Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers.

Introduction: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. Methods: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Results: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96). Conclusion: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

NELL1 membranous nephropathy: clinical associations provide mechanistic clues.

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 vs. 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 NELL1, 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.

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.

AA amyloidosis With Ig-Dominant Staining and Diagnostically Unusual Features.

Introduction: Although serum amyloid A (AA) amyloid may occasionally show nonspecific staining by immunofluorescence (IF), the correct diagnosis can usually be determined by integrating pathologic features and clinical scenario, and using AA amyloid immunohistochemistry (IHC) and/or mass spectrometry. A recent mass spectrometry-based study described false-positive Ig IF staining in a subset of AA amyloid cases. Methods: We sought to delineate clinicopathologic features of AA amyloid with Ig-dominant staining by using a retrospective review. Results: AA amyloid with Ig-dominant staining was identified in 10 patients from 5 institutions, representing 1.2% to 4% of AA amyloid kidney biopsies. Evidence of a monoclonal protein was documented in 0% to 2.7% of patients with AA amyloid screened for inclusion, but 30% of those with Ig-dominant staining. The patient population had equal sex distribution and presented at median age of 68.5 years with nephrotic proteinuria and kidney impairment. Etiologies of AA amyloid included injection drug use (30%), autoimmune disease (20%), and chronic infection (10%); 40% had no identified clinical association. On biopsy, heavy chain (co)dominant staining by IF (in 80%), discordant distribution in Ig staining (in 20%), tubulointerstitial nephritis (in 30%), and/or crescents (in 10%) were present. Two of 3 patients with paraproteinemia had concordant heavy and/or light chain dominant staining within the AA amyloid. Two cases were initially misdiagnosed as Ig-associated amyloidosis. Conclusion: We describe the morphologic spectrum of AA amyloidosis with Ig-dominant staining which may have clinical, laboratory, and pathologic overlap with amyloid light chain (AL), amyloid heavy chain, and heavy and light chain (AHL) amyloidosis.

ANCA-associated kidney disease preceded by orbital pseudotumor.

INTRODUCTION: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgG4-related disease (IgG4-RD) are distinct immune disorders with overlapping clinical and laboratory features. While ANCA positivity excludes IgG4-RD in the 2019 ACR/EULAR classification, this criterion is not uniformly applied, and AAV can form inflammatory masses in various organs and show increase in IgG4 + plasma cells, similar to IgG4-RD. CASE DIAGNOSIS/TREATMENT: A 5-year-old female with history of orbital mass diagnosed as IgG4-RD presents with acute kidney injury. She has a myeloperoxidase ANCA, and kidney biopsy shows pauci-immune crescentic glomerulonephritis and acute tubulointerstitial nephritis with increased IgG4 + plasma cells and tubular basement membrane (TBM) deposits. CONCLUSION: In isolation, TBM deposits and increased IgG4 + plasma cells are suggestive of IgG4-RD. In the context of a positive ANCA and pauci-immune crescentic glomerulonephritis, however, increased IgG4 + plasma cells due to AAV are favored. In cases with features of IgG4-RD, ANCA positivity suggests an alternate diagnosis of AAV to be more likely.

Increased Rates of Supplement-Associated Oxalate Nephropathy During COVID-19 Pandemic.

Introduction: Causes of secondary oxalate nephropathy include enteric dysfunction and excessive intake of oxalate or oxalate precursors. During the COVID-19 pandemic, there has been a dramatic rise in sales of supplements and vitamin C, during which time we observed an apparent increase in the proportion of ingestion-associated oxalate nephropathy. Methods: We retrospectively reviewed secondary oxalate nephropathy and compared pre-pandemic (2018-2019) and pandemic (2020-early 2022) time periods. Results: We identified 35 patients with kidney biopsy proven (30 native, 5 allograft) oxalate nephropathy at a single academic institution. Supplement-associated oxalate nephropathy comprised a significantly higher proportion of cases during COVID-19 pandemic compared with the preceding 2 years (44% vs. 0%, P = 0.002), and was associated with use of vitamin C, dietary changes, and supplements. Oxalate nephropathy in the kidney allograft, in contrast, remained associated with enteric hyperoxaluria, antibiotic use, and dehydration. Many patients had diabetes mellitus (57%), hypertension (40%) and/or pre-existing chronic kidney disease (CKD, 49%). Of 9 patients in which the potentially causative ingestion was identified and removed, 8 experienced improvement in kidney function. Conclusion: There was a shift toward supplements rather than enteric hyperoxaluria as a leading cause of secondary oxalate nephropathy during the COVID-19 pandemic. Kidney outcomes are better than those observed for enteric hyperoxaluria, if the offending agent is identified and removed.

