Kidney transplantation across minor ABO incompatibility: the use of A: 2: to B transplants Purpose of review On 4 December 2014, the new kidney allocation system (KAS) went into effect. As part of this system, UNOS approved for the first time a national system with a specific mechanism affording priority to allocate kidneys across so-called ‘minor ABO incompatibility’ from blood group A2 donors into blood group B recipients. This significantly increased the number of such transplants done and the opportunities to learn about the specifics of such transplants. Recent findings A2 to B transplants have been demonstrated to be well tolerated, effective, and cost-effective ways of addressing disparities in the allocation system. Further data about the use of anti-A titers and the limits to successful transplant have better defined the bounds of who can benefit from such transplants. Summary The success thus far with A2 to B transplants should increase comfort and acceptance of the allocation policy changes and we should see further increases in centers willing to use such transplants to better address inequalities in the system.

Epitope matching in kidney transplantation: recent advances and current limitations Purpose of review Evolution of human leukocyte antigen (HLA) molecular typing techniques has progressively enabled more accurate determination of the three-dimensional building blocks that form the antibody accessibility and binding sites of each HLA allele. These immunogenic HLA regions known as epitopes are composed of polymorphic sequences of amino acid residues termed eplets. This review provides a critical appraisal of the current understanding of epitope compatibility in kidney transplantation. Recent findings There is a tendency to suggest that epitope matching is likely to be superior to broad antigen HLA matching such that the allocation of donor kidneys to patients with a more favorable epitope compatibility profile may lead to better allograft outcomes. A growing body of work has highlighted the association between a greater number of eplet mismatches and adverse allograft outcomes, and approaches using eplet matching have been successfully implemented in organ allocation programs. However, our understanding of epitope compatibility remains in its infancy, requiring further and more in-depth evaluation. Critically, it remains unclear how best to translate findings derived at the population level to the care of individual patients. Questions that need to be answered include a lack of consensus in the definition and interpretation of epitope compatibility, are class I and II compatibility of similar clinical importance, how best to define predetermined mismatch thresholds for utilization in organ allocation, and whether other properties such as differences in electrostatic potential between donor and recipient HLA alleles are also important in determining immunological compatibility. Summary Epitope matching likely represents a valid progression in understanding donor–recipient HLA compatibility. However, more clinical data and a better understanding about differences in methods to determine epitope compatibility are required before the approach can be widely applied in clinical practice.

Machine perfusion in kidney transplantation Purpose of review The shortage of kidneys for transplantation has led to an urgent need to efficiently utilize the available cadaveric kidneys. Efficient use of machine perfusion may potentially lead to increased use of marginal kidneys by lowering the incidence of delayed graft function (DGF) and improving graft outcomes. Recent findings Machine perfusion has had a resurgence in the last 10–15 years over static cold storage (SCS). Hypothermic machine perfusion (HMP), the most commonly utilized type of machine perfusion reduces the rates of DGF when compared with SCS with a trend towards improving the overall graft survival. Summary Despite reduction in the rates of DGF by HMP, its effect on long-term renal and patient outcomes is not clearly known. There is limited clinical literature in the use of normothermic machine perfusion (NMP) but a few pilot studies have shown its potential to resuscitate commonly discarded kidneys. In addition to preservation, machine perfusion also allows for various diagnostic and therapeutic interventions during the preservation period to assess and optimize the viability of the procured kidney.

Novel therapeutic strategies for renal graft preservation and their potential impact on the future of clinical transplantation Purpose of review The current review aims to examine recent evidence about improvements, therapeutics and novel approaches for renal graft preservation along with presenting a pragmatic outlook on their potential for clinical translation. Recent findings Modifying established cold preservation methods (4 °C) with oxygenation, gene therapies and gasotransmitters such as hydrogen sulfide has been shown to improve renal graft outcomes with minimum modifications to current protocols. These strategies have also shown promise in the context of normothermic preservation (34–37 °C), which circumvents the damage caused by cold preservation. Although normothermic machine perfusion (NMP) is being evaluated in clinical trials, it is limited by high cost, the use of blood and the lack of standardized protocols. Recent studies confirmed that preservation at subnormothermic temperatures (∼20 °C) is effective with approved preservation solutions and, in conjunction with exogenous hydrogen sulfide therapy, this approach may expedite a static preservation alternative to NMP. Summary Progress has been made in investigating improvements and alternatives to cold preservation. Promising therapeutic strategies have also been studied in the context of cold, subnormothermic and normothermic preservation. Further research is needed to optimize clinical renal graft preservation.

The past, present, and future of costimulation blockade in organ transplantation Purpose of review Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve. Recent findings Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation. Summary Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.

