Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome. The effects of depleting agents on T‐cell subsets and subsequent T‐cell reconstitution ...are incompletely defined. We used flow cytometry to examine the effects of rabbit antithymocyte globulin (rATG) on the peripheral T‐cell repertoire of pediatric and adult renal transplant recipients. We found that while rATG effectively depleted CD45RA+CD27+ naïve and CD45RO+CD27+ central memory CD4+ T cells, it had little effect on CD45RO+CD27− CD4+ effector memory or CD45RA+CD31−, CD45RO+CD27+ and CD45RO+CD27− CD8+ T cell subsets. When we performed a kinetic analysis of CD31+ recent thymic emigrants and CD45RA+/RO+ T cells, we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution. We additionally examined the impact of rATG on peripheral CD4+Foxp3+ T cells. We found that in adults, administration of rATG‐induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype, while CD4+Foxp3+ T cells of thymic origin predominated in children, providing the first evidence that rATG induces Treg in vivo. Collectively our data indicate that rATG alters the balance of regulatory to memory effector T cells posttransplant, providing an explanation for how it positively impacts transplant outcome.
This prospective study examines the contribution of thymopoiesis versus homeostatic proliferation to immune reconstitution following rATG and the influence of rATG on the emergence of Treg in renal transplant recipients.
Deceased donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing ...admission‐to‐terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6‐month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08–1.52), 1.82 (1.45–2.30) and 2.74 (2.0–3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09–1.49), 1.70 (1.37–2.12) and 2.25 (1.74–2.91), respectively. Six‐month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 interquartile range: 31–61 vs. 58 45–75 ml/min/1.73m2 for no DGF, p < 0.001). There was significant favorable interaction between donor AKI and DGF such that 6‐month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 29–60, 49 32–64, 52 36–59 and 58 39–71 ml/min/1.73m2 for no AKI, stage 1, 2 and 3, respectively; interaction p = 0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6‐month allograft function, clinicians should consider cautious expansion into this donor pool.
This multicenter cohort study shows that clinically defined acute kidney injury in deceased donors is associated with kidney discarding as well as delayed graft function, but that the transplanted kidneys tend to have acceptable 6‐month function.
Autophagy developed into a rapidly expanding field detailing its molecular mechanism and relevance in health and disease. Autophagy is an evolutionarily conserved process that summarizes a pathway in ...which intracellular material is degraded within the lysosome and where the macromolecular constituents are recycled. This “self‐eating” process was originally described in a cell under starvation but now numerous studies established autophagy as a cellular response to stress. As a consequence, the autophagy machinery interfaces with most cellular stress–response pathways, including those involved in controlling immune response and inflammation. Autophagy also influences adaptive immunity through its effect on antigen presentation, naïve T cell repertoire selection and homeostasis and TH cell polarization. Data are emerging that dysregulated autophagy has an impact on human pathologies including infectious diseases, cancers, aging and neurodegenerative conditions. This review focuses on recent findings elucidating the ability of autophagy to be of significance in the transplant setting.
The process of autophagy was originally described in cells under starvation, but numerous studies now establish the link with most cellular stress‐response pathways, including those involved in controlling immune response and inflammation.
Toll-like receptors (TLRs) recognize both exogenous microbial components and endogenous molecules to promote immune activation. Both immune and nonimmune renal cells express TLRs, which are involved ...in the pathogenesis of a number of kidney diseases, including pyelonephritis, Leptospira nephritis, immune-complex glomerulonephritis, ischemic/reperfusion injury, and rejection of kidney transplant.
Hypothermic machine perfusion (HMP) is increasingly used in deceased donor kidney transplantation, but controversy exists regarding the value of perfusion biomarkers and pump parameters for assessing ...organ quality. We prospectively determined associations between perfusate biomarkers (neutrophil gelatinase–associated lipocalin NGAL, kidney injury molecule 1, IL‐18 and liver‐type fatty acid–binding protein L‐FABP) and pump parameters (resistance and flow) with outcomes of delayed graft function (DGF) and 6‐mo estimated GFR (eGFR). DGF occurred in 230 of 671 (34%) recipients. Only 1‐h flow was inversely associated with DGF. Higher NGAL or L‐FABP concentrations and increased resistance were inversely associated with 6‐mo eGFR, whereas higher flow was associated with higher adjusted 6‐mo eGFR. Discarded kidneys had consistently higher median resistance and lower median flow than transplanted kidneys, but median perfusate biomarker concentrations were either lower or not significantly different in discarded compared with transplanted kidneys. Notably, most recipients of transplanted kidneys with isolated “undesirable” biomarker levels or HMP parameters experienced acceptable 6‐mo allograft function, suggesting these characteristics should not be used in isolation for discard decisions. Additional studies must confirm the utility of combining HMP measurements with other characteristics to assess kidney quality.
This prospective cohort study of deceased donor kidney transplant recipients whose allografts underwent hypothermic machine perfusion finds an association of the greater perfusate flow on pump with lower rates of delayed graft function, while greater perfusate flow and lower concentrations of perfusate NGAL and L‐FABP measured at the end of pumping are associated with better allograft function by 6 months after transplantation.
