia time (CIT) with resulting increases in delayed graft function (DGF) and transplant-related costs (TRC). We sought to explore the impact of CIT on metrics that may influence TRC., Methods: Between 2006 and 2014, 81 945 adult solitary deceased donor kidney transplants were performed in the United States; 477 (0.6%) at our institution. Regression models were constructed to describe the relationship between CIT on DGF and length of stay (LOS). Using hospital accounting data, we created regression models to evaluate the effect of DGF on LOS and TRC., Results: In multivariable models, longer CIT was associated with an increased rate of DGF (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.38-1.44) and increased LOS (OR, 1.04; 95% CI, 1.02-1.05). Recipients at our institution who developed DGF had longer LOS (OR, 1.71; 95% CI, 1.50-1.95), suggesting that the effect is partially mediated by DGF. After adjusting for LOS, neither CIT nor DGF were independently associated with increased TRC. However, an increased LOS resulted in an increase in TRC by US $3422 (95% CI, US $3180 to US $3664) per additional day, indicating that the effect of CIT on TRC is partially mediated through LOS., Conclusions: The prolongation of CIT is associated with an increase in DGF rates and LOS, resulting in increased TRC. This study raises the need to balance increased access of traditionally underserved populations to kidney transplant with the inadvertent increase in TRC.

Background: The rate of measured glomerular filtration rate (GFR) change in kidney donor years after donation has not been adequately addressed. Whether this change is accelerated in the setting of 1 kidney is also understudied., Methods: Two hundred fourteen randomly selected donors underwent serial GFR measurements of nonradioactive iohexol. Estimated GFR at each visit was calculated using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease study equations., Results: Glomerular filtration rate visits were 4.8 ± 1.3 years apart and the second occurring 16.9 ± 9.1 years after donation. Most (97.7%) were white, 60.8% female, and 78.5% were related to their recipient. Most, 84.6%, had a GFR of 60 mL/min per 1.73 m or higher, 14.0% had a GFR between 45 and 60 mL/min per 1.73 m, and 1.4% had a GFR less than 45 mL/min per 1.73 m. Between visits 1 and 2, 56.5% had a GFR decline, 36.0% increase, and in 7.5%, there was no change. Overall, GFR declined at a rate of -0.42 mL/min per 1.73 m per year. Of GFR estimating models, only Chronic Kidney Disease Epidemiology Collaboration-Creatinine equation produced a slope that was steeper than measured GFR., Conclusions: Nearly 2 decades postdonation GFR declined at a rate similar to that seen in the general population, and in one third, GFR continues to increase.

Background: Infants (age, < 2 years) with end-stage renal disease (ESRD) have increased morbidity and mortality. We evaluated our long-term outcomes of kidney transplants (KTx) in infants., Methods: Between 1984 and 2014, 136 infants underwent KTx. We examined trends in survival rates and complications by era (1984-1993 [era 1], 1994-2003 [era 2], 2004-2014 [era 3])., Results: Patients were 92.6% white and 70.6% males. Posttransplant (Tx) initial length of hospital stay declined 37% over the 30-year period (P <0.01). Ten-year death-censored graft survival improved from 60% (era 1) to 80% (era 2) (P = 0.04). The incidence of acute rejection, graft thrombosis, cytomegalovirus, and urine leaks did not significantly change across eras. Frequency of Epstein-Barr virus diagnosis (era 2 vs era 3, P < 0.01) increased. Post-Tx lymphoproliferative disorder incidence was increased in era 2 compared with eras 1 and 3 (P = 0.03)., Conclusions: Infants deserve earlier consideration for KTx. Length of initial hospital stay and patient and graft survival rates after KTx have improved in infants since 1984.

Background: Living kidney donors have donation-related out-of-pocket costs (direct costs) and/or ongoing daily expenses while losing income (indirect costs). Yet there is little information about how much of a subjective burden these constitute for the donors., Methods: From December 2003 through December 2014, we surveyed donors 6 months postdonation to determine their financial burden related to donation (on a scale of 1 to 10) and what resources were used to cover expenses., Results: Of 1136 surveyed, 796 (70%) responded. Among respondents, mean age at donation was 43.6 ± 10.6 years, 64% were women, 96% were white, and 53% were related by blood to their recipient. Overall, 26% scored their financial burden as 5 or higher; 8% scored it as 8 or higher. Increased expenses were associated with a higher reported burden; however, significant burden was reported by some with no out-of-pocket expenses (presumably due to lost wages and continuing expenses). The burden was scored as 5 or higher by 27% of those employed outside the home (n = 660), 15% homemakers, 13% retirees, 40% students; 28% unemployed; and 26% whose occupation was unknown. Over half (51%) of those receiving a local or (means-tested) national grant still reported moderate to severe burden. Besides grants, donors used a variety of sources to help offset expenses: dipped into savings, borrowed from friends or family, took out a loan, and/or had a fundraiser. Those with the highest burden reported using the most additional sources., Conclusions: Donors should not have to incur costs or a financial burden to donate; the transplant community should strive to make donation financially neutral.