A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma.

Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-standing donor diabetes and pathologic findings are associated with shorter allograft survival in recipients of kidney transplants from diabetic donors.

Approximately 6% of deceased kidney donors (DKDs) are diabetic; their kidneys may be associated with worse allograft survival, but published studies suggest that recipient diabetes status has a greater impact on mortality and survival. Since biopsy findings are the most common reason for organ discard, we sought to understand histologic and clinical factors that influence graft survival in patients who receive a kidney from a diabetic DKD. We retrospectively reviewed our institutional experience from 2005 to 2019, and re-evaluated pre-implantation and earliest post-transplant biopsies. Histologic findings were compared against a control cohort of non-diabetic DKD. Of 829 adult DKD transplants, 37 (4.5%) came from diabetic donors. There was no significant difference in diabetic vs. non-diabetic DKD graft survival for all-comers; however, when stratified by duration of donor diabetes, donor diabetes ≥6 years was associated with graft failure. In 25 patients with post-transplant biopsies available, diabetic DKD allografts had significantly greater non-glomerular chronic injury than non-diabetic DKD allografts. Moderate arteriolar hyalinosis (in 24%), moderate tubular atrophy and interstitial fibrosis (IFTA, in 36%), and diabetic glomerulopathy (in 24%) on early post-transplant biopsy were associated with allograft failure. Pre-implantation frozen section discrepancies were more common in long-standing donor diabetes, and arteriolar hyalinosis and IFTA scores on frozen accurately prognosticated graft loss. There was no morphologic improvement in lesions of diabetic nephropathy on short-term follow-up. In conclusion, donor diabetes ≥6 years, and histologic findings on frozen section and early post-transplant biopsy are associated with diabetic DKD allograft loss.

Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain-restricted immunoglobulin and is rarely reported in children. METHODS: We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. RESULTS: Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. CONCLUSIONS: Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. Graphical abstract.

Duodenal Microbiota in Stunted Undernourished Children with Enteropathy.

BACKGROUND: Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine that is postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of this disorder, its pathophysiological features, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota). METHODS: In this study, among 110 young children (mean age, 18 months) with linear growth stunting who were living in an urban slum in Dhaka, Bangladesh, and had not benefited from a nutritional intervention, we performed endoscopy in 80 children who had biopsy-confirmed EED and available plasma and duodenal samples. We quantified the levels of 4077 plasma proteins and 2619 proteins in duodenal biopsy samples obtained from these children. The levels of bacterial strains in microbiota recovered from duodenal aspirate from each child were determined with the use of culture-independent methods. In addition, we obtained 21 plasma samples and 27 fecal samples from age-matched healthy children living in the same area. Young germ-free mice that had been fed a Bangladeshi diet were colonized with bacterial strains cultured from the duodenal aspirates. RESULTS: Of the bacterial strains that were obtained from the children, the absolute levels of a shared group of 14 taxa (which are not typically classified as enteropathogens) were negatively correlated with linear growth (length-for-age z score, r = -0.49; P = 0.003) and positively correlated with duodenal proteins involved in immunoinflammatory responses. The representation of these 14 duodenal taxa in fecal microbiota was significantly different from that in samples obtained from healthy children (P<0.001 by permutational multivariate analysis of variance). Enteropathy of the small intestine developed in gnotobiotic mice that had been colonized with cultured duodenal strains obtained from children with EED. CONCLUSIONS: These results provide support for a causal relationship between growth stunting and components of the small intestinal microbiota and enteropathy and offer a rationale for developing therapies that target these microbial contributions to EED. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02812615.).

Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation.

