IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis.

IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.

Spectrum of Kidney Biopsy Findings Associated With Methamphetamine Use.

Introduction: Methamphetamine (METH) is one of the most used drugs of abuse worldwide. However, there are few reports and series examining the toxic kidney effects of METH, and associated histopathological changes are not well-described. Methods: We retrospectively identified 112 patients with a history significant for METH abuse, of whom 62 were using METH-only and 60 were using METH plus other drugs of abuse. Results: In the METH-only cohort, the mean age was 41 years (interquartile range [IQR]: 33-49) and most (76%) were male. Almost all cases (97%) showed evidence of kidney dysfunction at the time of biopsy. Of the cases, 65% had proteinuria, of which 53% were nephrotic range and 10% had nephrotic syndrome. The most common biopsy diagnosis was acute tubular necrosis (ATN) (66%), of which 19% had myoglobin casts; followed by focal segmental glomerulosclerosis (FSGS) in 53% (not otherwise specified [NOS] in 76% and collapsing FSGS [cFSGS] in 18%). Biopsy findings also include tubulointerstitial nephritis (TIN) (37%), thrombotic microangiopathy (TMA) (24%), and diabetic glomerulosclerosis (DG) (31%). Glomerulonephritis (GN) was identified in one-third of cases, the most common of which were infection-related GN (IRGN) (15%) and IgA nephropathy (IgAN) (11%). Of those with GN, 64% had underlying infection. Of interest, there was increased association for myoglobinuric ATN in those with concurrent ethanol-abuse (P = 0.002). Moreover, the METH-only patients were more likely to have DG compared to those with multiple substance-use (P = 0.01). More than half of the patients demonstrated at least moderate to severe tubulointerstitial scarring and marked hypertensive vascular disease. Conclusion: Most patients with METH-use present with acute kidney injury (AKI) and often have proteinuria associated with a wide spectrum of renal pathology.

Podocyte injury as a potential therapeutic target in IgA nephropathy: should pathology guide us?

The Oxford histopathologic classification (MEST-C: scores for lesions indicating active glomerular inflammation, mesangial [M] and endocapillary [E] hypercellularity as well as cellular or fibrocellular crescents [C], and for segmental glomerulosclerosis [S] and interstitial fibrosis and/or tubular atrophy [T]) is useful in helping assess prognosis in patients with IgA nephropathy. Elements of this classification indicative of active glomerular inflammation, endocapillary hypercellularity and crescents, also have been found to be responsive to immunosuppressive therapy, potentially including newer agents specifically targeting mediators of such inflammation. In this issue of Kidney International, Bellur and coworkers identify histopathologic subtypes of segmental glomerulosclerosis in IgA nephropathy showing podocyte injury that also behave like active lesions, including showing improved outcomes with immunosuppression. This podocyte injury, identifiable only by kidney biopsy, may represent a potential therapeutic target in some patients with IgA nephropathy.

Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy.

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.

Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

IgA vasculitis nephritis: insights from kidney biopsies.

PURPOSE OF REVIEW: To present findings indicating the value of kidney biopsy in assessing prognosis and guiding clinical approach to patients with IgA vasculitis nephritis (IgAVN), including a recent international study examining the value of the Oxford (MEST-C) classification. RECENT FINDINGS: Historically, kidney biopsies with IgAVN are scored using the International Society for Kidney Diseases in Children (ISKDC) classification. However, this classification has limited prognostic value, and most biopsies fall into just two of the six ISKDC grades. There are few studies examining the clinical value of the Oxford classification, which is well documented to be predictive of kidney outcomes in IgA nephropathy, in IgAVN. However, a recent study of 361 biopsied patients with IgAVN showed that endocapillary hypercellularity (Oxford E1) predicted a subclass of patients showing initial improvement in kidney function with immunosuppressive treatment, followed by a later decline. SUMMARY: Kidney outcome in patients with biopsied IgAVN treated with immunosuppression is determined by clinical factors and endocapillary hypercellularity. The latter is not part of the ISKDC classification and supports including MEST-C scores in biopsy reports of IgAVN. Even patients showing a good initial response to immunosuppression require long-term follow-up due to risk of subsequent kidney function decline.

Improving frozen section evaluation of procurement donor kidney biopsies and reducing the discard rate: a promising role for artificial intelligence.

There is a worldwide shortage of deceased-donor kidneys available for transplantation, with too many patients dying while on waiting lists for organs. Meanwhile, and particularly in the United States, many recovered kidneys are discarded, often based on results of frozen section evaluation of a screening biopsy read by an on-call pathologist with limited renal pathology experience. A study in this month's issue of Kidney International uses an artificial intelligence-based approach to evaluate these biopsies, which not only improved correlation between biopsy findings and short-to-intermediate term graft survival, but also demonstrated the potential to reduce biopsy-associated organ discard rates by 25% to 30%.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

Colocalization of IgG and IgA Heavy Chains with Kappa and Lambda Light Chains in Glomerular Deposits of IgA Nephropathy Patients Using High-Resolution Confocal Microscopy and Correlation with Oxford MEST-C Scores.

Routine immunofluorescence microscopy of glomerular immunodeposits in IgA nephropathy shows IgA, C3, and lambda light chains, and sometimes IgG, IgM, and kappa light chains. However, a previous study using high-resolution confocal microscopy showed IgG in all IgA nephropathy cases, likely representing autoantibodies specific for galactose-deficient IgA1. Here, we used high-resolution confocal microscopy to examine the composition of glomerular immunodeposits and colocalization of kappa and lambda light chains with IgA or IgG heavy chains in kidney-biopsy samples from twenty patients with IgA nephropathy, seventeen without IgG, and nine with no or trace kappa light chains by routine immunofluorescence microscopy. IgG was detected in all biopsies by high-resolution confocal microscopy. Single-optical-plane images showed similar colocalization of IgG heavy chains with kappa and lambda light chains. Colocalization of IgA heavy chains was greater with lambda light chains than with kappa light chains. Colocalization of IgG heavy chain with kappa light chains was higher than with lambda light chains in biopsies with endocapillary hypercellularity and crescents, i.e., biopsies with active lesions. We confirmed the utility of high-resolution confocal microscopy to detect components of glomerular immunodeposits not apparent on routine immunofluorescence microscopy and for colocalization of different components, potentially clarifying the pathogenesis of IgA nephropathy.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Finding the right context of use for molecular transplant diagnostics in kidney allograft biopsies.

Biopsy-based molecular diagnostics holds promise to increase diagnostic precision. In this issue of Kidney International, Beadle et al. describe a molecular classifier derived from the Banff Human Organ Transplant panel. This new molecular test specifically identifies biopsies associated with higher risk for allograft failure showing microvascular inflammation, but not considered diagnostic for antibody-mediated rejection by current Banff rules. This study marks a milestone toward defining a valuable context for use for biopsy-based molecular transplant diagnostics.

An automated histological classification system for precision diagnostics of kidney allografts.

For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795 .