Safety and Efficacy of Avacopan in Patients with C3 Glomerulopathy: Randomized, Double-Blind Clinical Trial.

BACKGROUND: Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant C3 deposition in glomeruli. Patients with C3 glomerulopathy may develop progressive deterioration in kidney function and kidney failure. METHODS: We studied the safety and efficacy of avacopan 30 mg twice daily in patients with C3 glomerulopathy (N=57) with elevated (> 244 ng/mL) and normal (≤ 244 ng/mL) levels of C5b-9 in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed pre-randomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 glomerulopathy histologic index for disease activity. RESULTS: The study was conducted in patients with C3 glomerulopathy, including C3 glomerulonephritis and DDD. The median study duration was 60.0 weeks (interquartile range 59.9 to 61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group; least square mean treatment difference (95% CI) = -0.0 (-1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio (UPCR), and estimated glomerular filtration rate (eGFR) were not different between treatment groups. The overall incidence and type of adverse events for both treatment groups were comparable. No deaths were reported during the study, and no new safety signals were detected. CONCLUSIONS: The primary end point for the study was not met; other clinical effects of avacopan to improve certain key kidney function parameters and slow disease progression were variable and require further evaluation.

Kidney Biopsy Findings Among Patients With Diabetes in the Cleveland Clinic Kidney Biopsy Epidemiology Project.

Rationale & Objectives: Diabetic kidney disease (DKD) is a significant complication of diabetes mellitus, often leading to kidney failure. The absence of well-defined factors prevents distinguishing DKD from non-diabetic kidney disease (non-DKD; alternative primary diagnosis identified on kidney biopsy). Study Design: Retrospective cohort study. Setting & Participants: This study assessed 1,242 patients with a history of diabetes from the Cleveland Clinic Kidney Biopsy Epidemiology Project between January 2015 and September 2021. Exposure: Proteinuria, retinopathy, A1c levels, and estimated glomerular filtration rate. Outcomes: Non-DKD, defined as an alternative primary diagnosis identified on kidney biopsy other than DKD. Analytical Approach: Multivariate logistic regression model with backward elimination method. Results: At the time of biopsy, the median (IQR) age was 63 (53-71 years) years, and 58.8% were men. The median hemoglobin A1c value was 6.7% (6.0%-8.1%), and the median serum creatinine level was 2.5 (1.6-3.9 mg/dL) mg/dL. Among 1,242 patients, 462 (37.2%) had DKD alone, and 780 (62.8%) had non-DKD. Among those with non-DKD, the most common diagnoses were focal segmental glomerulosclerosis (24%), global glomerulosclerosis otherwise not specified (13%), acute tubular necrosis (9%), IgA nephropathy (8%), antineutrophil cytoplasmic antibody vasculitis (7%), and membranous nephropathy (5%). Factors associated with having non-DKD on biopsy were having no retinopathy (vs retinopathy) (adjusted odds ratio [aOR], 3.98; 95% CI, 2.69-5.90), lower A1c levels (<7% vs ≥7%) (aOR, 3.08; 95% CI, 2.16-4.39), higher estimated glomerular filtration rate (≥60 vs <60 mL/min/1.73 m2) (aOR, 2.39; 95% CI 1.28-4.45), microalbuminuria (<300 vs macroalbuminuria ≥300 [mg/g]) (aOR; 2.94; 95% CI, 1.84-4.72), and lower protein-creatinine ratio on random urine sample (<3 vs ≥3 mg/mg) (aOR; 1.80; 95% CI, 1.24-2.61). Limitations: Selection bias of clinically indicated biopsies, not protocol biopsies, which likely represent a ceiling (maximum) for non-DKD. Conclusions: Among patients with diabetes undergoing kidney biopsy, 63% have findings in addition to DKD on biopsy. We identified clinical parameters associated with non-DKD in the setting of diabetes. This provides valuable information for clinicians when kidney biopsy should be considered among patients with diabetes to capture all etiologies of proteinuria and kidney dysfunction.

Our study aimed to better understand when to perform kidney biopsies in patients with diabetes. Often, nephrologists diagnose diabetes-related kidney disease based on clinical parameters without a biopsy. We sought to look at what the spectrum of kidney biopsy findings were in patients with a clinical history of diabetes to see how many patients had diabetic kidney disease or other findings. Given the advent of several new medications that treat and slow the progression of diabetic kidney disease, we also sought to see what clinical factors were more likely to suggest a finding of nondiabetic kidney disease on biopsy to help guide clinicians when to biopsy in this population.

Association Between Causative Pathogen and Occurrence of Infection-Related Glomerulonephritis in Infective Endocarditis.

