Contactin-1-associated membranous nephropathy is a rare type of membranous nephropathy typically seen in the setting of chronic inflammatory demyelinating polyneuropathy. Here we present a case of a 79-year-old man who presented with ankle edema and was found to have 2,888 milligrams of proteinuria per 24 h and membranous nephropathy on kidney biopsy. Staining for multiple membranous antigens including phospholipase A-2 receptor, NELL-1, and EXT-2 were negative. Liquid chromatography tandem mass spectrometry was performed on glomeruli and identified contactin-1 as the target antigen. Classic secondary causes of membranous nephropathy were excluded including systemic autoimmune disease, malignancies, and medications. Interestingly, the membranous nephropathy occurred 1 month after receiving the last of five doses of mRNA COVID 1273 that occurred over a 19-month period. The patient subsequently underwent spontaneous remission without initiation of disease targeted therapy, suggesting a tentative association between the COVID-19 vaccination and the membranous nephropathy. Additionally, this patient did not have any significant neuropathies typically seen with contactin-1-associated membranous nephropathy. To our knowledge, this is the first case report demonstrating a temporal association between contactin-1-associated membranous nephropathy and vaccination against COVID-19 with mRNA 1273. Our findings in this case broaden the clinical spectrum of the rare contactin-1-associated membranous nephropathy.

INTRODUCTION:Recurrent IgA nephropathy (IgAN) after kidney transplantation has been reported in up to 20%-60% of recipients, through incidence varies by surveillance strategy. We aimed to define the incidence and clinical impact of biopsy-proven recurrence IgAN in a single center cohort. METHODS:We performed retrospective review of renal allograft biopsies performed at UCLA between 2020 and 2025. A total of 1474 patients underwent kidney allograft biopsies for clinical reasons. 40 patients had biopsy-proven recurrent IgAN and were included in analysis. Clinical, laboratory and histopathologic features at recurrence were analyzed for association with graft failure using Kaplan-Meier. Time-to event analyses were performed using Cox regression. RESULT:Biopsy-proven recurrent IgAN was identified in 40 of 1474 for-cause biopsy recipients (2.7%). Graft failure occurred in 10 of 40 patients (25.0%) over a median follow-up of 5.57 years. Median time from recurrence to graft failure was 2.46 years. Graft loss was attributed primarily to recurrent IgAN in 7 patients (70.0%) and associated with rejection in 3 (30.0%). IFTA >50% was the only significant predictor of graft failure (HR 4.00, 95% CI 1.12-14.27; p = 0.03). Rising creatinine, proteinuria, hematuria, Asian race, and C3 bright deposition showed non-significant trends toward worse graft survival. CONCLUSION:In this for-cause biopsy cohort, clinically detected recurrent IgAN was associated with meaningful graft loss. Severe chronic injury at recurrence identified patients with poorer prognosis, although this likely reflects advanced nonspecific allograft damage rather than a recurrence-specific mechanism.

A growing number of target antigens have been identified in membranous nephropathy (MN) in recent years. Clinical correlations exist for some MN antigens, whereas others remain poorly characterized because of their rarity. High-temperature requirement A serine peptidase 1 (HTRA1) is the target antigen in approximately 1%-2% of MN cases without any established disease associations. Recent studies suggest HTRA1-MN may associate with malignancies in approximately 12% of cases, mostly solid tumors. To date, only 2 cases of HTRA1-MN have been reported in the setting of atypical hematopoietic disorders, including chronic lymphocytic lymphoma and monoclonal gammopathy of uncertain significance. Here, we present a case of HTRA1-MN with polytypic IgG deposits in a 62-year-old man with a plasma cell dyscrasia (IgA monoclonal gammopathy and 20% bone marrow involvement by a λ-restricted plasma cell neoplasm) who presented with nephrotic syndrome. A limited initial kidney biopsy suggested early MN. Daratumumab-based induction therapy resulted in a partial renal response (urinary protein-creatinine ratio of 0.7 g/g). However, proteinuria subsequently recurred (∼6.7 g/g), prompting a repeat biopsy that demonstrated HTRA1-MN with polytypic IgG staining. Proteinuria has progressively worsened (12 g/g), with persistent minimal residual plasma cell disease despite ongoing daratumumab maintenance therapy. To our knowledge, this case represents only the second reported case of HTRA1-MN occurring in the setting of monoclonal gammopathy, the first in multiple myeloma, and a rare example of a nonmonotypic MN in this context. Temporal proximity and partial response to anti-plasma cell therapy suggest a possible paraneoplastic relationship, although a causal relationship remains unproven.