Background: The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes., Methods: All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques., Results: We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P < 0.001) and heavier (P < 0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P < 0.001). All 3 LDN modalities required a longer operative time (P < 0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P < 0.001) and reduced the incidence of intraoperative complications (P < 0.001) and hospital length of stay (P < 0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (<30 day, P < 0.001) and long-term (>30 day, P < 0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P < 0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15])., Conclusions: In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

Background: Living donor segmental pancreas transplants (LDSPTx) have been performed selectively to offer a preemptive transplant option for simultaneous pancreas-kidney recipients and to perform a single operation decreasing the cost of pancreas after kidney transplant. For solitary pancreas transplants, this option historically provided a better immunologic match. Although short-term donor outcomes have been documented, there are no long-term studies., Methods: We studied postdonation outcomes in 46 segmental pancreas living donors. Surgical complications, risk factors (RF) for development of diabetes mellitus (DM) and quality of life were studied. A risk stratification model (RSM) for DM was created using predonation and postdonation RFs. Recipient outcomes were analyzed., Results: Between January 1, 1994 and May 1, 2013, 46 LDSPTx were performed. Intraoperatively, 5 (11%) donors received transfusion. Overall, 9 (20%) donors underwent splenectomy. Postoperative complications included: 6 (13%) peripancreatic fluid collections and 2 (4%) pancreatitis episodes. Postdonation, DM requiring oral hypoglycemics was diagnosed in 7 (15%) donors and insulin-dependent DM in 5 (11%) donors. RSM with three predonation RFs (oral glucose tolerance test, basal insulin, fasting plasma glucose) and 1 postdonation RF, greater than 15% increase in body mass index from preoperative (Δ body mass index >15), predicted 12 (100%) donors that developed postdonation DM. Quality of life was not significantly affected by donation. Mean graft survival was 9.5 (±4.4) years from donors without and 9.6 (±5.4) years from donors with postdonation DM., Conclusions: LDSPTx can be performed with good recipient outcomes. The donation is associated with donor morbidity including impaired glucose control. Donor morbidity can be minimized by using RSM and predonation counseling on life style modifications postdonation.

Background: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are a significant cause of morbidity and mortality in transplant recipients and are often transmitted from the donor organ., Methods: In a pilot prospective, randomized, double-blinded, placebo-controlled trial, we studied whether 14 days of pretransplant donor treatment with valganciclovir (valG) versus placebo reduced donor-to-recipient transmission, making posttransplant recipient prophylaxis more effective in reducing EBV and CMV disease., Results: Seventeen D+ R- donor-recipient pairs were enrolled: 7 and 10 donors were randomized to valG and placebo, respectively. At study initiation, no donor had detectable CMV replication, five had EBV replication (two in valG, three in placebo group): EBV replication was undetectable during valG treatment, but resumed on stopping valG. Valganciclovir was tolerated without side effects or leukopenia. All recipients received routine posttransplant viral prophylaxis with valG. For recipients, viremia-free survival time, incidence, range, peak, and duration of CMV and EBV viremia were not significantly different between groups. There was no disease in the valG group but two serious viral diseases occurred in the placebo group (one CMV; one EBV-related posttransplant lymphoproliferative disorder). In the case of posttransplant lymphoproliferative disorder, the EBV DNA from the donor's oral wash and the recipient's lymphoid tissue biopsy had identical latent membrane protein 1 (LMP-1) sequence variations from the reference EBV strain, making it highly probable that the recipient's virus was of donor origin., Conclusion: Based on this pilot trial, we recommend an adequately powered study to determine if pretransplant donor treatment with valG can reduce posttransplant CMV and EBV disease with merely routine posttransplant recipient viral prophylaxis.

