Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?

The complement system, as part of the innate immune system, plays an important role in renal transplantation. Complement is involved in the protection against foreign organisms and clearance of apoptotic cells but can also cause injury to the renal allograft, for instance, via antibody binding or in ischemia–reperfusion injury. Numerous polymorphisms in complement factors have been identified thus far; some of them result in different functionalities or alter complement levels. In this review, we provide an overview of the literature on the role of complement polymorphisms in renal transplantation. Furthermore, we discuss functional complement polymorphisms that have not yet been investigated in kidney transplantation. By investigating multiple polymorphisms both in donor and recipient at the same time, a complotype can be constructed. Because the combination of multiple polymorphisms is likely to have a greater impact than a single one, this could provide valuable prognostic information.     

Acquired Downregulation of Donor‐Specific Antibody Production After ABO‐Incompatible Kidney Transplantation

The mechanism of long‐term B cell immunity against donor blood group antigens in recipients who undergo ABO‐incompatible (ABOi) living‐donor kidney transplantation (LKTx) is unknown. To address this question, we evaluated serial anti‐A and anti‐B antibody titers in 50 adult recipients. Donor‐specific antibody titers remained low (≤1:4) in 42 recipients (84%). However, antibodies against nondonor blood group antigens were continuously produced in recipients with blood type O. We stimulated recipients' peripheral blood mononuclear cells in vitro to investigate whether B cells produced antibodies against donor blood group antigens in the absence of graft adsorption in vivo. Antibodies in cell culture supernatant were measured using specific enzyme‐linked immunosorbent assays (ELISAs). Thirty‐five healthy volunteers and 57 recipients who underwent ABO‐compatible LKTx served as controls. Antibody production in vitro against donor blood group antigens by cells from ABOi LKTx patients was lower than in the control groups. Immunoglobulin deposits were undetectable in biopsies of grafts of eight recipients with low antibody titers (≤1:4) after ABOi LKTx. One patient with blood type A1 who received a second ABOi LKTx from a type B donor did not produce B‐specific antibodies. These findings suggest diminished donor‐specific antibody production function in the setting of adult ABOi LKTx.     

Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy

Related living kidney donors (LKDs) are at higher risk of end‐stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost‐effective evaluation of related LKDs.     

Towards Improving the Transfer of Care of Kidney Transplant Recipients

Kidney transplant recipients require specialized medical care and may be at risk for adverse health outcomes when their care is transferred. This document provides opinion‐based recommendations to facilitate safe and efficient transfers of care for kidney transplant recipients including minimizing the risk of rejection, avoidance of medication errors, ensuring patient access to immunosuppressant medications, avoidance of lapses in health insurance coverage, and communication of risks of donor disease transmission. The document summarizes information to be included in a medical transfer document and includes suggestions to help the patient establish an optimal therapeutic relationship with their new transplant care team. The document is intended as a starting point towards standardization of transfers of care involving kidney transplant recipients.     

Increased Mortality and Graft Loss With Kidney Retransplantation Among Human Immunodeficiency Virus (HIV)–Infected Recipients

Excellent outcomes have been demonstrated in primary human immunodeficiency virus (HIV)–positive (HIV+) kidney transplant recipients, but a subset will lose their graft and seek retransplantation (re‐KT). To date, no study has examined outcomes among HIV+ re‐KT recipients. We studied risk for death and graft loss among 4149 (22 HIV+ vs. 4127 HIV‐negative [HIV?]) adult re‐KT recipients reported to the Scientific Registry of Transplant Recipients (SRTR) (2004–2013). Compared to HIV? re‐KT recipients, HIV+ re‐KT recipients were more commonly African American (63.6% vs. 26.7%, p < 0.001), infected with hepatitis C (31.8% vs. 5.0%, p < 0.001) and had longer median time on dialysis (4.8 years vs. 2.1 years, p = 0.02). There were no significant differences in length of time between the primary and re‐KT events by HIV status (1.5 years vs. 1.4 years, p = 0.52). HIV+ re‐KT recipients experienced a 3.11‐fold increased risk of death (adjusted hazard ratio [aHR]: 3.11, 95% confidence interval [CI]: 1.82–5.34, p < 0.001) and a 1.96‐fold increased risk of graft loss (aHR: 1.96, 95% CI: 1.14–3.36, p = 0.01) compared to HIV? re‐KT recipients. Re‐KT among HIV+ recipients was associated with increased risk for mortality and graft loss. Future research is needed to determine if a survival benefit is achieved with re‐KT in this vulnerable population.     

Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT‐EXT at 7 Years After Transplant

The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors Trial (BENEFIT‐EXT) study compared more or less intensive belatacept‐based immunosuppression with cyclosporine (CsA)–based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.9% of patients received an expanded criteria donor kidney (United Network for Organ Sharing definition), 10.1% received a donation after cardiac death kidney, and 21.0% received a kidney with an anticipated cold ischemic time ≥24 h. Over 7 years, time to death or graft loss was similar between belatacept‐ and CsA‐based immunosuppression, regardless of donor kidney subtype. In all three donor kidney cohorts, estimated mean GFR increased over months 1–84 for belatacept‐based treatment but declined for CsA‐based treatment. The estimated differences in GFR significantly favored each belatacept‐based regimen versus the CsA‐based regimen in the three subgroups (p < 0.0001 for overall treatment effect). No differences in the safety profile of belatacept were observed by donor kidney subtype.     

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.