A diagnostic ‘C’ saw: the ups and downs of C1q testing Purpose of review The present review will focus on recently published data of solid organ allograft recipients reporting that patients with de-novo donor-specific HLA antibodies (DSA) that fix complement in vitro have a significantly higher risk for antibody-mediated rejection (AMR) and/or graft loss compared to patients whose de-novo DSA do not fix complement or patients who present with preexisting complement fixing DSA. Recent findings HLA DSAs that fix complement in vitro appear to be a key indicator for rejection and failure of kidney, heart, and lung allografts from studies performed around the world. The majority of these studies are population based and retrospective in nature. Although these studies seemingly indicate that in-vitro complement activating DSAs represent a higher clinical risk than noncomplement fixing DSAs, the majority have not accounted for false-negative reactions attributable to the so-called prozone/interference phenomenon. In the limited number of published studies addressing that concern, high mean fluorescence intensity (MFI) value noncomplement fixing DSAs correlate as well as complement fixing DSAs with AMR and graft loss. Combined with the cost of additional testing, these observations bring into question whether there is sufficient clinical applicability to warrant routine testing for complement fixing antibodies. Summary Complement fixing DSAs are clearly associated with AMR and/or loss of transplanted allografts. However, under appropriate testing conditions, complement fixing capability typically correlates with MFI values of the DSAs. As such, the routine implementation of in-vitro assays to determine whether DSAs fix complement is of questionable value especially when considering additional issues such as cost of testing, logistics, and whether the test results factor into individualized patient care.

Noninvasive biomarkers in monitoring kidney allograft health Purpose of review A key aspect of posttransplant management is to identify and treat graft injury before it becomes irreversible. The gold-standard for detection is histology, but biopsy is uncomfortable for the patient and carries a risk of complications. Detection of changes at a molecular level may preempt histological injury, and thereby identify injury earlier. Recent findings Indicators of immune system activation, such as candidate chemokines CXCL9 and CXCL10, and by-products of neutrophil activity, have been related to acute rejection and early allograft function. Transcriptomic studies of multiple-gene panels have identified candidate combinations that have proven very promising in risk-stratification and prediction of acute rejection, as well as diagnosis of both T-cell-mediated and antibody-mediated rejection. Serum and urine cell-free DNA is also a promising area of investigation, particularly in antibody-mediated rejection. Summary Noninvasive, rapid, and accurate tests for risk-prediction and diagnosis in renal transplant allografts are urgently required. The ideal candidate is one that can be measured in either urine or blood, is cheap, and is both sensitive and specific for the condition of interest. Numerous strategies have been proposed, with varying degrees of clinical and preclinical success. A few that meet the essential criteria have been evaluated; a few have made it as far as clinical testing.

Caring for the patient with a failing allograft: challenges and opportunities Purpose of review The population of kidney transplant recipients with advanced chronic kidney disease is growing but their outcomes are poor and care is not standardized. There has been wide variety of research in recent years on different aspects of care in failing allografts, and these research findings may help the providers in optimizing care. The purpose of the review is to outline the challenges and opportunities in management of failing allograft, and provide tools for improvement. Recent findings This review summarizes the recent research in field of failing allograft including outcomes, immunosuppression, risk factor management, multidisciplinary CKD care, dialysis initiation, nephrectomy and re-transplantation. Summary Kidney allograft failure is a period of higher risk of mortality compared with other transition periods for patients with ESRD. Risk mitigation is a complex challenge for patients and their care teams. In addition to summarizing the recent literature, we propose a checklist approach to the various issues, medical, surgical, psychological and nutritional as patients approach kidney transplant failure while they consider initiation of dialysis and possible repeat transplantation. Once standard algorithms are instituted, studies can be conducted to identify those high-value interventions that actually reduce morbidity and mortality risk during this transition period.

The true risk of living kidney donation Purpose of review The safety of living donor nephrectomy is essential to the continued success, growth, and sustainability of the clinical practice of living donor kidney transplantation. This review summarizes recent advances in our understanding of the perioperative and long-term risks faced by living kidney donors. Recent findings Although adverse perioperative complications are extremely rare, donors particularly men, Black, or obese, frequently experience minor complications that result in delayed return to normal duties at home and work. Similarly, although long-term complications such as end-stage renal disease (ESRD) are rare, recent studies suggest a relative increase in risk of ESRD that is attributable to donation. Several risk calculators have been developed to help donors and their care providers quantify the baseline and postdonation risk of ESRD based on demographic and health characteristics. Thresholds of risk may help define what is an acceptable level of risk to the donor and the transplant center. Summary Individualized risk calculators now allow care providers and potential donors to objectively and transparently participate in shared decision-making about the safety of living kidney donation.