Jan Ulrich Becker

Background Transplant arteriopathy involves a spectrum of Leukocyte Common Antigen-positive, hypoelastotic, foam cell intimal fibrosis. Transplant arteriopathy has been associated with both Chronic Active T Cell-Mediated Rejection and Antibody-Mediated Rejection chronicity. Aim of this study was to find clinicopathological correlates of transplant arteriopathy in a single centre retrospective cohort. Methods We retrieved 46 biopsies showing transplant arteriopathy from 33 patients, out of a total of 784 biopsies carried out between 2005 and 2014. We retrospectively evaluated Banff Lesion Scores and Additional Diagnostic Parameters as well as the transplant arteriopathy descriptors Leukocyte Common Antigen-positive, hypoelastotic, foam cell, and correlated these findings with clinical data and death-censored transplant survival. Results Transplant arteriopathy was frequently associated with antibody-mediated rejection-associated Banff Lesions Scores and Additional Diagnostic Parameters. Hypoelastotic, leukocyte common antigen-positive and foam cell lesions were often combined, with hypoelastotic lesion being the most frequent finding in transplant arteriopathy. Leukocyte common antigen-positive lesion appeared earlier and was associated with Banff Lesion Score v ≥ 1. About half were positive for donor-specific antibodies, about a third had concurrent transplant glomerulopathy, and about a sixth were C4d-positive. Twelve of thirty-three transplants were lost during follow-up, concurrent transplant glomerulopathy was associated with shorter transplant survival. Conclusions The frequent coincidence of transplant arteriopathy and indicators of antibody-mediated rejection suggests that this arterial remodelling could indeed be antibody-mediated rejection chronicity. The transplant community should re-examine transplant arteriopathy with an expanded definition including the previously ignored hypoelastotic lesion in order to re-confirm or reject with confidence transplant arteriopathy as Additional Diagnostic Parameter of Antibody-Mediated Rejection chronicity, and to learn about its prognostic and therapeutic implications. Graphical Abstract

Key Points: Permutation-invariant cascaded attentional set operator (PICASO) is a versatile set operator that uses Transformers to dynamically aggregate histopathologic features from a set of glomerular crops. For detecting active crescent in patients with IgA nephropathy on internal and external validation sets, PICASO achieved an area under the receiver-operating characteristic curve of 0.99 and 0.96, respectively. In the case-level classification of antibody-mediated rejection in kidney transplants, PICASO performed well, with an area under the receiver-operating characteristic curves of 0.97. Background: The advent of digital nephropathology offers the potential to integrate deep learning algorithms into the diagnostic workflow. We introduce permutation-invariant cascaded attentional set operator (PICASO), a novel permutation-invariant set operator to dynamically aggregate histopathologic features from instances. We applied PICASO to two nephropathology scenarios: detecting active crescent lesions in sets of glomerular crops with IgA nephropathy (IgAN) and case-level classification for antibody-mediated rejection (AMR) in kidney transplant. Methods: PICASO is a Transformer-based set operator that aggregates features from sets of instances to make predictions. It uses initial histopathologic vectors as a static memory component and continuously updates them on the basis of input embeddings. For active crescent detection in patients with IgAN, we obtained 6206 periodic acid–Schiff–stained glomerular crops (5792 no active crescent, 414 active crescent) from three different health institutes. For the AMR classification, we have 1655 periodic acid–Schiff–stained glomerular crops (769 AMR and 886 non-AMR images) from 89 biopsies. The performance of PICASO as a set operator was compared with other set operators, such as DeepSet, Set Transformer, DeepSet++, and Set Transformer++, using metrics including area under the receiver-operating characteristic curve (AUROC), area under the precision-recall curves, recall, and accuracy. Results: PICASO achieved superior performance in detecting active crescent in patients with IgAN, with an AUROC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) on internal validation and 0.96 (95% CI, 0.95 to 0.98) on external validation, significantly outperforming other set operators (P < 0.001). It also attained the highest AUROC of 0.97 (95% CI, 0.90 to 1.0, P = 0.02) for case-level AMR classification. The area under the precision-recall curve, recall, and accuracy scores were also higher when using PICASO, and it significantly outperformed baselines (P < 0.001). Conclusions: PICASO can potentially advance nephropathology by improving performance through dynamic feature aggregation.

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice.

Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies. Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children. As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world. Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation. This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes.

Background: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40–50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. Methods: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case–control group (n = 20). Results: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. Conclusions: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism. Graphical

Background: The decision to accept or discard the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and 1-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. Methods: The training set was n = 620 for DGF and n = 711 for 1y-tl, with validation sets n = 158 and n = 162, respectively. In Step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In Step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. Results: Step 1 revealed an increased risk of DGF with increased cold ischaemia time (CIT), donor and recipient body mass index, dialysis vintage, number of HLA-DR mismatches or recipient cytomegalovirus immunoglobulin G positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c-statistics of 0.696 and 0.701, respectively). Risk of 1y-tl increased in recipients with CIT, sum of HLA-A, -B, -DR mismatches, and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. Conclusion: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Kidney transplantation is the best treatment for end-stage renal disease since it offers the greatest survival benefit compared to dialysis. The gap between the number of renal transplants performed and the number of patients awaiting renal transplants leads to a steadily increasing pressure on the scientific community. Kidney preimplantation biopsy is used as a component of the evaluation of organ quality before acceptance for transplantation. However, the reliability and predictive value of biopsy data are controversial. Most of the previously proposed predictive models were not associated with graft survival, but what has to be reaffirmed is that histologic examination of kidney tissue can provide an objective window on the state of the organ that cannot be deduced from clinical records and renal functional studies. The balance of evidence indicates that reliable decisions about donor suitability must be made based on the overall picture. This work discusses recent trends that can reduce diagnostic timing and variability among players in the decision-making process that lead to kidney transplants, from the pathologist’s perspective.

Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at 3 and 12 months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores [i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR] were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. More than one-third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the 3- to the 12-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 [odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.03–1.18]. Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95% CI 1.19–22.57) could be confirmed in our cohort. These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.