Background: Organ donors are often implicated as the source of posttransplant recipient infection. We prospectively studied kidney and liver donor-recipient pairs to determine if donor viral replication of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) at transplant was a risk factor for posttransplant recipient infection and disease., Methods: Donors and recipients were studied for antibodies against CMV and EBV and for quantitative viral replication of CMV, EBV, and BKV in oral washes, urine, and whole blood pretransplant. Recipient testing continued every 3 months after transplantation. Demographic and clinical data on infections and graft and subject outcomes were obtained., Results: The 98 donor-recipient pairs included 15 liver and 83 kidney transplants (18 of whom were children). No donor had detectable CMV replication; therefore, its impact on recipient CMV replication could not be analyzed. Donor EBV replication occurred in 22%, mostly in the oral wash and showed no impact on posttransplant recipient EBV replication (P=0.9) or EBV viremia (P=0.6) in kidney or liver recipients. Donor BKV replication occurred in 17%, mostly in the urine and although not associated with posttransplant recipient urinary BKV replication in recipients, it was associated with BKV viremia (P=0.02), and a significantly shorter time to BKV viremia (P=0.01) in kidney recipients., Conclusion: Donor replication of CMV or EBV did not impact posttransplant recipient viral replication in kidney or liver transplants. Donor urinary BKV replication is associated with recipient BKV viremia in kidney transplants.

Background: The performance of glomerular filtration rate (GFR) equations incorporating both cystatin C (CysC) and serum creatinine (Creat) in living kidney donors has not been studied before., Methods: From a population of 3,698 living kidney donors, 257 donors were randomly selected to undergo GFR measurement (mGFR) by the plasma disappearance of iohexol. GFR was estimated with the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Collaboration study eGFR(CKD-EPI-Creat) in 257 donors and the two newly developed equations using CysC with and without Creat, eGFR(CKD-EPI-CysC) and eGFR(CKD-EPI-Creat+CysC), in 215 donors., Results: Mean mGFR was 71.8±11.8 mL/min/1.73 m. The eGFR(MDRD) exhibited least and only negative bias and the three other models were comparable in terms of bias. The eGFR(CKD-EPI-Creat+CysC) equation was most precise; r=0.64. Both eGFR(MDRD) and eGFR(CKD-EPI-Creat+CysC) had high percentage (94.4% and 92.6%, respectively) of estimates falling within 30% of mGFR versus estimates by eGFR(CKD-EPI-Creat) and eGFR(CKD-EPI-CysC) equations (87.2% and 85.1%, respectively). The eGFR(MDRD) was by far most accurate in identifying those with mGFR less than 60 mL/min/1.73 m whereas the CKD-EPI models were extremely accurate in classifying those with mGFR greater than or equal to 60 mL/min/1.73 m., Conclusions: eGFR(CKD-EPI-Creat+CysC) equation provides comparable accuracy to the eGFR(MDRD) in overall estimation of mGFR, but with higher precision. However, eGFR(CKD-EPI-Creat+CysC) clearly misses many of those with a post-donation GFR less than 60 mL/min/1.73 m and therefore eGFR(MDRD) is preferable in detecting donors with GFR less than 60 mL/min/1.73 m.

Background: Uric acid has been linked to the progression of native kidney disease. Studies evaluating its contribution to allograft function in kidney transplant recipients, among whom hyperuricemia is common, have yielded mixed results., Methods: We evaluated the association between baseline uric acid and the primary composite outcome of doubling of interstitium or ESRD from interstitial fibrosis and tubular atrophy (IF/TA) in the Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN) Trial participants. Subjects underwent uric acid, iothalamte GFR, and urine albumin to creatinine (ACR) measurements annually for 5 years in addition to an allograft biopsy at baseline and 5 years., Results: Baseline uric acid was 5.57±1.48 mg/dL; male sex, higher BMI, diuretic use, and lower GFR were associated with higher uric acid, whereas older age, less than 3 HLA matches and having a female donor were associated with lower levels. In multivariate analysis adjusting for baseline GFR, uric acid was associated with doubling of interstitium or ESRD from IF/TA (OR 1.83, 95% CI, 1.06-3.17, P=0.03). Over time, a 1 mg/dL increase in time-varying uric acid was associated with a 2.39 mL/min lower final GFR (P<0.001) but not with the secondary outcome of creatinine doubling, ESRD, or death., Conclusions: These data suggest that uric acid is associated with IF/TA and thus may be a viable target for intervention.

Background: A biological marker that would allow clinicians to determine the length of time an allograft will remain functional after transplantation would greatly aid the ability to stratify donors by risk and to use biologically "young" allografts in young recipients, maximizing the use of this rare resource. Telomere length (TL) has been proposed to be such a marker to determine the biological age of a tissue., Methods: We genotyped DNA from 1805 recipients and 1038 living kidney donors for TL to determine the association of TL with acute rejection (AR), chronic graft dysfunction (CGD), and graft failure of kidney allografts. DNA was isolated from peripheral blood white blood cells and TL was measured in DNA using the multiplexed monochrome quantitative polymerase chain reaction assay., Results: As has been previously shown, we found a significant association between log-transformed TL and donor age (P=3.8×10) and recipient age (P=5.6×10). Univariate and multivariate analysis did not show any significant associations between log-transformed TL in donor or recipient DNA with AR, CGD, or graft failure, although we did observe an association between donor chronological age and CGD (P=0.018)., Conclusion: Although older allografts have been shown to be at greater risk for AR and CGD, this does not appear to be associated with shorter TL. Different markers will need to be identified to determine how biological age impacts transplant outcome, such as age-related fibrosis or tubular atrophy and tubular loss.

