Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study

Background Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. Methods This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. Discussion The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. Trial registration The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell “cross-dressing” by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).

Focal Segmental Glomerulosclerosis Superimposed on Transplant Glomerulopathy: Implications for Graft Survival

<b><i>Introduction:</i></b> Transplant glomerulopathy (TG) is a morphological lesion resulting from chronic glomerular endothelium injury, and it is strongly associated with poor graft survival. TG coexisting with focal segmental glomerulosclerosis (FSGS) can be found in renal allograft biopsies, but few related studies are available. <b><i>Methods:</i></b> Consecutive kidney transplant recipients with biopsy-proven TG were studied retrospectively. Patients concomitant with FSGS were identified and compared with those without FSGS. The influence of FSGS on allograft outcomes was assessed using univariate and multivariate Cox regression models. <b><i>Results:</i></b> Of the 66 patients with TG, 40 (60.6%) had concomitant FSGS. TG patients with FSGS had higher proteinuria (median, 2.6 vs. 0.8 g/24 h, <i>p</i> &#x3c; 0.001) and serum creatinine levels (median, 2.5 vs. 2.1 mg/dL, <i>p</i> = 0.04), lower serum albumin levels, higher chronic glomerulopathy (cg) score, larger glomerular tuft area, lower number of podocytes, and higher incidences of podocyte hyperplasia, pseudotubule formation, and diffuse foot process effacement than those without FSGS (all <i>p</i> &#x3c; 0.05). The kidney allograft loss rate of patients with FSGS was higher than that of patients without FSGS (65.7% vs. 37.5%, <i>p</i> = 0.03). The presence of FSGS was independently associated with allograft loss in TG (hazard ratio (HR) = 3.42, 95% confidence interval (CI): 1.30–8.98, <i>p</i> = 0.01). Other independent predictors were proteinuria (HR = 1.18, 95% CI: 1.02–1.37, <i>p</i> = 0.02), estimated glomerular filtration rate (HR = 0.94, 95% CI: 0.91–0.97, <i>p</i> &#x3c; 0.001), and panel reactive antibody (HR = 3.99, 95% CI: 1.14–13.99, <i>p</i> = 0.03). Moreover, FSGS (odds ratio (OR) = 4.39, 95% CI: 1.29–14.92, <i>p</i> = 0.02) and cg (OR = 5.36, 95% CI: 1.56–18.40, <i>p</i> = 0.01) were independent risk factors for proteinuria. <b><i>Conclusion:</i></b> In this cohort of patients with TG, the presence of FSGS was strongly associated with more severe clinicopathological features and worse allograft survival.

Intrapatient Variability in Tacrolimus Trough Levels Over 2 Years Affects Long-Term Allograft Outcomes of Kidney Transplantation

This study aimed to determine the impact of tacrolimus (TAC) trough level (C0) intrapatient variability (IPV) over a period of 2 years after kidney transplantation (KT) on allograft outcomes. In total, 1,143 patients with low immunologic risk were enrolled. The time-weighted coefficient variability (TWCV) of TAC-C0 was calculated, and patients were divided into tertile groups (T1: &lt; 24.6%, T2: 24.6%–33.7%, T3: ≥ 33.7%) according to TAC-C0-TWCV up to post-transplant 1st year. They were classified into the low/low, low/high, high/low, and high/high groups based on a TAC-C0-TWCV value of 33.7% during post-transplant 0–1st and 1st–2nd years. The allograft outcomes among the three tertile and four TAC-C0-TWCV groups were compared. The T3 group had the highest rate of death-censored allograft loss (DCGL), and T3 was considered an independent risk factor for DCGL. The low/low group had the lowest and the high/high group had the highest risk for DCGL. Moreover, patients with a mean TAC-C0 of ≥5 ng/ml in the high/high group were at the highest risk for DCGL. Thus, TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0. Furthermore, to improve allograft outcomes, a low TAC-IPV should be maintained even after the first year of KT.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance

Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multi-center study. MethodsAll kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized to 1:1:1 to receive belatacept with alemtuzumab induction, belatacept with rabbit antithymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite endpoint consisted of death, kidney allograft loss, or an MDRD calculated eGFR of <45 ml/min/1.73m2 at 2 years. ResultsThe composite endpoint was observed for 11/107 (10%) participants assigned to belatacept/alemtuzumab, 13/104 (13%) assigned to belatacept /rATG, and 21/105 (21%) assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.99: belatacept/rATG vs tacrolimus/rATG p = 0.66). Patient and graft survival rates were similar between all groups. eGFR <45 ml/min/1.73m2 was observed for 9/107 (8%) participants assigned to belatacept/alemtuzuab, 8/104 (8%) participants assigned to belatacept/rATG, and 20/105 (19%) participants assigned to tacrolimus/rATG (p<0.05 for each belatacept group vs tacrolimus/rATG). Biopsy-proven acute rejection was observed for 20/107 (19%) participants assigned to belatacept/alemtuzuab, 26/104 (25%) participants assigned to belatacept/rATG, and 7/105 (7%) participants assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.006: belatacept/rATG vs tacrolimus/rATG p < 0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin based immunosuppression. ConclusionsOverall two-year outcomes were similar comparing maintenance immunosuppression based on belatacept versus tacrolimus, each protocol with rapid steroid withdrawal. The incidence of eGFR <45 ml/min/1.73m2 was significantly lower but the incidence of biopsy proven acute rejection significantly higher with belatacept compared with tacrolimus.

Primary hyperoxaluria as an indication of liver and kidney transplantation: Case report and literature review

Primary Hyperoxaluria (PH) is a metabolic liver disease that results in oxalate overproduction that cannot be metabolized by the liver [1]. PH is caused by mutations in one of three genes that encode enzymes involved in glyoxylate metabolism. As oxalate is primarily excreted in the urine, the kidney is the prime target for oxalate deposition, which leads to end-stage kidney disease [2]. A patient named MN with Nephrocalcinosis (NC) was referred to the Children`s Memorial Health Institute of Warsaw in early childhood. The patient was diagnosed with PH type 1. PH type 1 is caused by mutations in a gene called AGXT that encodes alanine-glyoxylate aminotransferase. This enzyme is found in hepatic peroxisomes. It converts a compound called glyoxylate to the amino acid glycine [3]. In 02.12.1996, at the age of 13 the patient received a first kidney transplant from family member. In 16/09/1998 graftectomy was performed due to rapidly progressive kidney failure, nephrocalcinosis and infections. The patient had to return to hemodialysis after renal allograft loss. Also the patient was diagnosed with chronic HCV genotype 4 infection in 1998. In 08.11.2002, at the age of 19, the patient was qualified for a simultaneous liver and second kidney transplantation due to primary hyperoxaluria. The patient was treated with combination of: Daclizumab, steroid, tacrolimus, mycophenolate mofetil. Since October, 2015 the patient had been treating with combination of ombitasvir, paritaprevir, ribavirin and ritonavir. Hepatitis C Virus (HCV) was successfully eliminated. Patients with kidney failure from primary hyperoxaluria type 1 should not undergo kidney transplantation alone due to the very high risk of recurrence. Combined liver and kidney transplantation is the treatment of choice [4]. Keywords: Primary hyperoxaluria; kidney insufficiency; kidney transplantation; combined liver; kidney transplantation.