Kidney Exchange to Overcome Financial Barriers to Kidney Transplantation

Organ shortage is the major limitation to kidney transplantation in the developed world. Conversely, millions of patients in the developing world with end‐stage renal disease die because they cannot afford renal replacement therapy—even when willing living kidney donors exist. This juxtaposition between countries with funds but no available kidneys and those with available kidneys but no funds prompts us to propose an exchange program using each nation's unique assets. Our proposal leverages the cost savings achieved through earlier transplantation over dialysis to fund the cost of kidney exchange between developed‐world patient–donor pairs with immunological barriers and developing‐world patient–donor pairs with financial barriers. By making developed‐world health care available to impoverished patients in the developing world, we replace unethical transplant tourism with global kidney exchange—a modality equally benefitting rich and poor. We report the 1‐year experience of an initial Filipino pair, whose recipient was transplanted in the United states with an American donor's kidney at no cost to him. The Filipino donor donated to an American in the United States through a kidney exchange chain. Follow‐up care and medications in the Philippines were supported by funds from the United States. We show that the logistical obstacles in this approach, although considerable, are surmountable.     

Relationship Among Viremia/Viral Infection,Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation

The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy‐proven acute rejection (BPAR), de novo donor‐specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein–Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (?2.1) (p = 0.028) and BMI (?1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.     

Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference

Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end‐stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence‐based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision‐making process were considered. This report summarizes the group's deliberations.     

Parainfluenza 3 Infections Early After Kidney or Simultaneous Pancreas–Kidney Transplantation

Parainfluenza virus (PIV) can cause serious infections after hematopoietic stem cell or lung transplantation. Limited data exist about PIV infections after kidney transplantation. We describe an outbreak of PIV‐3 in a transplant unit. During the outbreak, 45 patients were treated on the ward for postoperative care after kidney or simultaneous pancreas–kidney (SPK) transplantation. Overall, 29 patients were tested for respiratory viruses (12 patients with respiratory symptoms, 17 asymptomatic exposed patients) from nasopharyngeal swabs using polymerase chain reaction. PIV‐3 infection was confirmed in 12 patients. One patient remained asymptomatic. In others, symptoms were mostly mild upper respiratory tract symptoms and subsided within a few days with symptomatic treatment. Two patients suffered from lower respiratory tract symptoms (dyspnea, hypoxemia, pulmonary infiltrates in chest computed tomography) and required supplemental oxygen. Four of six SPK patients and eight of 39 of kidney transplant patients were infected with PIV (p = 0.04). In patients with follow‐up tests, PIV‐3 shedding was still detected 11–16 days after diagnosis. Despite rapid isolation of symptomatic patients, PIV‐3 findings were diagnosed within 24 days, and the outbreak ceased only after closing the transplant ward temporarily. In conclusion, PIV‐3 infections early after kidney or SPK transplantation were mostly mild. PIV‐3 easily infected immunosuppressed transplant recipients, with prolonged viral shedding.     

BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis

Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus‐mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high‐grade BK virus–associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH‐2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH‐2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus‐associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus‐mediated oncogenesis.     

Harnessing Scientific and Technological Advances to Improve Equity in Kidney Allocation Policies

We reported that current assignment of HLA‐DQ is a barrier to organ allocation. Here we simulated the impact of incorporating HLA‐DQ antigens and antibodies as A/B and αβ allelic variants, respectively, on calculated panel reactive antibody (cPRA) and probability of finding potential compatible donors (PCD). A cohort of 1224 donors and 2075 sensitized candidates was analyzed using HLA‐DQαβ allelic (study) versus serologic (current practice) nomenclature. A significant (p < 10^?4) decrease in cPRA was observed with higher impact for male versus female, and first transplant versus retransplant (p < 10^?4), affecting mostly patients with moderate cPRA (30–80%). Consequently, the number of patients qualifying for 100% cPRA points according to the United Network for Organ Sharing–Kidney Allocation System decreased by 37%. More critically, by using allelic versus serologic nomenclature for HLA‐DQ, the number of PCDs for all patients was increased, with male and first‐transplant patients showing a higher expansion compared with female and retransplants. Patients of blood group O showed the highest benefit. The goal of reporting unacceptable antigens is to improve accuracy of virtual crossmatching and increase the likelihood of finding immunologically compatible donors. Our simulation provides strong support for the need to re‐evaluate the use of allele typing and how HLA‐DQ antigens and antibodies are incorporated into allocation policies to ensure equity.     