Background: The upper age limit to receive a kidney transplant has progressively risen, but the outcomes of elderly (ages ≥65 years) transplant recipients remain understudied. We therefore evaluated mortality, graft failure, and predictors of these outcomes in this population., Methods: Three cohorts of recipients transplanted between 1963 and 2012 (ages <50 years [n=2900], 50-64 years [n=1218], and ≥65 years [n=364] at transplantation) were compared for allograft and patient outcomes. Three similar age cohorts transplanted after 2000 (n=1410) were studied separately to address era effect., Results: Death-censored graft survival was higher in recipients ages ≥65 years: 5, 10, and 15 years was 90.7%, 80.4%, and 73.7%; for ages 50-64 years, it was 87.2%, 77.6%, and 71.5%; and for ages <50 years was 79.8%, 70.3%, and 60.8%. Risk factors for graft failure in those ages ≥65 years included panel-reactive antibody >10%, congestive heart failure (CHF), delayed graft function, and cellular rejection. The 5-, 10-, and 15-year patient survival rate was 69.7%, 36.0%, and 14.0% for those ages ≥65 years; 76.4%, 54.8%, and 34.0% for those ages 50-64 years; and 81.7%, 66.7%, and 52.2% for those ages <50 years. For the entire cohort of elderly recipients, coronary artery disease and CHF were associated with mortality, and in those recipients transplanted after 2000, the risk factors for mortality were coronary artery disease, graft failure, peripheral vascular disease, and cause of end-stage renal disease listed as other. For graft failure, only CHF and cellular rejection were associated with this outcome., Conclusions: The overall outcomes of transplantation in elderly kidney transplant recipients ages ≥65 years are excellent, but the risk factors for mortality and graft failure are distinctly different than those observed in younger recipients.

Background: The Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry was established to assess clinical experience with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant recipients., Methods: From 2003 to 2008, US transplant centers prospectively entered information on patients who received rATG induction. In addition to standard United Network for Organ Sharing registry data elements, information was collected regarding immunosuppression, viral prophylaxis, acute rejection, and adverse events., Results: Data on 2322 patients from 49 transplant centers were enrolled and met inclusion criteria for analysis. Patient and graft survival were 99.3% and 99.0% at 6 months and 98.4% and 98.2% at 12 months as recorded in Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry and were 91.5% and 83.2% at 5 years by Kaplan-Meier estimates based on linked United Network for Organ Sharing registry records. Freedom from rejection was 93.6% through 5 years. Mean rATG cumulative dose was 5.29 mg/kg. More than one-third of patients (37.6%) were steroid-free at discharge, and nearly half of patients (48%) were steroid-free at 12 months. Before discharge, 3.2% experienced serious adverse events, with 11 events (0.005%) reported as possibly or probably related to rATG. Incidence of cytomegalovirus infection was 4.2% at 12 months, and 99.1% of patients were posttransplant lymphoproliferative disorder-free through 5 years., Conclusions: rATG induction in living donor renal transplantation is safe and associated with a low incidence of acute rejection and posttransplantation complications.

Background: Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity., Methods: We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant., Results: Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity., Conclusion: We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.

Background: Defining living donor (LD)-related risk factors affecting kidney transplant outcome will allow better donor selection and more educated informed consent when there is more than one potential donor. We studied risk factors in a large cohort at a single institution., Methods: We reviewed 1632 recipients who underwent LD kidney transplantation at the University of Minnesota between January 1, 1990, and October 1, 2009. Using Cox regression, we studied the effect of donor and recipient risk factors on patient and graft survival. We specifically examined the effect of donor age and human leukocyte antigen (HLA) matching because these are variables that may help clinical decision making when multiple potential donors exist., Results: Mean donor age was 40.6 years for all transplants; 180 (11%) donors were 55 years or older, and 24 (1.5%) donors were older than 65 years. Mean number of HLA mismatches (per transplant) was 2.9 (29.2% of recipients had one to two HLA mismatches, 39.8% had three to four HLA mismatches, and 25% had five to six HLA mismatches). Donor age more than 65 years, five to six HLA mismatches, delayed graft function, and acute rejection were independent predictors of decreased patient and graft survival. When controlling for recipient age, donor age more than 65 years remained a risk factor for worse outcome., Conclusions: Our data suggest that advanced donor age (>65 years) and degree of HLA mismatch (≥5) are independent donor-related risk factors associated with worse outcome. When multiple potential LDs exist, it may be ideal to attempt to use a donor younger than 65 years and with less than five HLA mismatches.

