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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.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, eGFR45 mL/min/1.73 m 2 ) were compared between groups using proportional hazards models.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 eGFR30 or eGFR45 mL/min/1.73 m 2 .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.

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.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).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 FPG126 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).Donors with IFG and the majority of donors with ≥126 mg/dL do well and perhaps should not be routinely excluded from donation.

BACKGROUND: Obesity is associated with the two archetypal kidney disease risk factors: hypertension and diabetes. Concerns that the effects of diabetes and hypertension in obese kidney donors might be magnified in their remaining kidney have led to the exclusion of many obese candidates from kidney donation. METHODS: We compared mortality, diabetes, hypertension, proteinuria, reduced eGFR and its trajectory, and the development of kidney failure in 8583 kidney donors, according to body mass index (BMI). The study included 6822 individuals with a BMI of

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.

There are several choices for induction immunosuppression in kidney-after-liver transplantation. We examined the impact of induction type on kidney graft and patient survival in kidney-after-liver recipients. We utilized the Scientific Registry of Transplant Recipients (SRTR) database and included patients transplanted between 1/1/2000 and 7/31/2017 to study kidney graft and patient outcomes of all kidney-after-liver transplant recipients in the United States. We only included those who were discharged on tacrolimus and mycophenolate with or without steroids and who had a negative crossmatch prior to kidney engraftment. We grouped recipients by kidney induction type into three groups: depletional (N=550), non-depletional (n=434), and no antibody induction (n=144). We studied patient and kidney allograft survival using Cox PH regression, with transplant center included as a random effect. Models were adjusted for liver induction regimen, recipient and donor age, gender, Human Leukocyte Antigen (HLA) mismatches, payor type, live-donor kidney transplant, dialysis status, time from liver engraftment, hepatitis C status, and the presence of diabetes mellitus at time of kidney transplant and transplant year. Six-month and one-year rejection rates did not differ between groups. In the multivariable models, as compared to no induction, neither depletional nor non-depletional induction was associated with improved recipient or graft survival. Depletional induction at the time of liver transplantation was associated with worse patient survival after kidney transplant [HR 1.71, 95%C.I. (1.09, 2.67), P 0.02]. Live-donor kidney transplantation was associated with a 48.1% improved graft survival [HR 0.52, 95%C.I. (0.33, 0.82), P 0.00]. In conclusion, in the settings of a negative crossmatch and maintenance with tacrolimus and mycophenolate, induction use was not associated with a patient or graft survival benefit in kidney after liver transplants.

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 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.

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.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.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.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 Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at >= 18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age >= 30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.

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

BACKGROUND Short- and intermediate-term results have been reported after rapid discontinuation of prednisone (RDP) in kidney transplant recipients. Yet there has been residual concern about late graft failure in the absence of maintenance prednisone. METHODS From October 1, 1999, through June 1, 2015, we performed a total of 1553 adult first and second kidney transplants-1021 with a living donor, 532 with a deceased donor-under our RDP protocol. We analyzed the 15-year actuarial overall patient survival (PS), graft survival (GS), death-censored GS (DCGS), and acute rejection-free survival (ARFS) rates for RDP compared with historical controls on maintenance prednisone. RESULTS For living donor recipients, the actuarial 15-year PS rates were similar between groups. But RDP was associated with increased GS (P = 0.02) and DCGS (P = 0.01). For deceased donor recipients, RDP was associated with significantly better PS (P < 0.01), GS (P < 0.01) and DCGS (P < 0.01). There was no difference between groups in the rate of acute or chronic rejection, or in the mean estimated glomerular filtration rate at 15 years. However, RDP-treated recipients had significantly lower rates of avascular necrosis, cytomegalovirus, cataracts, new-onset diabetes after transplant, and cardiac complications. Importantly, for recipients with GS longer than 5 years, there was no difference between groups in subsequent actuarial PS, GS, and DCGS. CONCLUSIONS In summary, at 15 years postkidney transplant, RDP did not lead to decreased in PS or GS, or an increase in graft dysfunction but as associated with reduced complication rates.

Background Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients. Study Design Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM. Results Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years). Conclusions Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely for the development of PTM.

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P 1% indicate a probability of active rejection.