Among patients with pathologically proven infective endocarditis, the association of pathogen with occurrence of infection-related glomerulonephritis (IRGN) was examined in 48 case patients with IRGN and 192 propensity score-matched controls. Bartonella was very strongly associated with IRGN (odds ratio, 38.2 [95% confidence interval, 6.7-718.8]; P < .001); other microorganisms were not.

Novel biomarker discovery through comprehensive proteomic analysis of lupus mouse serum.

OBJECTIVES: The difficulty of monitoring organ-specific pathology in systemic lupus erythematosus (SLE) often complicates disease prognostication and treatment. Improved non-invasive biomarkers of active organ pathology, particularly lupus nephritis, would improve patient care. We sought to validate and apply a novel strategy to generate the first comprehensive serum proteome of a lupus mouse model and identify mechanism-linked lupus biomarker candidates for subsequent clinical investigation. METHODS: Serum levels of 1308 diverse proteins were measured in eight adult female MRL/lpr lupus mice and eight control MRL/mpj mice. ELISA validation confirmed fold increases. Protein enrichment analysis provided biological relevance to findings. Individual protein levels were correlated with measures of lymphoproliferative, humoral, and renal disease. RESULTS: Four hundred and six proteins were increased in MRL/lpr serum, including proteins increased in human SLE such as VCAM-1, L-selectin, TNFRI/II, TWEAK, CXCL13, MCP-1, IP-10, IL-10, and TARC. Newly validated proteins included IL-6, IL-17, and MDC. Results of pathway enrichment analysis, which revealed enhancement of cytokine signaling and immune cell migration, reinforced the similarity of the MRL/lpr disease to human pathology. Fifty-two proteins positively correlated with at least one measure of lupus-like disease. TECK, TSLP, PDGFR-alpha, and MDC were identified as novel candidate biomarkers of renal disease. CONCLUSIONS: We successfully validated a novel serum proteomic screening strategy in a spontaneous murine lupus model that highlighted potential new biomarkers. Importantly, we generated a comprehensive snapshot of the serum proteome which will enable identification of other candidates and serve as a reference for future mechanistic and therapeutic studies in lupus.

Immunotactoid hepatopathy: A novel entity with histologically proven recurrence post liver transplantation.

Immunotactoid deposition is a rare fibrillary deposition disease that is primarily seen in the kidney and is associated with paraproteinemia. Here, we report a case of hepatic immunotactoid deposition in a 67-year-old male with a history of smoldering myeloma and chronic kidney disease who underwent liver transplantation for metabolic dysfunction-related cirrhosis. Immunotactoid deposition was first identified in the explanted liver and recurred in the allograft within only 7 weeks following transplantation, presenting as ascites with normal liver function tests. The patient's posttransplant course was complicated by proteinuria and renal failure requiring dialysis. Histologic examination of both native and allograft livers demonstrated pink amorphous material occupying sinusoidal spaces that were Congo-red negative and immunoglobulin M Kappa-restricted. Electron microscopy revealed characteristic deposits of electron-dense bundles of hollow microtubules with a 40 nm diameter within the sinusoids and space of Disse, consistent with immunotactoids. Therapy of the patient's underlying plasma-cell dyscrasia utilizing a daratumumab-based regimen showed decreased serum paraproteins, resolution of ascites, and improved kidney function, no longer requiring dialysis, without inducing rejection. The patient continues to respond to treatment 10 months posttransplant.

A Tangled Autoimmune Trio: Multiple Sclerosis, Systemic Lupus Erythematosus and Antineutrophil Cytoplasmic Antineutrophil Cytoplasmic Antibody Vasculitis.

The coexistence of multiple autoimmune diseases in the same individual is unusual and has received little attention in the literature. We present a young female patient with multiple sclerosis, systemic lupus erythematosus, and biopsy-proven renal proteinase 3 antineutrophil cytoplasmic antibodyassociated vasculitis who responded well to intravenous rituximab clinically and serologically.

Defining the molecular correlate of arteriolar hyalinosis in kidney disease progression by integration of single cell transcriptomic analysis and pathology scoring.

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated. Co-expression network analysis of the endothelial genes yielded three gene set modules as significantly associated with arteriolar hyalinosis. Pathway analysis of these modules showed enrichment of transforming growth factor beta / bone morphogenetic protein (TGFß / BMP) and vascular endothelial growth factor (VEGF) signaling pathways in the endothelial cell signatures. Ligand-receptor analysis identified multiple integrins and cell adhesion receptors as over-expressed in arteriolar hyalinosis, suggesting a potential role of integrin-mediated TGFß signaling. Further analysis of arteriolar hyalinosis associated endothelial module genes identified focal segmental glomerular sclerosis as an enriched term. On validation in gene expression profiles from the Nephrotic Syndrome Study Network cohort, one of the three modules was significantly associated with the composite endpoint (> 40% reduction in estimated glomerular filtration rate (eGFR) or kidney failure) independent of age, sex, race, and baseline eGFR, suggesting poor prognosis with elevated expression of genes in this module. Thus, integration of structural and single cell molecular features yielded biologically relevant gene sets, signaling pathways and ligand-receptor interactions, underlying arteriolar hyalinosis and putative targets for therapeutic intervention.