Background: Recurrent glomerulonephritis (GN) remains an important cause of kidney allograft loss and whether rapid discontinuation of steroids (RDS) is associated with a higher risk of recurrence is not known., Methods: We studied recurrence rate, and graft and patient survival in four groups of recipients: 216 recipients with GN transplanted under RDS (group 1), 978 concurrent non-GN recipients transplanted under RDS (group 2), 260 historic comparator group transplanted for GN between 1994 and 1999 with steroid maintenance (group 3), and 950 recipients who were also transplanted between 1994 and 1999 for non-GN and also maintained on steroids (group 4). Regression analysis adjusting for donor and recipient factors, steroid and sirolimus use, and also GN type was used to address factors associated with recurrent disease., Results: The 1-, 5-, and 7-year recurrence rate in the GN group under RDS was 6.7%, 13.7%, and 19.2% and in historic GN recipients maintained on steroids it was 2.4%, 3.8%, and 5.3%, respectively (P<0.0001). RDS was associated with a higher adjusted risk of recurrent disease for all GN types (hazard ratio 4.86; 95% confidence interval 2.34-10.07; P<0.0001). Graft and patient survival were similar in the two GN groups and both were highest among all groups. Notably, death-censored graft survival was not different among the groups., Conclusion: Steroid avoidance may be associated with a higher rate of recurrent GN but no apparent increase in risk of graft loss. This group of recipients needs to be studied more carefully, in larger numbers, and for a longer time period.

Little is published regarding the effect of advertising for kidney donors on transplant centers. At our center, families of nine children used media appeals. Per candidate, there were 8 to 260 potential donor calls, 92 (11.6%) were medically ineligible, 326 (41.1%) voluntarily did not proceed or an alternate donor had been approved, 38 (4.8%) were ABO incompatible, and 327 (41.1%) had positive crossmatch or unsuitable human leukocyte antigens. Media appeals resulted in four living donor transplants and five nondirected donors to other candidates, and we made directed changes in our center. The ethical debate of advertising for organ donors continues.

Background: Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear., Methods: We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed up to time of first anemia (hemoglobin<10 gm/dL or hematocrit<30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm), which required clinical intervention in the first 6 months after transplant., Results: Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia, allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use, and stratifying by clinical center., Conclusion: Although these SNPs require validation in an independent population, our results suggest that genetics may play a role in risk of mycophenolate-related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs.

Background: The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in whites relative to African Americans (AA)., Methods: We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single-nucleotide polymorphism chip with 2722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a seven-center consortium., Results: During the 6-month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4-8.4) ng/mL vs. 8.3 (6.4-10.4) ng/mL (P<0.0001), despite 60% higher daily doses, 8 (5-10) mg vs. 5 (4-7) mg (P<0.0001). The median tacrolimus trough concentration in week 1 posttransplant was particularly low in AAs (2.1 [1.2-3.5] ng/mL) compared with non-AAs (5.0 [3.1-8.2] ng/mL) (P<0.0001), despite similar initial doses. In single-variant analysis, CYP3A5*3 (rs776746) was the top variant (P=2.4×10) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, 35 additional variants were identified (P<0.01, not significant at false discovery rate 20%). In the final multivariant, regression models beginning with these variants and clinical factors, seven variants were identified in the non-AA and seven variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations., Conclusion: We identified variants beyond CYP3A5*3, which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.

Background: Acute rejection (AR) is associated with worse renal allograft outcomes. Therefore, this study investigated single-nucleotide polymorphisms (SNPs) to identify genetic variants associated with AR, accounting for center variation, in a multicenter, prospective, observation study., Methods: We enrolled patients from six transplant centers, five in the United States and one in Canada. A total of 2724 SNPs were genotyped. We accounted for center variation in AR rates by stratifying by transplant center and using novel knowledge discovery methods., Results: There was significant center variation in AR rates across the six transplant sites (P<0.0001). Accounting for this difference and clinical factors independently associated with AR, we identified 15 novel SNPs associated with AR with stratification by transplant center (P<0.05). We also identified 15 novel SNPs associated with severity of tubulitis scores, after adjusting for transplant center and other clinical factors independently associated with severity of tubulitis (P<0.05). There was some overlap with one SNP associated with AR and also associated with severity of tubulitis, among the top 15 SNPs., Conclusion: Center-to-center variation is a major challenge to genomic studies focused on AR. The SNPs associated with AR and severity of tubulitis in this study will need to be validated in independent cohort of kidney transplant recipients.