Background and objectives Two recent studies reported increased risk of ESRD after kidney donation. In both, the majority of ESRD was seen in those donating to a relative. Confounding this observation is that, in the absence of donation, relatives of those with ESRD are at increased risk for ESRD. Understanding the pathogenesis and risk factors for postdonation ESRD is critical for both donor selection and counseling. Design, setting, participants, & measurements We hypothesized that if familial relationship was an important consideration in pathogenesis, the donor and linked recipient would share ESRD etiology. We obtained information from the Organ Procurement and Transplantation Network (OPTN) on all living kidney donors subsequently waitlisted for a kidney transplant in the United States between January 1, 1996 and November 30, 2015, to determine ( 1 ) the donor–recipient relationship and ( 2 ) whether related donor–recipient pairs had similar causes of ESRD. Results We found that a significant amount of information, potentially available at the time of listing, was not reported to the OPTN. Of 441 kidney donors listed for transplant, only 169 had information allowing determination of interval from donation to listing, and only 99 (22% of the total) had information on the donor–recipient relationship and ESRD etiology. Of the 99 donors, 87 were related to their recipient. Strikingly, of the 87, only a minority (23%) of donor–recipient pairs shared ESRD etiology. Excluding hypertension, only 8% shared etiology. Conclusions A better understanding of ESRD in donors requires complete and detailed data collection, as well as a method to capture all ESRD end points. This study highlights the absence of critical information that is urgently needed to provide a meaningful understanding of ESRD after kidney donation. We found that of living related donors listed for transplant, where both donor and recipient cause of ESRD is recorded, only a minority share ESRD etiology with their recipient.

Supplemental Digital Content is available in the text., Background. Gaps in our knowledge of long-term outcomes affect decision making for potential living kidney donors. Methods. The Scientific Registry of Transplant Recipients was asked to determine the feasibility of a candidate registry. Results. Ten living kidney donor programs evaluated 2107 consecutive kidney donor candidates; 2099 of 2107 (99.6%) completed evaluations, 1578 of 2099 (75.2%) had a decision, and 790 of 1578 (50.1%) were approved to donate as of March 12, 2020. By logistic regression, candidates most likely to be approved were married or had attended college or technical school; those least likely to be approved had ≥1 of the following characteristics: Black race, history of cigarette smoking, and higher blood pressure, higher triglycerides, or higher urine albumin-to-creatinine ratios. Reasons for 617 candidates not being approved included medical issues other than chronic kidney disease risk (25.3%), chronic kidney disease risk (18.5%), candidate withdrawal (15.2%), recipient reason (13.6%), anatomical risk to the recipient (10.3%), noneconomic psychosocial (10.3%), economic (0.5%), and other reasons (6.4%). Conclusions. These results suggest that a comprehensive living donor registry is both feasible and necessary to assess long-term outcomes that may inform decision making for future living donor candidates. There may be socioeconomic barriers to donation that require more granular identification so that active measures can address inequities. Some candidates who did not donate may be suitable controls for discerning the appropriateness of acceptance decisions and the long-term outcomes attributable to donation. We anticipate that these issues will be better identified with modifications to the data collection and expansion of the registry to all centers over the next several years.

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.All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques.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 (P0.001) and heavier (P0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P0.001). All 3 LDN modalities required a longer operative time (P0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P0.001) and reduced the incidence of intraoperative complications (P0.001) and hospital length of stay (P0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (30 day, P0.001) and long-term (30 day, P0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P0.001). 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]).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.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor–reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

There are little data on longterm outcomes, health-related quality of life (HRQoL), and issues related to living donor right hepatectomy specifically. We studied longterm HRQoL in 127 living liver donors. A donor-specific survey (DSS) was used to evaluate the living liver donor morbidity, and the 36-item short-form health survey (short-form 36 health survey, version 1 [SF-36]) was used to assess generic outcomes. The DSS was completed by 107 (84.3%) donors and the SF-36 by 62 (49%) donors. Median follow-up was 6.9 years. Of the 107 donors, 12 (11.2%) donors reported their health as better, whereas 84 (78.5%) reported their health the same as before donation. Ninety-seven (90.7%) are currently employed. The most common postdonation symptom was incisional discomfort (34%). Twenty-four donors (22.4%) self-reported depression symptoms after donation. Ninety-eight (91.6%) rated their satisfaction with the donation process ≥ 8 (scale of 1-10). Three factors-increased vitality (correlation, 0.44), decreased pain (correlation, 0.34), and a recipient who was living (correlation, 0.44)-were independently related to satisfaction with the donor experience. Vitality showed the strongest association with satisfaction with the donor experience. Mental and physical component summary scale scores for donors were statistically higher compared to the US population norm (P

