Fibrillary GN is a rare form of GN of uncertain pathogenesis that is characterized by the glomerular accumulation of randomly arranged, nonbranching fibrils (12-24 nm) composed of Ig and complement ...proteins. In this study, we used mass spectrometry to comprehensively define the glomerular proteome in fibrillary GN compared with that in controls and nonfibrillary GN renal diseases. We isolated glomeruli from formalin-fixed and paraffin-embedded biopsy specimens using laser capture microdissection and analyzed them with liquid chromatography and data-dependent tandem mass spectrometry. These studies identified DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sampled protein detected only in fibrillary GN cases. The glomerular proteome of fibrillary GN cases also contained IgG1 as the dominant Ig and proteins of the classic complement pathway. In fibrillary GN specimens only, immunofluorescence and immunohistochemistry with an anti-DNAJB9 antibody showed strong and specific staining of the glomerular tufts in a distribution that mimicked that of the immune deposits. Our results identify DNAJB9 as a putative autoantigen in fibrillary GN and suggest IgG1 and classic complement effector pathways as likely mediators of the destructive glomerular injury in this disease.
Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. As progression of DN is related to podocyte loss, reversal of DN requires ...restoration of podocytes. Here, we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (PECs) (claudin-1), and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowman’s capsule in controls, but significantly increased in histologically early DN. Ki-67-expressing cells were identified on the glomerular tuft and Bowman’s capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.
Primary focal segmental glomerulosclerosis (FSGS), typically characterized by diffuse podocyte foot process effacement and nephrotic syndrome (diffuse podocytopathy), is generally attributed to a ...circulating permeability factor. Primary FSGS can recur after transplantation where it manifests as diffuse foot process effacement in the early stages, with subsequent evolution of segmental sclerotic lesions. Previous published literature has been limited by the lack of stringent selection criteria to define primary FSGS. Although immunogenetic factors play an important role in many glomerular diseases, their role in recurrent primary FSGS post-transplantation has not been systematically investigated. To address this, we retrospectively studied a multicenter cohort of 74 kidney allograft recipients with end stage kidney disease due to primary FSGS, confirmed by clinical and histologic parameters. After adjusting for race/ethnicity, there was a numeric higher frequency of HLA-A30 antigen in primary FSGS (19%) compared to each of 22,490 healthy controls (7%, adjusted OR=2.0, P=0.04) and 296 deceased kidney donors (10%, OR=2.1, P=0.03). Within the group of transplant patients with end stage kidney disease due to primary FSGS, donor HLA-A30 was associated with recurrent disease (OR=9.1, P=0.02). Multivariable time-to-event analyses revealed that recipients who self-identified as Black people had lower risk of recurrent disease, probably reflecting enrichment of these recipients with
high-risk genotypes. These findings suggest a role for recipient and donor immunogenetic makeup in recurrent primary FSGS post-transplantation. Further larger studies in well-defined cohorts of primary FSGS that include high-resolution HLA typing and genome-wide association are necessary to refine these hereditary signals.
Acute kidney injury (AKI) is rapidly increasing in global incidence and a healthcare burden. Prior maternal AKI diagnosis correlates with later pregnancy complications. As pregnancy influences ...developmental programming, we hypothesized that recovered parental AKI results in poor pregnancy outcomes, impaired fetal growth, and adult offspring disease.
Using a well-characterized model of rhabdomyolysis-induced acute kidney injury (RIAKI), a form of AKI commonly observed in young people, we confirmed functional renal recovery by assessing glomerular filtration rate (GFR) 2 weeks following RIAKI. We bred sham and recovered RIAKI sires and dams in timed, matched matings for gestational day (GD) 16.5 and offspring (birth-12 weeks, 6 months) study.
Despite a normal GFR pre-pregnancy, recovered RIAKI dams at GD16.5 had impaired renal function, resulting in reduced fetoplacental ratios and offspring survival. Pregnant RIAKI dams also had albuminuria and less renal megalin in the proximal tubule brush border than shams, with renal subcapsular fibrosis and higher diastolic blood pressure. Growth-restricted offspring had a reduced GFR as older adults, with evidence of metabolic inefficiency in male offspring; this correlated with reduced renal AngII levels in female offspring from recovered RIAKI pairings. However, the blood pressures of 6-month-old offspring were unaffected by parental RIAKI.