Complement detection in kidney biopsies - utility and challenges.

PURPOSE OF REVIEW: This review discusses the important role of staining for components of the complement cascade in both native and transplant kidney biopsies. The use of complement staining as a marker of prognosis, disease activity, and as a potential future tool in identifying patients who may benefit from complement-targeted therapies is discussed. RECENT FINDINGS: While staining for C3, C1q and C4d can yield valuable information about complement activation in kidney biopsies, to adequately assess complement activation and potential therapeutic targets, expanded staining panels looking at multiple split products and complement regulatory proteins are needed. Recent progress has been made in identifying markers of disease severity in C3 glomerulonephritis and IgA nephropathy, such as Factor H-related Protein-5, which may serve as future tissue biomarkers. In the transplant setting, the limitation of relying on C4d staining to identify antibody mediated rejection is giving way to molecular diagnostics, including The Banff Human Organ Transplant (B-HOT) panel, which includes numerous complement complement-related transcripts, with the classical, lectin, alternative, and common pathways. SUMMARY: Staining for complement components in kidney biopsies to understand how complement is activated in individual cases may help to identify patients who may benefit from complement-targeted therapies.

Ketogenic-Diet Shake Containing Uncaria tomentosa-Associated Acute Interstitial Nephritis.

Uncaria tomentosa is a plant that has been used in traditional medicine for its anti-inflammatory, immunomodulatory, and immunostimulant properties. As a result, it can be found in several over-the-counter supplements worldwide. Acute interstitial nephritis (AIN) can be due to an offending medication, infection, or autoimmunity. We present a case of a patient who was on a strict ketogenic diet, utilizing over-the-counter diet shakes containing the herbal supplement Uncaria tomentosa who developed acute kidney injury with a serum creatinine of 3.6 mg/dL up from a baseline of 0.7 mg/dL. Serological evaluation was negative, and kidney biopsy revealed interstitial inflammatory infiltrates including focally prominent eosinophils and multifocal tubulitis. Stopping the keto-diet shake containing Uncaria tomentosa and concomitant corticosteroid therapy resulted in improvement in kidney function to near baseline. To our knowledge, this is the only biopsy-proven case of AIN in the setting of Uncaria tomentosa use.

Case Report: Guillain-Barré Syndrome as Primary Presentation of Systemic Lupus Erythematosus (SLE-GBS) in a Teenage Girl.

Peripheral nervous system involvement accounts for fewer than 10% of SLE cases with neuropsychiatric manifestations. Guillain-Barré syndrome (GBS) as the presenting, major manifestation of pediatric SLE is extremely rare, and the best treatment approach is unknown. A 14-year-old, previously healthy female teenager developed classic features of GBS with ascending bilateral muscle weakness leading to respiratory insufficiency, associated with protein-cell dissociation in cerebro-spinal fluid, nerve root enhancement by MRI and reduction in compound muscle action potential amplitude. SLE was diagnosed serologically and histologically (lupus nephritis WHO class II). Despite immediate treatment with intravenous immunoglobulin (IVIg), methylprednisolone pulses and subsequently, rituximab, the patient required prolonged mechanical ventilation. She achieved full recovery following 14 PLEX treatments and two more rituximab infusions. Anti-dsDNA, C3, C4 and urinalysis normalized while anti-Smith and Sjögren antibodies persisted 15 months after disease onset, with no other lupus manifestations. Review of the literature revealed two pediatric cases of GBS at the onset of SLE and a third case with GBS 6 years after the diagnosis of SLE. Conventional GBS therapy may not be adequate to treat SLE-GBS. SLE should be included in the differential diagnosis of GBS. Importantly, treatment experiences and outcomes of such cases need be reported to inform future treatment recommendations.

The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.

The Cleveland Clinic Kidney Biopsy Epidemiological Project.

