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.

Polyomavirus nephropathy: diagnosis, histologic features, and differentiation from acute rejection.

Polyomaviruses, particularly BK virus, are ubiquitous latent infections that may reactivate with immunosuppression during kidney transplantation, resulting in polyomavirus nephropathy (PVN). The levels of viruria and viremia serve as tools for screening and making a presumptive diagnosis of PVN, respectively, while a definitive diagnosis requires a kidney biopsy. There are histologic classifications of PVN based on the extent of tubular cell viral infection, interstitial fibrosis, and interstitial inflammation. These classifications correlate to some degree with graft function and loss, aiding in determining treatment efficacy and prognostication. PVN has histologic overlap with acute cell-mediated rejection, making the differential diagnosis challenging, although there are suggestive features for these different causes of graft dysfunction. This article reviews the diagnosis, histologic findings, and classifications of PVN, and discusses how to differentiate viral nephropathy from acute rejection.

Kidney Histopathology of Patients with Hepatitis C Infection and Diabetes Mellitus before and after Availability of Direct-Acting Antiviral Therapy.

Introduction: Type 2 diabetes mellitus (DM) and diabetic kidney disease are increasing. Hepatitis C infection (HCV) occurs in 1% of the world population and can induce several kidney diseases. DM prevalence is increased in individuals with HCV; however, kidney diseases in those with both DM and HCV have not been assessed. Direct-acting antiviral agents (DAAs) became available for HCV treatment in 2014; it is unknown if DAAs altered the spectrum of kidney disease in patients with DM and HCV. Methods: Case review identifying patients with kidney biopsy and clinical history of DM and HCV between 2009-2013 (pre-DAA) and 2016-2020 (post-DAA), excluding kidney transplant, hepatitis B, HIV, and inadequate biopsy, identified 245 biopsies. Biopsies were evaluated for diabetic glomerulosclerosis (DGS) class, global and focal segmental glomerulosclerosis (FSGS), other glomerular diseases, interstitial fibrosis/tubular atrophy (IFTA), interstitial nephritis, acute tubular injury and degree of arterial and arteriolar sclerosis. Kidney disease differences in pre-DAA versus post-DAA eras and in mild versus severe DGS were assessed by χ2 and Fisher's exact tests. Results: The most common non-DGS lesions were non-collapsing FSGS (41%), HCV-related IgM dominant immune complex glomerulonephritis (IgM-ICGN, 18%), IgA nephropathy (9%), and membranoproliferative glomerulonephritis (MPGN, 7%). Collapsing FSGS was more common pre-DAA versus post-DAA (8% vs. 1%, p = 0.03). Biopsies from patients with HCV and DM were reduced in post-DAA (0.7%) versus pre-DAA (1.3%) (p < 0.0001). Post-DAA there were less MPGN (2% vs. 10%, p = 0.02) and more advanced DGS (85% vs. 61%, p = 0.0002), non-collapsing FSGS (57% vs. 31%, p < 0.0001), IFTA (2.0 vs. 1.6, p = 0.0002), and vascular sclerosis (2.1 vs. 1.6, p < 0.0001). Conclusion: Post-DAA there were reduced biopsies and MPGN, with more severe DGS class, non-collapsing FSGS, IFTA, and chronic vascular changes. This suggests a modulating effect of DAAs on HCV-related kidney pathology with DM and chronic changes driving indications for kidney biopsy.

Fibronectin glomerulopathy in a kidney allograft biopsy.

BACKGROUND: Fibronectin glomerulopathy is a rare genetic nephropathy with only a few cases of post-transplant recurrence being reported previously. We highlight a case that was initially misdiagnosed and emphasize the importance of full immunofluorescence and electron microscopy evaluation in allograft biopsies. CASE PRESENTATION: A 36-year-old male with a history of end-stage kidney disease secondary to biopsy-proven type 1 membranoproliferative glomerulonephritis (MPGN) status-post living unrelated donor kidney transplant 12 years prior, presented with increasing creatinine and proteinuria. Biopsy was performed and was consistent with fibronectin glomerulopathy. Subsequent genetic testing revealed an FN1 mutation, the primary gene associated with this condition. CONCLUSIONS: Full histologic evaluation of the allograft biopsy corrected the diagnosis and additionally suggested that the patient's mother, who had expired in her 30s and had received a diagnosis of type 1 MPGN on autopsy, likely also had fibronectin glomerulopathy, enabling appropriate genetic counseling for the family.

Cure Glomerulonephropathy Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations.

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes.

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population.

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.

Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities.

CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.

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.

Linear IgA bullous dermatosis and elevated bullous interleukin-6 levels: Responsive to treatment with Anti-IL-6 receptor monoclonals.

Linear IgA bullous dermatosis (LABD) is  a rare autoimmune/inflammatory skin condition. Here, we report on a patient who developed treatment resistant LABD. At diagnosis, elevations of IL-6 and C-reactive protein in the blood and extreme elevations of IL-6 in LABD bullous fluid were seen. The patient responded well to tocilizumab (anti-IL-6 receptor) treatment.

Chronic kidney disease with unknown cause across the global spectrum.