BACKGROUND: Environmental Enteropathy (EE), characterized by alterations in intestinal structure, function, and immune activation, is believed to be an important contributor to childhood undernutrition and its associated morbidities, including stunting. Half of all global deaths in children < 5 years are attributable to under-nutrition, making the study of EE an area of critical priority. METHODS: Community based intervention study, divided into two sub-studies, 1) Longitudinal analyses and 2) Biopsy studies for identification of EE features via omics analyses. Birth cohorts in Matiari, Pakistan established: moderately or severely malnourished (weight for height Z score (WHZ) < - 2) children, and well-nourished (WHZ > 0) children. Blood, urine, and fecal samples, for evaluation of potential biomarkers, will be collected at various time points from all participants (longitudinal analyses). Participants will receive appropriate educational and nutritional interventions; non-responders will undergo further evaluation to determine eligibility for further workup, including upper gastrointestinal endoscopy. Histopathological changes in duodenal biopsies will be compared with duodenal biopsies obtained from USA controls who have celiac disease, Crohn's disease, or who were found to have normal histopathology. RNA-Seq will be employed to characterize mucosal gene expression across groups. Duodenal biopsies, luminal aspirates from the duodenum, and fecal samples will be analyzed to define microbial community composition (omic analyses). The relationship between histopathology, mucosal gene expression, and community configuration will be assessed using a variety of bioinformatic tools to gain better understanding of disease pathogenesis and to identify mechanism-based biomarkers. Ethical review committees at all collaborating institutions have approved this study. All results will be made available to the scientific community. DISCUSSION: Operational and ethical constraints for safely obtaining intestinal biopsies from children in resource-poor settings have led to a paucity of human tissue-based investigations to understand and reverse EE in vulnerable populations. Furthermore, EE biomarkers have rarely been correlated with gold standard histopathological confirmation. The Study of Environmental Enteropathy and Malnutrition (SEEM) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology and accelerate progress towards the 2030 Sustainable Development Goals. TRIAL REGISTRATION: Retrospectively registered; clinicaltrials.gov ID NCT03588013 .

Collagenous Enteritis is Unlikely a Form of Aggressive Celiac Disease Despite Sharing HLA-DQ2/DQ8 Genotypes.

Collagenous enteritis is an uncommon small intestinal injury pattern with unclear pathogenesis. While it has been speculated that collagenous enteritis represents a form of refractory celiac disease, recent clinical studies suggest a potential link to exposure to the antihypertensive medication olmesartan. Here we hypothesized that the pathogenesis of collagenous enteritis involves both genetic and environmental factors. All subjects with biopsy-proven collagenous enteritis diagnosed between 2002 and 2015 were identified from 2 tertiary care medical centers. Human leukocyte antigen (HLA)-DQ genotyping was performed by polymerase chain reaction on archived tissue. Celiac disease serology, past medical history, medications, smoking history, demographics, histology, clinical management, and follow-up were recorded. A total of 32 subjects were included. In contrast to celiac disease, subjects with collagenous enteritis were mostly elderly (median age at diagnosis, 69 y; range, 33 to 84 y). Seventy percent of collagenous enteritis subjects harbored celiac disease susceptibility alleles HLA-DQ2/DQ8; however, only 1 subject had elevated serum levels of celiac disease-associated autoantibodies while on a gluten-containing diet. Furthermore, 56% of subjects were taking nonsteroidal anti-inflammatory drugs, 36% proton-pump inhibitors, 28% statins, and 32% olmesartan at the time of diagnosis. Discontinuation of olmesartan and treatments with steroids and/or gluten-free diet resulted in symptomatic and histologic improvement. Neither lymphoma nor collagenous enteritis-related death was seen in this cohort. Therefore, while collagenous enteritis shares similar HLA genotypes with celiac disease, the difference in demographics, the lack of celiac disease-associated autoantibodies, and potential link to medications as environmental triggers suggest the 2 entities are likely distinct in pathogenesis.

Expression of interleukin-5- and granulocyte macrophage-colony-stimulating factor-responsive genes in blood and airway eosinophils.

Because interleukin (IL)-5 family cytokines are critical regulators of eosinophil development, recruitment, and activation, this study was initiated to identify proteins induced by these cytokines in eosinophils. Using oligonucleotide microarrays, numerous transcripts were identified as responsive to both IL-5 and granulocyte macrophage-colony-stimulating factor (GM-CSF), but no transcripts were markedly affected by one cytokine and not the other. Expression of several gene products were seen to be increased following in vitro stimulation of human blood eosinophils, including the IL-3 receptor alpha subunit, lymphotoxin beta, Pim-1, and cyclin D3. Given that eosinophils recovered from the bronchoalveolar lavage fluid of allergic patients after antigen challenge are exposed to IL-5 or GM-CSF in the airway prior to isolation, the hypothesis was tested that selected IL-5- and GM-CSF-responsive genes are upregulated in airway eosinophils relative to the expression in blood cells. Airway eosinophils displayed greater cell surface expression of the IL-3 receptor alpha subunit, CD44, CD25, and CD66e, suggesting that these proteins may be markers of eosinophil activation by IL-5 family cytokines in airway eosinophils. Other genes that were induced by both IL-5 and GM-CSF showed protein expression at similar or decreased levels in airway eosinophils relative to their circulating counterparts (i.e., lymphotoxin beta and CD24). These studies have identified several transcriptional targets of IL-5 and GM-CSF in human eosinophils and suggest that a number of protein products are critical to the responsiveness of airway eosinophils.