Renal Consequences of Diabetes After Kidney Donation

Whether diabetes after kidney donation is associated with an accelerated GFR decay in the remaining kidney has not been studied. We determined the incidence of diabetes in kidney donors, and compared GFR change over time in diabetic to nondiabetic donors, in addition to the effect of diabetes mellitus (DM) on the development of proteinuria, hypertension, and end‐stage renal disease (ESRD). Of the 4014 donors, 309 (7.7%) developed diabetes at a median age of 56.0 years and after a median of 18 years after donation. The difference in annual estimated GFR (eGFR) change between diabetic and nondiabetic donors in the 7 years before the development of DM was ?0.08 mL/min/year; p = 0.51. After DM development, the difference was ?1.10 mL/min/year for diabetic donors with hypertension and proteinuria, p < 0.001; ?0.19 for diabetic donors with hypertension but no proteinuria, p = 0.29; ?0.75 mL/min/year for diabetic donors with proteinuria but no hypertension, p = 0.19; and ?0.09 mL/min/year for diabetic donors without proteinuria or hypertension, p = 0.63. When DM was considered as a time‐dependent covariate, it was associated with the development of proteinuria (hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.89–3.70; p < 0.001) and hypertension (HR 2.19, 95% CI 1.74–2.75; p < 0.001). It was not, however, associated with ESRD. eGFR decline after DM development exceeds that of nondiabetic donors only in diabetic donors with concomitant proteinuria and hypertension.     

Incidence and Predictors of Cancer Following Kidney Transplantation in Childhood

Cancer risk is increased substantially in adult kidney transplant recipients, but the long‐term risk of cancer in childhood recipients is unclear. Using the Australian and New Zealand Dialysis and Transplant Registry, the authors compared overall and site‐specific incidences of cancer after transplantation in childhood recipients with population‐based data by using standardized incidence ratios (SIRs). Among 1734 childhood recipients (median age 14 years, 57% male, 85% white), 289 (16.7%) developed cancer (196 nonmelanoma skin cancers, 143 nonskin cancers) over a median follow‐up of 13.4 years. The 25‐year cumulative incidences of any cancer were 27% (95% confidence intervals 24–30%), 20% (17–23%) for nonmelanoma skin cancer, and 14% (12–17%) for nonskin cancer (including melanoma). The SIR for nonskin cancer was 8.23 (95% CI 6.92–9.73), with the highest risk for posttransplant lymphoproliferative disease (SIR 45.80, 95% CI 32.71–62.44) and cervical cancer (29.4, 95% CI 17.5–46.5). Increasing age at transplantation (adjusted hazard ratio [aHR] per year 1.10, 95% CI 1.06–1.14), white race (aHR 3.36, 95% CI 1.61–6.79), and having a functioning transplant (aHR 2.27, 95% CI 1.47–3.71) were risk factors for cancer. Cancer risk, particularly for virus‐related cancers, is increased substantially after kidney transplantation during childhood.     

Impact of Protease Inhibitor–Based Anti‐Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients

Excellent outcomes have been demonstrated among select HIV‐positive kidney transplant (KT) recipients with well‐controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01–10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre‐ and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non–PI‐based ART (88 PI vs. 244 non‐PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI‐based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p = 0.02) than those on non‐PI regimens. On adjusted analyses, PI‐based regimens were associated with a 1.8‐fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22–2.77, p = 0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75–11.48, p = 0.002), and a 1.9‐fold increased risk of death as compared to non‐PI regimens (aHR 1.91, 95% CI 1.02–3.59, p = 0.05). These results suggest that whenever possible, recipients should be converted to a non‐PI regimen prior to kidney transplantation.