Riella, Leonardo V

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely “microvascular inflammation/injury donor-specific antibodies–negative and C4d negative” and “probable antibody-mediated rejection,” into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell–mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell–mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.

Significance Statement Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. Background Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. Methods We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. Results A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood ( n =821, 71.8%), intragraft ( n =169, 14.8%), or urine ( n =81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8–35.5) between 2005 and 2012 and 57.5 (IQR, 53.3–59.8) between 2013 and 2022 ( P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96–629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0–6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. Conclusions Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.

Significance Statement Although corticosteroids are an effective first-line therapy for minimal change disease, relapse, steroid dependence, and intolerance are common in this podocytopathy of unknown etiology. The efficacy of B cell–targeted therapies in some patients suggests an autoantibody-mediated etiology. This study describes the novel discovery in both adults and children with minimal change disease of autoantibodies targeting nephrin, a critical component of the podocyte slit diaphragm that ensures integrity of the glomerular filtration barrier. This observation aligns with the established proteinuric effect of antinephrin antibodies demonstrated in animal models. These findings identify an important autoimmune mechanism in a subset of patients with minimal change disease and provide a framework for the application and development of precision medicine strategies in this condition. Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell–targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. Results In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.

AbstractAn unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community “Outstanding Questions in Transplantation,” hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.