Background: Although C4d deposition in peritubular capillaries has been identified as a strong risk factor for subsequent renal allograft loss, the optimal cutoff for the fraction of peritubular capillaries needed to establish a positive stain in formalin-fixed, paraffin-embedded material has not been defined systematically. The objective of this study was to establish the threshold for positive staining that best predicts renal outcome in renal biopsies in a multicenter study in which local and central pathologic conditions were compared., Methods: Unstained renal biopsy slides were obtained from 296 patients. The percentage of peritubular capillaries staining positively for C4d was detected by immunoperoxidase staining., Results: The percentage C4d deposition ranged from 0% to 90% with 44% (129/296) having a positive percentage of C4d staining. The median for positive cases was 25%. Local C4d+ results were reported qualitatively, with 28% recorded as positive for C4d. Using a centrally determined cutoff of 10%, tests for agreement of local and central C4d staining were fair (κ 0.40, 95% confidence interval 0.29-0.51). Raising the centrally determined cutoff to 25% or 50% did not change the κ values (0.44 and 0.41, respectively). By Cox proportional hazards model, C4d positivity (centrally determined assessment) using a cutoff of 10% was the strongest predictor of time to graft loss (hazard ratio 2.66, 95% confidence interval 1.68-4.21). Centrally determined C4d positivity correlated with Banff scores indicative of acute inflammation but not with scores indicative of fibrosis/atrophy or transplant glomerulopathy., Conclusions: Our findings indicate that C4d positivity, defined as more than or equal to 10% by immunoperoxidase, is a strong predictor of graft loss.

Background: Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF., Methods: One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations., Results: Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF., Conclusions: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Background: The use of biopsies to determine kidney health after kidney transplantation is an invasive procedure with some risk to the patient. Consequently, a noninvasive test for transplanted kidney health would provide a significant advantage over current clinical practice., Methods: Urines from kidney donors before nephrectomy, pretransplant patients with native kidney disease, and posttransplant kidney recipients were examined for protein biomarkers to diagnose or prognose kidney disease. Proteins were extracted by C4 reverse phase affinity and analyzed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry., Results: Urine from individuals with healthy kidneys showed few components other than two ubiquitous saposin B glycoisoforms. Patients with kidney disease lacked saposin B and showed new components in two patterns: the most common contained beta-2 microglobulin (B2M, m/z=11,732) plus one or more peaks at m/z=10,350, 9480, 4337, and 4180. Pattern 2 lacked beta-2 microglobulin but contained several degradation products of alpha-1 antitrypsin. Other pathologic components included urinary protein 1 (m/z=15,835), transthyretin (m/z=13,880), and a component at m/z=13,350., Conclusions: Patients with acute rejection showed profiles that ranged from those of kidney donors to those of advanced kidney disease. The range of patterns may be useful for analysis of transplant patients without complications and persons with developing kidney disease before or after transplant.

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.

Background: The benefits (e.g., low acute rejection [AR] rate) vs. the long-term risk of each immunosuppressive protocol may determine the protocol's value., Methods: We studied the long-term impact of new-onset posttransplant diabetes (PTDM) and/or AR in 1,487 adult, primary transplant, nondiabetic recipients. Per Cox regression, donor source, AR, and PTDM were independent risk factors for graft loss (each, p<.0001). Recipients were subdivided by donor source and into these 4 groups: no AR, no PTDM [n=857]; no AR, PTDM [n=134]; > or =1 AR, no PTDM [n=403]; > or =1 AR, PTDM [n=93]., Results: There was a significant difference between groups in 15-yr actuarial graft survival (GS) and death-censored (DC) GS (p<.0001). Importantly, > or =1 AR had more impact on 15-yr GS and DC GS than did PTDM; the worst outcome was for those having both AR and PTDM. In separate analyses, we censored those with >1 AR; and then only compared those developing AR or PTDM in the first year. The results were similar--the AR (no PTDM) group did worse than the PTDM (no AR) group (p<.001)., Conclusions: Determining long-term risks associated with immunosuppressive protocols is important for treating future patients. Our data suggests that 15-year actuarial outcome (GS and DC GS) is worse for those developing AR than for those developing PTDM.