Fibrillary glomerulonephritis (FGN) and amyloidosis are disorders with fibrillary deposits which share overlapping morphologic features on biopsy. Differentiating between these two diagnoses often requires ancillary testing such as Congo red staining, DNAJB9 (DnaJ heat shock protein family member 9) immunostain, and in some cases mass spectrometry tissue analysis. Rarely both disorders may occur together which can make accurate biopsy diagnosis challenging. Such dual cases have been rarely reported in the literature and in such cases the amyloid and FNG fibrils typically exhibit distinct tissue distributions allowing for more ready discrimination. Here we present a case of a 65 year old woman with acute kidney injury and proteinuria whose kidney biopsy revealed an overlap case of ALECT2 (leukocyte chemotactic factor 2) amyloidosis and DNAJB9 positive FGN with tight overlap of fibril distribution within glomeruli and tubulointerstitial spaces which required liquid chromatography tandem mass spectrometry (LC-MS/MS) for definitive diagnosis. The case highlights how both these fibril disorders can spatially overlap in the same biopsy and how a high index of suspicion may be required to recognize this unique dual pathology.

Immunotactoid Glomerulonephritis (ITGN) is a rare entity, reported only in 0.06% of native kidney biopsies. ITGN has been commonly reported in association with hematological malignancies or autoimmune disorders including B-cell lymphoproliferative disorders or plasma cell dyscrasias, and a few different autoimmune conditions. Herein, we present a case of IT GN in a patient with sarcoidosis. To the best of our knowledge, this is the first reported case of IT GN coinciding with sarcoidosis.

C3 glomerulopathy (C3G) is characterized by prominent deposition of complement component C3 in the kidney glomeruli, leading to glomerular inflammation. C3G is a rare and complex pattern of injury caused by dysregulation of the alternative pathway of complement system and occurs in both children and adults. It can happen because of genetic and acquired factors. Kidney biopsy is the gold standard for diagnosing C3G. About 50% of cases progress to kidney failure, and traditional treatment strategies, including immunosuppression and supportive care, have demonstrated variable efficacy. In this review, we aim to provide a comprehensive overview of pathophysiology, clinical presentations, and diagnostic criteria of C3G. Additionally, we will discuss current treatment guidelines and ongoing clinical trials.

Modulation of miRNA expression in glomerular cells is associated with renal disease. Here, we investigated the role of miR-93-5p in mitigating glomerular damage in Alport syndrome and whether the disease-modifying activity of extracellular vesicles from human amniotic fluid stem cells (hAFSC-EVs) is mediated by their miR-93-5p cargo. We identified downregulation of miR-93-5p specifically in glomerular endothelial cells in Alport syndrome along disease progression. Silencing of miR-93-5p in hAFSC-EVs changed the transcriptomic and proteomic profile, regulating EV disease-modifying activity. Compared with naive hAFSC-EVs, silenced hAFSC-EVs did not rescue glomerular endothelial function in vitro and did not restore kidney function in vivo. We established that hAFSC-EVs regulate VEGFR1 and VEGFR2 signaling by miR-93-5p cargo transfer, highlighting that miR-93-5p can restore glomerular endothelial cell biology. Spatial transcriptomics analysis of hAFSC-EV-injected kidneys showed that these EVs can reverse pathways altered during disease progression by stimulating proregenerative processes, specifically in the glomerulus, by regulating miR-93-5p targets. Alteration of glomerular endothelial cell transcriptomics and miR-93-5p targets was also confirmed in biopsies of patients with Alport syndrome using spatial molecular imaging. We demonstrated the critical role of miR-93-5p in glomerular endothelial cells and the capability of hAFSC-EVs to regulate miR-93-5p and its targets in Alport syndrome.