It is unclear whether structural findings in the kidneys of living kidney donors predict post-donation kidney function. We studied living kidney donors who had a kidney biopsy during donation. Nephron size was measured by glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area. Age-specific thresholds were defined for low nephron number (calculated from CT and biopsy measures) and nephrosclerosis (global glomerulosclerosis, interstitial fibrosis/tubular atrophy (IF/TA), and arteriosclerosis). These structural measures were assessed as predictors of post-donation measured GFR, 24-hour urine albumin, and hypertension. Analyses were adjusted for baseline age, gender, body mass index, systolic and diastolic blood pressure, hypertension, measured GFR, urine albumin, living related donor status, and time since donation. Of 2,673 donors, 1,334 returned for a follow-up visit at a median 4.4 months after donation, with measured GFR 5 mg/24h in 13%, and hypertension in 5.3%. Larger glomerular volume and IF/TA predicted follow-up measured GFR 5 mg/24h. Arteriosclerosis predicted hypertension. Microstructural findings predict GFR

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2–35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.

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.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.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.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.

A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made—in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in long-term studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival.

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.

The identification of biomarkers that can measure the biological age of an allograft could aid in optimizing the allocation of the allograft to specific recipients to maximize the life of each transplanted organ. Older kidneys have been shown to be more susceptible to chronic graft dysfunction (CGD) and graft failure (GF) when compared with younger kidneys after transplantation (1, 2). Older kidneys have a faster progression of tubular atrophy and tubular loss when compared younger kidneys (3) as well as having an increased incidence of delayed graft function (4), and this is felt to be an intrinsic feature of the older donated kidney. This has become an important issue, as older kidney allografts are increasingly being used in transplantation along with the poorer outcomes associated with these older kidneys, especially when transplanted into young recipients (5). Cellular replicative senescence, due to aging, is thought to play an important role in loss of graft function and this senescence may be linked to telomere length (TL) (6). Additionally, it has been suggested that younger recipients have a higher risk of acute rejection (AR) events than older recipients (7, 8), although these results are controversial (9). This reduced risk for AR in older recipients may be due to an older immune system that is less responsive, resulting in a lower risk of AR. Progressively shorter TL in immune cells due to aging in recipients may be a reason reduced immune response potentially making TL a better predictor of AR than chronological age. The aging of tissues and organs is a controlled biological process. Somatic cells have been shown to have a limited replicative capacity (10) and this is thought to be associated, in part, with the reduction in TL as chromosome replication occurs with each cell division (11). Telomeres consist of multiple copies (100s–1000s) of short (6 nucleotide) repeats at the end of all chromosomes, playing a protective role against chromosome deterioration. With every round of DNA replication in somatic cells, TL is reduced and this progressive shorting is thought to have a fundamental role in cell senescence. TL is thought to reflect the remaining replicative potential of a population of cells (10). TL is heritable and shortens throughout life, making TL a potential marker for the “biological age” of a tissue (12). The analysis of TL as a predictive marker of transplant outcome has been previously reported. It has been shown that TL may be a marker of treatment-related mortality in hematopoietic stem cell transplantation (13). A study by Bansal et al. (14) found that reduced TL was associated with reduced kidney function, but the significance was lost after adjustment for age. A modest significance associating TL and variation in serum creatinine levels in transplanted kidneys has also been reported (15). Using senescence-associated β-galactosidase (SA-β-Gal) enzyme as a marker, donor age appeared to be the major determinant factor in replicative senescence, as seen in higher expression of SA-β-Gal in donor kidneys with chronic allograft nephropathy (16). It was found that TL was significantly shorter in SA-β-Gal–expressing cells. Additionally, ischemia-reperfusion during transplantation of primate kidneys was associated with a more rapid decrease in TL (17). It has also been shown that TL shortens more rapidly in transplanted human liver allografts than in untransplanted livers resulting in a shorter than expected life for liver allografts, as would be predicted by the chronological age of the donor (18). Because of this progressive decrease in the TL, individuals who obtain a kidney from a donor with shorter than normal telomeres may be at greater risk for reduced graft survival and more susceptible to age associated disease, including allograft dysfunction. The DeKAF Genomics study contains a large number of recipient/living donor pairs along with clinical outcomes (19). We hypothesized that the biological age of the allograft, as estimated using TL from peripheral blood DNA, would be more reflective of risk for transplant outcomes than the chronological age of the allograft. We investigated if TL, in either the recipient or the donor, is associated with kidney allograft outcome.