Accurate and reliable assessment tools are needed in transplantation. The objective of this prospective, multi‐center study was to determine the associations of the alpha and pi iso‐enzymes of ...glutathione S‐transferase (GST), measured from perfusate solution at the start and end (base and post) of kidney allograft machine perfusion, with subsequent delayed graft function (DGF). We also compared GST iso‐enzyme perfusate levels from discarded versus transplanted kidneys. A total of 428 kidneys were linked to outcomes as recorded by the United Network of Organ Sharing. DGF, defined as any dialysis in the first week of transplant, occurred in 141 recipients (32%). Alpha‐ and pi‐GST levels significantly increased during machine perfusion. The adjusted relative risks (95% confidence interval) of DGF with each log‐unit increase in base and post pi‐GST were 1.14 (1.0–1.3) and 1.36 (1.1–1.8), respectively. Alpha‐GST was not independently associated with DGF. There were no significant differences in GST values between discarded and transplanted kidneys, though renal resistance was significantly higher in discarded kidneys. We found pi‐GST at the end of machine perfusion to be independently associated with DGF. Further studies should elucidate the utility of GST for identifying injured kidneys with regard to organ allocation, discard and recipient management decisions.
The authors show that kidney machine pump perfusate levels of the pi iso‐enzyme of glutathione S‐transferase are associated with delayed graft function but are no different between discarded and transplanted kidneys, whereas renal resistive indices are different and may be driving discard decisions.
The Organ Procurement Transplant Network/United Network for Organ Sharing (OPTN/UNOS) has increased the amount of data collected before and after donation and increased the duration of donor ...follow‐up to 2 years, yet there is evidence that reporting is incomplete. We examined the frequency of missing data in the OPTN/UNOS donor follow‐up registry and found that reporting rates were low, particularly for donors who may have limited access to health care. We argue that a national donor follow‐up registry is essential to ensure transparency in ascertaining long‐term health outcomes among all living donors and in providing assessments of quality assurance within transplant programs. We have suggested approaches to strengthen the donor follow‐up registry system. These include setting clear and high standards for follow‐up reporting, a system of incentives and penalties that would motivate transplant centers to comply with these standards and would encourage donors to follow‐up and lifelong follow‐up reporting by primary care providers. We argue that the US government must provide funding to support a donor follow‐up registry that can allow for meaningful and valid conclusions, in recognition of donors’ public service and to maintain trust in the system of living organ donation.
The authors detail the incompleteness of data in two donor follow‐up registries, argue for a strengthened national donor follow‐up registry, and suggest an approach to a national registry that can obtain meaningful and valid longterm donor follow‐up data. See also meeting report on page 2561.
Autophagy is required for T cell homeostasis and activation‐induced T cell expansion. Whether autophagy participates in tolerance induction to foreign antigens, including allografts, is unknown. We ...tested the role of an essential autophagy protein, Beclin1, in heart transplant survival in mice. We observed that long‐term allograft survival induced by donor‐specific transfusion plus anti‐CD154 mAb required homozygous lymphocyte expression of Beclin1. Following adoptive transfer into allogeneic recipients, autophagy‐deficient, Beclin1 heterozygous effector T cells (Teffs) exhibited enhanced proliferation with diminished cell death and increased production of interferon gamma. Whereas the induction and function of regulatory T cells (Tregs) in Beclin1 heterozygous mice were normal, Teffs from these mice were resistant to Treg‐mediated suppression. Our findings identify a requisite role for Beclin1 in facilitating Teff death during tolerance induction.
This study demonstrates that the autophagy‐related protein Beclin‐1 facilitates T cell death and permits Treg cellmediated suppression required for costimulatory blockade–induced heart allograft survival in mice. See editorial by Vokaer and Le Moine on page 503.
With improved survival in the antiretroviral era, data from ongoing studies suggest that HIV patients can be safely transplanted. The disproportionate burden of HIV‐related end‐stage renal disease in ...minority populations may impose additional obstacles to successful completion of the transplant evaluation. We retrospectively reviewed 309 potentially eligible HIV patients evaluated for kidney transplant at our institution since 2000. Only 20% of HIV patients have been listed, compared to 73% of HIV‐negative patients evaluated over the same period (p < 0.00001). Failure to provide documentation of CD4 and viral load (36% of candidates) was the most common reason for failure to progress beyond initial evaluation. Other factors independently associated with failure to complete the evaluation included CD4 < 200 at initial evaluation (OR 15.17; 95% CI 1.94–118.83), black race (OR 2.33; 95% CI 1.07–5.06), and history of drug use (OR 2.56; 95% CI 1.22–5.37). More efficient medical record sharing and an awareness of factors associated with failure to list HIV‐positive transplant candidates may enable transplant centers to more effectively advocate for these patients.
This study retrospectively analyzes the HIV+ patients referred for kidney transplant evaluation and examines the barriers to listing they experience.
Chemokines and their corresponding receptors likely play a central role in directing mononuclear cells to the graft sites during rejection. Genes for the chemokine stromal derived factor‐1 (SDF1) and ...CC chemokine receptors CCR2 and CCR5 are characterized by polymorphisms which alter their function. We genotyped DNA of 207 liver transplant recipients by PCR or PCR‐RFLP for CCR2–64I, CCR5Δ32, and SDF1–3′A polymorphisms, and examined their association on outcomes in liver allograft recipients. Due to the low number of patients homozygous for CCR2–64I and CCR5Δ32, only the effects of their heterozygous variants were addressed in this study. None of the investigated polymorphisms showed a significant shift in gene frequency in acute rejection and rejection‐free groups, or for graft survival. The gene frequency of the SDF1–3′A allele was significantly (p = 0.034) higher in patients who died (29.0%, n = 31) compared to recipients still alive (17.1%, n = 172). The mean patient survival time post transplant was 134 months in patients with SDF1 wild‐type, significantly (log rank p = 0.014) longer than 98 months in patients with at least one SDF1–3′A allele. The CCR2 and CCR5 polymorphisms were not associated with significant differences in mortality rate. In conclusion, CCR2–64I, CCR5Δ32, and SDF1–3′A genotypes did not influence the risk for acute rejection or graft survival. However, in liver allograft recipients SDF1–3′A is significantly associated with higher mortality.
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