The emergence of pegylated liposomal doxorubicin (PLD) as a preferred treatment for various malignancies, because of its reduced cardiotoxicity compared with conventional doxorubicin, has raised significant interest. However, the association between PLD and thrombotic microangiopathy (TMA) remains a concerning and relatively rare complication. Here, we present the case of an 80-year-old man with metastatic Kaposi sarcoma who underwent extended PLD monotherapy, subsequently developing kidney-limited TMA demonstrated on kidney biopsy. This led to acute kidney injury necessitating hemodialysis. The patient’s clinical history, laboratory, and kidney biopsy data supported PLD chemotherapy as the primary etiologic factor for the observed kidney-limited TMA, an insidious condition with poor prognosis. This report highlights the need for vigilance and early kidney biopsy in patients with rising serum creatinine concentrations or worsening proteinuria/hematuria during PLD therapy. Understanding the mechanisms underlying PLD-induced TMA, likely involving reactive oxygen species-mediated endothelial dysfunction and platelet aggregation, remains a crucial area for future research to optimize monitoring and management strategies for this rare yet severe complication associated with PLD therapy.

Background:Idiopathic multicentric Castleman disease (iMCD) is a rare lymphadenopathic disorder characterized by hyperplasia of multiple lymph nodes and can be associated with a wide range of symptoms and presentations, from mild disease to life-threatening organ failure. Varied histopathological features and heterogeneous presentation of this rare entity can make the diagnosis quite challenging for both hematologists and other specialists who may encounter patients at various stages of disease progression. Method:We analyze five different clinical presentations at our institution to demonstrate challenging routes of diagnosis and treatment complexities of iMCD. We aim to raise awareness to the importance of early diagnosis and appropriate management of this rare condition. Results:All patients in this series presented with symptomatic lymphadenopathy. We highlight one rare instance of thrombocytopenia, anasarca/ascites, fever, reticulin fibrosis or renal dysfunction, and organomegaly (TAFRO) syndrome with elusive iMCD, which illustrates the challenges in the diagnosis of this rare condition and the importance of early recognition of its symptoms to avoid decompensation of patients. We also review established treatment guidelines and response criteria to siltuximab as outlined in the international consensus treatment guidelines. Conclusion:These cases highlight the heterogeneity and challenging diagnosis of this rare cytokine-driven hematological disorder and the role of siltuximab in the treatment of iMCD.

Glioblastoma (GBM) remains the most lethal primary brain tumor, largely due to therapy-resistant glioma stem cells (GSCs) and the ability of non-stem cells to dedifferentiate under therapeutic pressure. We developed MXC-017, a novel urea-based compound that crosses the blood–brain-barrier, directly targets GSCs, and prevents radiation-induced GSC formation. Using click chemistry pull-down and mass spectrometry, we identified vimentin as the target of MXC-017, further validated by in silico docking. Global transcriptomic profiling (bulk RNA-seq) and single-cell RNA-seq analyses revealed MXC-017’s efficacy with minimal off-target effects, supported by metabolic and kinome assays. Normal cell toxicity was negligible in fibroblasts, microglia, astrocytes, and murine neural progenitors. Maximum tolerated dose was identified and we observed significantly extended median survival in 17 PDOX GBM models when treated with MXC-017 plus radiation, benchmarked against standard-of-care temozolomide. These findings underscore the therapeutic potential of vimentin-targeting agents to overcome radiation resistance and improve outcomes for GBM patients. Statement of Significance Glioblastoma’s distinctive nature and the blood–brain barrier hamper therapies targeting therapy-resistant GSCs. We developed a novel urea-based agent that crosses the barrier, targets GSCs, and prevents radiation-induced GSC formation. With minimal off-target effects, reduced toxicity, and superior survival in PDOX models, it offers potential to improve outcome in GBM. ### Competing Interest Statement MEJ, FP, LH, XC, and HD are listed as inventors on the patent application PCT/US2023/035704, WO/2024/091450.