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.Three cohorts of recipients transplanted between 1963 and 2012 (ages50 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.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 ages50 years was 79.8%, 70.3%, and 60.8%. Risk factors for graft failure in those ages ≥65 years included panel-reactive antibody10%, 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 ages50 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.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.

Unilateral nephrectomy for kidney donation results in loss of about 30% of baseline GFR, leaving some donors with GFR

There have been many reports showing significant associations between recipient genetic variants and allograft outcome, including acute rejection and graft failure, but less is known about the contribution of the donor genotypes. 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, rs11536865 (HR=2.5, p=0.0003) and rs5030717 (HR=1.67, p=0.00079), after adjusting for donor and recipient race and correcting for multiple test comparisons. An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR 1.62, p=0.00055) and two SNPs exhibited a suggestive association in African American donors, rs11536865 (HR=2.45, p=0.00205) and rs5030717 (HR=2.32, p=0.0024). Additionally, the Liver Donor Risk Index (HR 2.56, 95% CI=(1.54, 4.26, p=0.00031) and hepatitis C virus (HCV) status (HR=1.53, 95% CI=(1.04, 2.24), p=0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusting for recipient race. Donor polymorphisms in TLR4 could be an important factor in modulating TLR4 activity and therefore affect the risk of graft loss. Additionally, there is a suggestion for an interaction between polymorphisms within TLR4 and HCV status.

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.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.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 (P0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups.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.

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.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.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.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.

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.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.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 (P0.0001). 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; P0.0001). 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.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.

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

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

Kidney allograft transplantation is an effective therapy for persons with end-stage kidney disease. Typically, the health of transplanted kidneys is monitored by serum creatinine (SC) levels and calculated glomerular filtration rates (GFR). A 25% increase in SC triggers further evaluation usually including percutaneous biopsy. Biopsy 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. A common target for a noninvasive assay is urine with anomalous protein biomarkers as indicators of kidney health. The study of the urine proteome for biomarkers of other conditions has been extensive with several recent reviews (1–5). Initial studies attempting to identify biomarkers associated with kidney health after kidney transplant have used surface enhanced laser desorption ionization (SELDI) to generate a list of potential biomarkers of acute rejection (AR). One group (6, 7) reported 13 features of the SELDI spectrum that increased and three features that disappeared in patients with AR. Another group reported seven features that increased with AR (8). One component that increased with AR was identified as a degradation peptide of α-1-antichymotrpysin, whereas another that declined was β-1-defensin (8). Schaub et al. (9) found that fragments of β-2 microglobulin (B2M) were better biomarkers of rejection than the intact protein (10). None of these markers was as effective as protocol biopsy (11). Oetting et al. (12) used reverse phase extraction and matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to identify B2M in urine of patients with AR. B2M was the only biomarker that was found in more than one study. Other studies have examined biomarkers of acute kidney transplant rejection from peptides separated by capillary electrophoresis (13). This method has been used for urinary biomarkers for several other conditions (1–5). In this study, we have used MALDI-TOF MS, a method with some similarity to SELDI but distinct advantages. SELDI is an automated, commercial method for biologic sample extraction and MALDI-TOF analysis. This technology has been the focus of considerable controversy. Examples include substantial negative feedback and failure to reproduce (14, 15) some truly outstanding reports of biomarker discovery in several disease states (16, 17). SELDI uses a two-dimensional surface that restricts sample volume to be extracted, and the automated application of matrix virtually eliminates the use sinapinic acid, which is optimal for larger peptide and protein analysis. SELDI also uses an automated data analysis program that attempts to identify hundreds of “features” within the SELDI spectrum. In contrast, MALDI-TOF uses manual extraction by a column format that allows larger volume extraction, allows use of sinapinic acid matrix, uses versatile instrumentation that is more commonly available in research institutions, and enables one to direct analysis to the most intense and reliable peaks of the profile, thereby avoiding a tendency of SELDI software to overinterpret features that appear just above background in the spectrum. Kidney loss arises primarily from the process of chronic graft deterioration associated with tubular atrophy and interstitial fibrosis (TA/IF). A major risk factor for TA/IF is AR, and a method to detect AR, especially subclinical AR, would have value for early intervention to protect the patient from TA/IF. This study used a mass spectrometry method to detect intense protein biomarkers in urine of three groups of individuals: kidney recipients with normal function, persons with native kidney disease, and recipients with AR. We have identified a protein profile associated with normal kidney function and structure. We have also identified proteins that are shared between transplanted patients with AR and those with native kidney disease. These protein biomarkers could help provide the basis for a noninvasive method to determine the health of kidney allografts.