Background: The kidney biopsy is the gold standard for diagnosing glomerular diseases. Large-scale, epidemiologic studies describing the prevalence of kidney diseases are lacking, especially in the United States. We aimed to determine the spectrum of biopsy-proven kidney disease across the Cleveland Clinic enterprise. Methods: We identified all patients with a native kidney biopsy performed or reviewed at the Cleveland Clinic from January 2015 to September 2021. Retrospective chart review was performed to obtain clinical and demographic characteristics. Results were stratified by age, sex, race, and location to determine epidemiologic trends. Results: Of >9600 patients, we excluded transplant and donor biopsies and unavailable records, and included 4128 patients with native kidney biopsy data. The median age was 60 years, with 46% female patients. Self-reported racial demographics included 73% White, 22% Black, 3% multiracial, and 2% Asian background, with 5% Hispanic. Common diagnoses were: FSGS (n=633, 15%), diabetic kidney disease (DKD) (n=602, 15%), IgA nephropathy (n=319, 8%), lupus nephritis (LN) (n=289, 7%), pauci-immune glomerulonephritis (n=275, 7%), membranous nephropathy (n=211, 5%), and amyloidosis (n=110, 3%). There were 3322 patients in Ohio, with 361 patients in Florida. Using multivariate analysis, those aged >70 years were more likely to have FSGS, whereas those <45 years were more likely to have IgA nephropathy or LN. Males were more likely to have FSGS or IgAN, and less likely to have LN. Black patients were more likely to have FSGS, DKD, or LN. Hispanic patients were more likely to have DKD. Finally, patients in Florida were more likely to have LN. There was no change in the disease spectrum before and during the COVID-19 pandemic. Conclusion: Our study catalogs the spectrum of biopsy-proven kidney disease across the Cleveland Clinic enterprise. This lays the foundation for glomerular disease clinical trials, and highlights the need for a standardized national kidney biopsy registry to bolster glomerular and kidney disease research in the United States.

The Crystalline Nephropathies.

Crystalline nephropathies are a unique form of kidney disease characterized by the histologic finding of intrarenal crystal deposition. The intrinsic nature of some molecules and ions combined with a favorable tubular fluid physiology leads to crystal precipitation and deposition within the tubular lumens. Crystal deposition promotes kidney injury through tubular obstruction and both direct and indirect cytotoxicities. Further kidney injury develops from inflammation triggered by these crystals. From a clinical standpoint, the crystalline nephropathies are associated with abnormal urinalysis and urinary sediment findings, tubulopathies, acute kidney injury (AKI), and/or chronic kidney disease (CKD). Urine sediment examination is often helpful in alerting clinicians to the possibility of crystal-related kidney injury. The identification of crystals within the kidneys on biopsy by pathologists prompts clinicians to evaluate patients for medication-related kidney injury, dysproteinemia-related malignancies, and certain inherited disorders. This review will focus on the clinical and pathologic aspects of these 3 categories of crystalline nephropathies.

Bile acid nephropathy induced by anabolic steroids: A case report and review of the literature.

Bile acid nephropathy also known as cholemic nephropathy is a rare and overlooked form of acute kidney injury that occurs in the setting of severe hyperbilirubinemia. The exact etiology remains unknown, and there is a lack of treatment guidelines for this clinical condition. Anabolic steroids are known to cause hepatoxicity occasionally leading to acute kidney injury. We report the case of a 27-year-old male patient who developed bile acid nephropathy as a result of severe hyperbilirubinemia secondary to anabolic steroids-induced liver injury. He was conservatively managed. We review the current literature touching on the etiology, pathophysiology, diagnosis, and management of bile acid nephropathy in an attempt to shed light on this clinical condition, which may present as a diagnostic and therapeutic challenge.

Granulomatous Tubulointerstitial Nephritis in a Kidney Transplant Recipient: Case Report and Review of the Literature.

BACKGROUND: Granulomatous tubulointerstitial nephritis (GTIN) is a rare pathologic finding on kidney biopsy. GTIN can be associated with drugs, infection, systemic granulomatous disease, and tubulointerstitial nephritis with uveitis syndrome. We present a case of GTIN in a kidney transplant recipient (KTR) and a literature review of published cases of GTIN in KTRs. CASE PRESENTATION: A 65-year-old man with a history of pulmonary and ocular tuberculosis (TB), who had undergone deceased donor kidney transplant 8 years prior, was admitted for acute kidney injury, hypercalcemia, and uveitis. His medications included rifabutin, isoniazid, and tacrolimus. Serum laboratory tests revealed creatinine of 2.65 mg/dL (baseline 1.1-1.5 mg/dL) and corrected calcium of 13.2 mg/dL. Hypercalcemia workup showed parathyroid hormone 7 pg/mL, 1,25(OH) vitamin D 54 pg/mL, parathyroid hormone-related peptide <2.0 pmol/L, and angiotensin-converting enzyme 47 U/L. Kidney biopsy showed GTIN with noncaseating granulomas. Universal polymerase chain reaction testing for acid-fast bacilli, fungus, and bacteria was negative. He was treated with prednisone, and his kidney function returned to baseline, and his hypercalcemia resolved. DISCUSSION: GTIN is a rare entity seen in less than 1% of transplanted kidney biopsies. The exactly etiology of this GTIN case remains unknown. TB could not be entirely ruled out, because the patient was receiving active anti-TB therapy. Our literature review showed infection to be the leading cause of GTIN in KTRs and that GTIN with concomitant uveitis remains exceedingly rare. Steroids may be useful in certain cases.