Native kidney biopsies are high-risk for bleeding complications due to the vascularity of the kidney and the inability to compress the biopsy site within a deep retroperitoneal location. Recommended parameters to minimize bleeding risk include a platelet count above 100 x 109 /L, hemoglobin above 10 g/dL, systolic blood pressure <140 mm Hg, and minimizing the number of biopsy cores. In this paper we present patient cases to discuss management of other factors pertinent to kidney biopsy planning including interruption of anticoagulation, treatment of anxiety which can elevate blood pressure, and use of Doppler. Undiagnosed chronic kidney disease can affect triaging of tissue to light, immunofluorescence and electron microscopy, as sclerosed glomeruli are difficult to visualize in fresh cores. It is recommended to have a back-up retrieval protocol in place to obtain immunofluorescence and electron microscopy results, in the event that only limited kidney tissue was acquired for light histology. A collaborative effort between nephrology, interventional radiology and pathology is essential to optimize the diagnostic yield while minimizing bleeding risk with kidney biopsies. Of paramount importance is physician judgment of whether there is an acceptable balance of benefits/risks to proceed with a kidney biopsy.

Cases of lupus nephritis (LN) with substructured deposits detected by electron microscopy are not uncommon in nephropathology practice. Rare cases of LN have been reported to show fibril formation similar to the type found in fibrillary glomerulonephritis (FGN). It is uncertain if fibril formation in such cases represents a unique manifestation of LN or LN with a superimposed FGN. FGN is a rare disease with unknown pathogenesis and a poor prognosis. Diagnosis of FGN has required the demonstration, by electron microscopy, of haphazardly arranged fibrils measuring 10 to 30 nm in thickness in the mesangium or along the glomerular basement membranes. DnaJ homolog subfamily B member 9 (DNAJB-9) immunohistochemical staining is a recently discovered sensitive and specific marker for FGN and is now considered essentially pathognomonic for FGN. No cases of bone fide LN with concurrent DNJAB-9 positive FGN have been reported. Here, we report on one such overlap glomerulopathy showing well developed features of LN (full house immunofluorescence staining, strong C1q staining, extraglomerular deposits, tubuloreticular inclusions) with concurrent fibrillar deposits with strong DNAJB-9 positivity highly consistent with FGN.

Obesity can cause the progression of kidney disease through hemodynamic, structural, and metabolic changes, and predispose individuals to arterio-nephrosclerosis, diabetic nephropathy, and focal segmental glomerulosclerosis (FSGS), leading to chronic kidney disease (CKD). Obesity-Related Glomerulopathy (ORG) is defined as clinical obesity and biopsy-proven glomerulomegaly with or without the existence of FSGS. However, pathologic changes of ORG are not pathognomonic or specific. Glomerular hypertrophy, maladaptive segmental glomerulosclerosis, as well as in some cases diabetic-like changes may be seen secondary to any cause of acquired or congenital reduced nephron mass with compensatory hypertrophy as well as glomerular hypoxia. This review aims to provide a comprehensive overview of the mechanisms causing ORG and explore current diagnostic challenges and therapeutic strategies, emphasizing the role of weight management and emerging targeted therapies.