Our mouse model demonstrated a causal relationship among RIAKI, gestational risk, and developmental programming of the adult-onset offspring GFR and metabolic dysregulation despite parental recovery.
Neural epidermal growth factor-like 1 (NELL1) membranous nephropathy (MN) is notable for its segmental deposit distribution, IgG1 dominant deposits, and comparatively high rate of spontaneous ...remission. It has been associated with a variety of exposures and secondary conditions, specifically use of thiol-containing medications - including lipoic acid, bucillamine, and tiopronin - as well as traditional indigenous medications (TIM) particularly those with high mercury content, and non-steroid anti-inflammatory drugs (NSAIDs). Malignancies, graft
host disease (GVHD), infection, and autoimmune conditions have also been associated with NELL1 MN. Herein, we provide a detailed summary of the clinicopathologic features of NELL1 and associations with underlying conditions, with a focus on treatment and outcomes. Rare cases of dual NELL1 and phospholipase A2 receptor (PLA2R) positive MN are reviewed. Genome-wide association study of
, role of NELL1 in other physiologic and pathologic processes, and connection between NELL1 MN and malignancy with relevance of NELL1 tumor staining are examined. Finally, relationships and potential disease mechanisms of thiol- and mercury- associated NELL1 MN are discussed.
DnaJ homolog subfamily B member 9 (DNAJB9) is a sensitive and specific marker of fibrillary glomerulonephritis (FGN) in kidney biopsies. In this issue, Nasr and Dasari et al. demonstrate ...significantly elevated concentrations of DNAJB9 in serum from patients with FGN. This advances our understanding of DNAJB9 as a biomarker in FGN and reframes questions about pathogenesis and potential clinical applications of DNAJB9 serum testing.
Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. ...Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).
Introduction: Kidney biopsy findings in patients with human immunodeficiency virus (HIV) are diverse, and optimal therapy for the various immune complex diseases in the setting of HIV is unknown. ...Case Presentation: A man with well-controlled HIV developed nephrotic range proteinuria, and kidney biopsy revealed lupus-like glomerulonephritis with a predominantly membranous pattern of injury. He opted for conservative therapy and experienced spontaneous and sustained remission. Subsequent testing revealed neural epidermal growth factor-like 1 (NELL1)-positive glomerular immune deposits. NELL1-positive glomerular immune deposits were identified in a total of 2 of 5 tested HIV-associated membranous nephropathy (MN), which were morphologically dissimilar and one of which weakly co-expressed phospholipase A2 receptor (PLA2R). Discussion: This case suggests potentially different outcomes in patients with immune complex diseases in the setting of HIV based on disease etiology and histopathology. HIV-associated MN is occasionally NELL1-positive.
The pathologic approach to glomerulonephritis (GN) with fibrillar IgG deposits and light chain restriction remains a diagnostic challenge.
All GN with fibrillar deposits of IgG and apparent light ...chain restriction on standard immunofluorescence on frozen tissue (IF-F) accessioned at the Columbia Renal Pathology Laboratory from 2012 to 2019 were identified. Additional studies including staining for Congo red, DNAJB9, IgG subtypes, and immunofluorescence on pronase-digested paraffin sections (IF-P) were performed.
Based on the results, biopsy samples were reclassified as polytypic DNAJB9-positive fibrillary glomerulonephritis (pFGN, n = 14), monotypic DNAJB9-positive FGN (mFGN, n = 7), GN with polytypic DNAJB9-negative fibrillar IgG deposits (n = 2), and GN with monotypic DNAJB9-negative fibrillar IgG deposits (n = 6). Among DNAJB9-positive FGN samples, IgG subtype staining was able to exclude monotypic deposits by demonstrating reactivity for ≥2 IgG subtypes (usually IgG1 and IgG4) in 67% (14 of 21), including 9 that would have been misclassified as monotypic by IF-F and IF-P alone. Monotypic DNAJB9-positive fibrillary glomerulonephritis (FGN) was not associated with monoclonal gammopathy in 5 of 6 patients. GN with monotypic DNAJB9-negative fibrillar IgG deposits exhibited focal parallel fibril alignment and frequent association with chronic lymphocytic leukemia, but lacked the diagnostic microtubules of immunotactoid GN.
A systematic diagnostic approach with ancillary techniques is essential for proper classification and assignment of monoclonal gammopathy of renal significance status in cases of GN with fibrillary IgG deposits and light chain restriction by IF-F.
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