Background: The long-term renal consequences of kidney donation need to be accurately quantitated. Cystatin C is a freely filtered glycoprotein that may not have the limitations of creatinine as a measure of glomerular filtration rate (GFR). Whether cystatin C is superior to creatinine-based estimates of GFR in those who have donated a kidney in the past has not been tested., Methods: We assessed the performance of seven cystatin C and two creatinine-based GFR prediction equations in 187 former kidney donors against iohexol GFR for measuring GFR. We calculated bias, precision, and relative accuracy of these models., Results: The majority of former donors had a GFR >60 mL/min/1.73 m(2). All cystatin C models, except the Rule model, overestimated GFR (range 5.3-31.4 mL/min/1.73 m(2)). Among the cystatin C models, the Hoek and Rule formulas were least biased at 5.3 and -3.8 mL/min/1.73 m(2), most precise at 0.41, and were within 30% of iohexol GFR, 89.3 and 96% of the time, respectively. The Modification of Diet in Renal Disease (MDRD) formula underestimated GFR by 7.2 mL/min/1.73 m(2), was most precise (R(2)=0.47) and fell within 30% of measured GFR at the highest frequency of 96%. When all models were given a rank based on their performance in the bias, precision and accuracy domains, the MDRD model was clearly superior., Conclusion: The MDRD equation is superior to cystatin C-based equations for estimating GFR in former kidney donors. Creatinine measurement is cheaper and the MDRD GFR is given out by most laboratories and therefore it should be the preferred model in this population.

Background: Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function., Methods: We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients., Results: The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses., Conclusions: Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.

Background: Asymptomatic, microscopic hematuria is seen in 8-21% of the general population, has a good prognosis, and is generally not an indication for kidney biopsy. But whether it should preclude kidney donation is unclear., Methods: Of 512 consecutive prospective donors, 14 (2.7%) continued to have asymptomatic, microscopic hematuria over 1 month. If the medical history, physical examination, and computerized tomographic angiography were unremarkable, and if they still wished to donate, a kidney biopsy was performed., Results: In two prospective donors, hematuria resolved after treatment for urinary tract infection; two others declined donation and were referred to their primary care provider. Kidney biopsy in the remaining 10 showed: two normal; four thin basement membrane nephropathy (TBMN); one nonhomogeneous basement membrane abnormalities; one IgA nephropathy, 5 of 16 glomeruli globally sclerotic; one in a patient with a family history of Schimke's Syndrome, 7 of 30 glomeruli globally sclerotic; and one TBMN and early hypertensive changes without systemic hypertension. Only 4 of the 10 who underwent kidney biopsy donated (two normal, two TBMN)., Conclusions: Kidney abnormalities are common in young, otherwise healthy, prospective kidney donor candidates with persistent, asymptomatic, microscopic hematuria. A kidney biopsy is often abnormal and aids in the decision-making process.

Prednisone-minimization protocols have been successful in low-risk recipients. We report on the use of a protocol incorporating rapid discontinuation of prednisone in a cohort of kidney transplant recipients (n = 79) at increased immunologic risk. Our data suggests that such recipients should not be excluded from prednisone-minimization protocols.

After renal transplantation, immunosuppressive medications must be taken long-term to avoid acute rejection and the cascade of events leading to "chronic allograft dysfunction" and loss. In the past, when posttransplant immunosuppression was limited to azathioprine and prednisone, acute rejection episodes were common, and it was difficult to identify the impact of medication noncompliance. However, with more potent and effective drugs, acute rejection is uncommon, and medication noncompliance emerges as an increasingly important factor in the outcome of solid-organ transplantation. Recent studies have clearly demonstrated that medication noncompliance leads to an increased incidence of acute rejection, chronic rejection, and graft loss. Today, although a number of questions remain unanswered, new methodologies, such as electronic monitors, provide opportunities to study medication noncompliance and its risk factors, and the potential for earlier intervention to improve clinical outcomes.

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: A positive crossmatch with a "current" recipient serum (drawn shortly before the proposed transplant) is a contraindication to renal transplantation because of the risk of hyperacute rejection. Conflicting data have been reported concerning the significance of a positive crossmatch with "remote" sera (obtained months or years earlier) when the current crossmatch is negative., Methods: Recipients of a first or second cadaver transplant between June 1988 and April 1994 were studied. All transplants were performed with a negative "current" crossmatch. Retrospective crossmatches using "remote" sera were performed for all sensitized recipients., Results: Recipients with a positive remote crossmatch (RXM) demonstrated a higher incidence of delayed graft function and of acute rejection and graft loss occurring in the first year posttransplant than did sensitized recipients with a negative RXM or unsensitized recipients. In multivariate analysis, only recipients with both a positive RXM and delayed graft function were at significantly higher risk for graft loss. Grafts surviving the first year demonstrated similar half-lives whether the RXM was positive or negative., Conclusions: The positive RXM, possibly in conjunction with other factors leading to very early graft damage, is a significant predictor of unfavorable transplant outcome in first and second renal transplants. This effect is seen early in the transplant course, and there seems to be no impact on outcome after the first year. Newer immunosuppressive modalities may help to reduce the early negative impact.