Several factors have generated interest in proposals to offer incentives in exchange for kidneys from living donors, including the growing shortage of available organs, the apparent asymptote of traditional means of organ procurement, and the intimate link between the inadequacies of organ procurement policies in developed countries with the flourishing of underground organ trafficking in developing countries.Herein, we review the scope and dimensions of the growing shortage of organs in the United States, with attention to how each of the proposed solutions to same has proven insufficient. With special attention to the concerns leveled by Gabriel Danovitch in his 'Open Letter,' we conclude that each of his concerns are unfounded, and offer a prospectus on how a trial of such systems might be pursued in the United States.The failure of current approaches to organ procurement in the United States and other developed countries has led to unnecessary suffering and death, with morally unacceptable consequences for developing countries. For these reasons, a structured trial of incentives for organ procurement in the United States is a moral imperative.

Purpose of review The organ shortage is the major problem in kidney transplantation today. Despite aggressive organ procurement efforts, the supply of donated kidneys, living and deceased, has not matched the growing demand; as a consequence, more and more qualified candidates are suffering on dialysis and then dying before being transplanted. Herein, we provide justification for a regulated system of compensation for donation. Recent findings The main argument in favor of compensation is simple-financial incentives will increase donation, so fewer transplant candidates will suffer and die while waiting. In addition, development of a regulated system of compensation is the most effective means of crippling the core economic support for transplant tourism. Because dialysis is so much more expensive than a transplant, compensated donation could be cost-neutral to the healthcare system. Importantly, opinion polls suggest that the public would support compensation. As uncompensated kidney donation is widely accepted, persuasive arguments against compensation must explain why such a system would be morally distinguishable from uncompensated donation. Summary We suggest that the potential advantages of a regulated system of compensation for donation far outweigh any potential disadvantages. It is time to advocate for a change in the law so that trials can be done.

Without direct comparison or randomized controlled trials, two experts square off on the difficult choice of trying to reduce the usage of one of two drugs with well-known side effects after kidney transplantation.

Tacrolimus extended-release (XL) is a once-daily formulation recently developed to reduce the frequency of dosing for patients currently using the twice-a-day formulation of tacrolimus (TAC). As reported previously, 67 kidney transplant recipients were safely converted (1:1 mg basis, total daily dose) from TAC twice-a-day to XL once-daily in the morning and were maintained on an am dosing regimen of XL using the same therapeutic monitoring and patient care techniques currently employed with TAC. The 2-year postconversion patient (100%) and graft (98.5%) survival, incidence of biopsy-confirmed acute rejection (6.0%), incidence of multiple rejections (1.5%), and safety profile (posttransplant diabetes, hyperlipidemia, hypertension, infections, renal dysfunction, hepatic dysfunction, and malignancies) were consistent with or more favorable than those previously reported for TAC twice-a-day.