PURPOSE OF REVIEW: In the 1990s, a type of chronic kidney disease with unknown cause (CKDu) was identified in Central America and Sri Lanka. Patients lacked hypertension, diabetes, glomerulonephritis, or other usual causes of kidney failure. Affected patients are predominantly male agricultural workers aged 20-60 years, living in economically disadvantaged areas with poor access to medical care. Patients typically present late and progress to end-stage kidney disease within 5 years, resulting in social and economic hardship for families, regions, and countries. This review covers the current state of knowledge for this disease. RECENT FINDINGS: The prevalence of CKDu is increasing in known endemic regions and across the globe, reaching epidemic proportions. There is primary tubulointerstitial injury with secondary glomerular and vascular sclerosis. No definitive etiologic factors have been identified, and these may vary or overlap in different geographic locations. The leading hypotheses include exposure to agrochemicals, heavy metals and trace elements, and kidney injury from dehydration/heat stress. Infections and lifestyle factors may play a role, but are likely not key. Genetic and epigenetic factors are beginning to be explored. SUMMARY: CKDu is a leading cause of premature death in young-to-middle-aged adults in endemic regions and has become a public health crisis. Studies are underway to investigate clinical, exposome, and omics factors, and hopefully will provide insights into pathogenetic mechanisms resulting in biomarker discovery, preventive measures, and therapeutics.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model.

BACKGROUND: Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D. METHODS: Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks (N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose). RESULTS: 4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy (p < 0.05) but with inconsistent responses by monotherapies. CONCLUSION: Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.

Clinicopathologic Significance of Predominant Lambda Light Chain Deposition in IgA Nephropathy.

Introduction: IgA nephropathy (IgAN) differs from other glomerular diseases by the frequently predominant lambda over kappa light chain deposition. Using the Cure Glomerulonephropathy (CureGN) IgAN cohort, we aimed to determine whether predominant lambda chain deposition is associated with worse clinical outcomes or histopathologic markers of more active disease. Methods: Patients were categorized based on the intensity of light chain staining. The lambda dominant (LD) group was defined by a difference in intensity score of lambda minus kappa ≥ 1+ and the kappa-lambda codominant (KL) group by a difference < 1+. We compared the clinical course of patients in each category from the time of kidney biopsy and time of enrollment into CureGN to the time of remission (proteinuria < 0.3 g/g), 50% reduction in estimated glomerular filtration rate (eGFR), or progression to end-stage kidney disease (ESKD). We also analyzed differences in histopathologic characteristics between the 2 groups. Results: Among 440 patients, we found no significant differences between groups in baseline clinical characteristics nor in rates of remission, 50% reduction in eGFR, or progression to ESKD. Patients in the LD group had a modestly greater frequency of IgG staining ≥ 1+. The biopsy results of 234 patients reviewed by CureGN pathologists revealed a greater frequency of endocapillary hypercellularity (51.1% vs. 36.3%, P = 0.04) in the LD group, but no other significant difference in histopathologic features. Conclusion: In IgAN, we found an association between lambda predominance and increased endocapillary hypercellularity, but no association with clinical outcomes.

Influence of Sodium Bicarbonate on Wall Teichoic Acid Synthesis and ß-Lactam Sensitization in NaHCO3-Responsive and Nonresponsive Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) strains pose major treatment challenges due to their innate resistance to most ß-lactams under standard in vitro antimicrobial susceptibility testing conditions. A novel phenotype among MRSA, termed "NaHCO3 responsiveness," where certain strains display increased susceptibility to ß-lactams in the presence of NaHCO3, has been identified among a relatively large proportion of MRSA isolates. One underlying mechanism of NaHCO3 responsiveness appears to be related to decreased expression and altered functionality of several genes and proteins involved in cell wall synthesis and maturation. Here, we studied the impact of NaHCO3 on wall teichoic acid (WTA) synthesis, a process intimately linked to peptidoglycan (PG) synthesis and functionality, in NaHCO3-responsive versus -nonresponsive MRSA isolates. NaHCO3 sensitized responsive MRSA strains to cefuroxime, a specific penicillin-binding protein 2 (PBP2)-inhibitory ß-lactam known to synergize with early WTA synthesis inhibitors (e.g., ticlopidine). Combining cefuroxime with ticlopidine with or without NaHCO3 suggested that these latter two agents target the same step in WTA synthesis. Further, NaHCO3 decreased the abundance and molecular weight of WTA only in responsive strains. Additionally, NaHCO3 stimulated increased autolysis and aberrant cell division in responsive strains, two phenotypes associated with disruption of WTA synthesis. Of note, studies of key genes involved in the WTA biosynthetic pathway (e.g., tarO, tarG, dltA, and fmtA) indicated that the inhibitory impact of NaHCO3 on WTA biosynthesis in responsive strains likely occurred posttranslationally. IMPORTANCE MRSA is generally viewed as resistant to standard ß-lactam antibiotics. However, a NaHCO3-responsive phenotype is observed in a substantial proportion of clinical MRSA strains in vitro, i.e., isolates which demonstrate enhanced susceptibility to standard ß-lactam antibiotics (e.g., oxacillin) in the presence of NaHCO3. This phenotype correlates with increased MRSA clearance in vivo by standard ß-lactam antibiotics, suggesting that patients with infections caused by such MRSA strains might be amenable to treatment with ß-lactams. The mechanism(s) behind this phenotype is not fully understood but appears to involve mecA-PBP2a production and maturation axes. Our study adds significantly to this body of knowledge in terms of additional mechanistic targets of NaHCO3 in selected MRSA strains. This investigation demonstrates that NaHCO3 has direct impacts on S. aureus wall teichoic acid biosynthesis in NaHCO3-responsive MRSA. These findings provide an additional target for new agents being designed to synergistically kill MRSA using ß-lactam antibiotics.

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis.

BACKGROUND AND OBJECTIVES: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. RESULTS: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. CONCLUSIONS: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.