Background: The success of kidney transplantation from a genetically unrelated living spouse or friend has influenced transplant physicians to consider the requests of individuals wishing to volunteer to be a kidney donor who have no intended recipient specified. Representatives of the transplant community gathered in Boston, MA, on May 31, 2001, to deliberate on the experience of live kidney donation from such volunteers, currently termed nondirected donors (NDD)., Objective of Conference Participants: The objective of the conference was to recommend ethical and practice guidelines for health care professionals considering the transplantation of a kidney from a live NDD., Conference Participants: This conference was convened under the sponsorship of The National Kidney Foundation, with representation from The American Society of Transplantation and The American Society of Transplant Surgeons, The American Society of Nephrology, The United Resource Networks, The United Network for Organ Sharing, The Association of Organ Procurement Organizations, The National Institutes of Health, and The Division of Transplantation of the Health Resources and Services Administration (see Appendix)., Conference Report: The suggested content of screening interviews, which provide information regarding the donation process, elicits pertinent medical and psychosocial history, and assesses NDD motivation are presented in this report. Approaches to identifying the center that would evaluate the suitability of the NDD, to performing the kidney recovery, and to selecting the NDD recipient are also proposed. Other ethical issues such as the use of prisoners as an NDD, compensation for the NDD, media involvement, and communication between the NDD and recipient are discussed., Conclusion: The willingness of health care professionals to consider NDD volunteers is driven by the compelling need to provide organs for an ever-expanding list of patients awaiting a kidney transplant. However, the psychological impact and emotional reward of donation has yet to be determined for NDD who may not have any relationship to the recipient or knowledge of the recipient's outcome. Transplant centers that accept NDD should document an informed consent process that details donor risks, assures donor safety, and determines that the goals and expectations of the NDD and the recipient can be realized.

Transplant candidates are extensively evaluated before being wait-listed for cadaver transplantation. Yet many wait a number of years before being transplanted. We propose guidelines for regular cardiac re-evaluation for patients on the waiting list.

Background: The most common surgical complication after a kidney transplant is likely related to the wound. The purpose of this analysis was to determine the incidence of, and risk factors for, wound complications (e.g., infections, hernias) in kidney recipients and to assess whether newer immunosuppressive drugs increase the risk for such complications., Methods: Between January 1, 1984 and September 30, 1998, we performed 2013 adult kidney transplants. Of these 2013 recipients, 97 (4.8%) developed either a superficial or a deep wound infection. Additionally, 73 (3.6%) recipients developed either a fascial dehiscence or a hernia of the wound. We used univariate and multivariate techniques to determine significant risk factors and outcomes., Results: Mean time to development of a superficial infection (defined as located above the fascia) was 11.9 days posttransplant; to development of a deep infection (defined as located below the fascia), 39.2 days; and to development of a hernia or fascial dehiscence, 12.8 months. By multivariate analysis, the most significant risk factor for a superficial or deep wound infection was obesity (defined as body mass index>30 kg/m2) (RR=4.4, P=0.0001). Other significant risk factors were a urine leak posttransplant, any reoperation through the transplant incision, diabetes, and the use of mycophenolate mofetil (MMF) (vs. azathioprine) for maintenance immunosuppression (RR=2.43, P=0.0001). Significant risk factors for a hernia or fascial dehiscence were any reoperation through the transplant incision, increased recipient age, obesity, and the use of MMF (vs. azathioprine) for maintenance immunosuppression (RR=3.54, P=0.0004). Use of antibody induction and treatment for acute rejection were not significant risk factors for either infections or hernias. Death-censored graft survival was lower in recipients who developed a wound infection (vs. those who did not); it was not lower in recipients who developed an incisional hernia or facial dehiscence (vs. those who did not)., Conclusions: Despite immunosuppression including chronic steroids, the incidence of wound infections, incisional hernias, and fascial dehiscence is low in kidney recipients. As with other types of surgery, the main risk factors for postoperative complications are obesity, reoperation, and increased age. However, in kidney recipients, use of MMF (vs. azathioprine) is an additional risk factor -one that potentially could be altered, especially in high-risk recipients.