INTRODUCTION:The sudden onset of nephrotic syndrome (NS) and acute interstitial nephritis (AIN) seems to be an uncommon but distinct nonsteroidal anti-inflammatory drug (NSAID)-related renal syndrome. CASE PRESENTATION:We present such a case in a patient who took a "magic pill" for gout. Renal biopsy revealed minimal change disease (MCD), acute interstitial nephritis (AIN), severe acute tubular injury (ATI), and IgA nephropathy (IgAN). He was treated with an aborted course of high-dose prednisone, with complete resolution of his renal diseases. The pathologic finding of the combination of MCD and AIN raised the possibility of a drug effect. One of the pills was analyzed and found to be primarily composed of diclofenac. Initially, we considered IgAN a bystander, considering primary IgAN is the most common glomerulonephritis worldwide, especially in Asians and Hispanics. However, the complete resolution of urinary findings after discontinuation of the pill followed by a few days' treatment with prednisone, together with no recurrence of the kidney disease over 6 years, made us speculate that IgAN may have also been triggered by diclofenac. CONCLUSION:We presented a case of AIN, MCD, and IgAN associated with diclofenac masquerading as a "herbal" medicine. The cause was suggested by pathology and confirmed with high-resolution liquid chromatography mass spectrometry testing of the pills. A history of NSAID use should be diligently sought in any patient who presents with NS and AIN. In addition, this is the first report of IgAN possibly induced by NSAID without recurrence after 6 years' follow-up.

Rationale & Objective:Pathological connection between the kidney tubules and veins is known as a microscopic tubulovenous communication we refer to as a tubulovenous fistula (TVF). This finding has been reported in a few small case reports, but no systematic examination of cases across various clinical settings detailing their histologic spectrum and associated clinical/pathologic findings has been performed. Study Design:Case series and literature review. Setting & Participants:Nonneoplastic kidney pathology reports from an academic medical center (February 1, 1990, to February 1, 2024) were queried for mention of TVF. In total, 30,537 nonneoplastic kidney reports were queried, and 22 cases of TVF were identified. Results:In total, 72.7% of TVF cases were from native kidney biopsies. Median patient age was 66 (range, 25-84) with a male predominance (68.2%). Clinically, 82.4% had microscopic hematuria, and 17.6% had gross hematuria. TVFs were usually singular and involved arcuate size veins. Microscopically, 95.5% of cases had acute tubular injury, and 73.3% had at least focal pathologic intratubular casts/calcium crystals. In total, 56.3% of native cases had interstitial nephritis. Of the transplant cases (n = 6), 66.7% exhibited rejection. Limitations:Laboratory data, clinical follow-up, and original slides were not available in all cases examined. Although rare in our repository, TVFs are likely an under-reported finding. In addition, the focality of TVFs could play a role in their limited rate of detection. Conclusions:This is the largest case series exploring the clinical and histologic features associated with TVFs in the kidney. Our findings support the assertion that TVFs are associated with hematuria without glomerulonephritis and occur in the setting of significant tubular injury, intratubular casts/crystals, and obstructive phenomena likely because of disruption of tubular basement membranes adjacent to veins.

Thrombotic microangiopathy (TMA) is a recognized sequela of inborn errors of metabolism impacting vitamin B12 (cobalamin) synthesis. Methylmalonic aciduria and homocystinuria, cobalamin deficiency type C is a well-known etiology for TMA. TMA has only rarely previously been reported in methionine synthase (cobalamin G) deficiency. Furthermore, results of only 7 kidney biopsies have previously been reported in this clinical setting. Here, we report a case of kidney- and glomerular-limited chronic active microangiopathy demonstrated on kidney biopsy in a patient with biochemically confirmed cobalamin G deficiency. A literature review of all prior reported cases is also presented and demonstrates hypertension, proteinuria, and hematuria to be common presenting symptoms. Age on onset ranged from 7 months to 14 years. Kidney-limited phenotype was less common and occurred only in older children. Acute kidney injury was more common in younger patients. Therapy with hydroxocobalamin and angiotensin-converting enzyme inhibitors resulted in variable clinical responses.