The main argument in favor of a regulated system of payment to living kidney sellers is simple: Financial incentives will increase donation, so fewer of our wait-listed transplant candidates will die while waiting. Wait-list deaths are a relatively new and increasingly severe problem for patients with ESRD. As recently as the early 1980s, the average wait for a deceased donor (DD) kidney transplant was 5 yr. Despite decades of effort, there has been little increase in DD organ donation, and that increase has come from the use of expanded-criteria donor (ECD) kidneys (which are associated with decreased patient and graft survival rates and would have been rejected routinely 20 yr ago). In addition, Sheehy et al. (1) reported that even if every potential donor in the United States became an actual donor, there still would be a shortage of kidneys, yet the reality is that in countries such as Spain, which has maximized donation, only 75% of potentially available kidneys are recovered. Associated with the increasing waiting time is an increased rate of candidate death while waiting. In 2001, Ojo et al. (2) reported that 6.3% of wait-listed candidates died each year; by 2005, this rate had increased to >8% per year (3). If the average wait is >5 yr, then >40% of wait-listed candidates may die before undergoing a transplant. Remember, these were acceptable candidates when listed. Review of our data at the University of Minnesota showed that the average (±SE) age of candidates who died while waiting for a kidney was 53 ± 11 yr; 70% were waiting for a first transplant, and 70% had a panel-reactive antibody level of

Background. Induction immunosuppressive therapy with the anti-T-cell antibody Thymoglobulin decreases the incidence of acute rejection in adult kidney transplant (KTx) recipients, but limited data are available for pediatric KTx recipients. Methods. We conducted a historical cohort study to compare rates of survival, rejection, and infection in pediatric (age

Successful clinical allotransplants only became possible with the development of immunosuppression. Initially, 6-mercaptopurine, or its derivative azathioprine (AZA), was used.1–3 Shortly thereafter, Starzl et al4 reported improved graft survival when AZA was combined with prednisone. Since that time, transplant clinical research has focused on improving short- and long-term graft survival while simultaneously minimizing immunosuppression-related complications. Prednisone has a well-defined side effect profile, which includes hypertension, osteoporosis (and fractures), avascular necrosis, cataracts, mood alterations, posttransplant diabetes, easy bruisability, and skin changes. Some of these side effects are related to the cumulative steroid dose.5 Others develop rapidly posttransplant6 and can occur early, even with use of relatively low-dose steroids.7–9 Consequently, even early in the history of transplantation, attempts were made to minimize the daily prednisone dose.10 In general, however, kidney transplant recipients who began prednisone at the time of their transplant tended to have better long-term graft survival than those who did not take prednisone. Throughout the 1980s and 1990s, many transplant centers studied whether selected, clinically well, immunologically low-risk kidney transplant recipients, without a previous acute rejection episode, could undergo prednisone withdrawal. Those studies showed that, even in carefully selected recipients, prednisone withdrawal was associated with an increased risk of acute rejection11,12 and of graft loss.12 Of particular concern was a Canadian multicenter, prospective, randomized study in which recipients on cyclosporine (CSA) and prednisone, without active rejection, were randomized at 90 days posttransplant to continue on CSA and either low-dose prednisone or placebo. The Canadian study found no difference in graft survival for the first 3 years posttransplant, but thereafter the steroid-free group had significantly worse graft survival (P = 0.03 versus the low-dose prednisone group).13 More recently, with the introduction of new, more potent immunosuppressive agents, interest in steroid-sparing protocols has resurged. Two prospective randomized studies of steroid withdrawal in recipients on CSA, mycophenolate mofetil (MMF), and prednisone showed an increased incidence of acute rejection episodes in the steroid withdrawal arm.14,15 In contrast, numerous other studies have now shown a low acute rejection rate when steroids are completely avoided or discontinued in the first week after kidney or simultaneous kidney-pancreas transplants.16–24 Outcome at 1 year posttransplant has been excellent with protocols incorporating prednisone avoidance or rapid discontinuation. Yet concern remains, fueled by the results of the Canadian study, that long-term outcome will be worse in prednisone-free recipients. We herein report 4-year outcome in a cohort of kidney transplant recipients who discontinued their prednisone in the first posttransplant week.

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 creatini