Autoimmunity in Infection-Related Glomerulonephritis.

Introduction: Autoimmune (AI) reactivity in the setting of infection-related GN (IRGN) is often viewed as an epiphenomenon and is not well described. Methods: We report a cohort of 17 patients with IRGN during a 7-year period that highlights cases with AI reactivity and describes the clinical and pathologic characteristics of IRGN cases associated with AI reactivity. Results: Of the IRGN cases, 76% had clinical evidence of an autoimmune disease (AD) and/or positive AI serologies. Within the IRGN group with AI reactivity, 12 had positive AI serologies (92%) and 10 had AD (77%). 30% had a prior diagnosis of AD, while the remaining 70% did not have a history of AD and were either diagnosed or suspected of having an AD at the time of biopsy. The most common autoantibody detected was anti-nuclear antibody followed by anti-neutrophil cytoplasmic antibodies and autoantibodies associated with antiphospholipid syndrome. Conclusion: The study is not sufficiently powered to determine any significance but demonstrates the frequency with which AI features occur in IRGN and should prompt further future investigation. In summary, our findings suggest AI manifestations are common in IRGN.

The Clinicopathologic Spectrum of Membranous Nephropathy with Lupus-Like Features.

INTRODUCTION: The pathologic features of membranous lupus nephritis (MLN) are occasionally encountered in secondary membranous nephropathy (sMN) without overt clinical evidence of systemic lupus erythematosus. Moreover, some sMN with lupus-like features (lupus-like membranous nephropathy [LL-MN]) have a clinical presentation more typical of primary membranous nephropathy (pMN). Based on the confounding clinical and pathologic presentation, it is unclear how to categorize and treat these patients. METHODS: We performed immunohistochemical staining for recently discovered target antigens associated with MN -NELL-1, THSD7A, and EXT1/2 and compared the clinicopathologic presentation of patients with LL-MN to those with pMN and MLN. RESULTS: From 2015 to 2020, there were 21 patients with MLN and 99 with MN, of which 59% were diagnosed pMN and 41% sMN. 44% of sMN patients showed lupus-like features (LL-fx). All LL-MN patients were negative for PLA2R and NELL1, but 12% were positive for EXT1/2. 50% of LL-MN patients had an identifiable systemic disease, of which 56% were autoimmune disease (AD) and 44% infection. Compared to pMN, LL-MN had a higher incidence of underlying AD (p = 0.02). Within pMN, 24% also had LL-fx (LL-pMN), and all but 1 were PLA2R- (78%) or NELL1-positive (15%). Only 5% of pMN patients had an AD, 66% of which showed LL-fx. Most idiopathic LL-MN were treated and behaved clinically similarly to pMN. There were no differences in outcome in terms of progression toward end-stage renal disease or mortality between LL-MN versus pMN and MLN. CONCLUSION: LL-MN appears to have a significant association with underlying AD and has a subset showing EXT1/2 positivity, whereas most LL-pMN and idiopathic LL-MN likely represent an atypical pathologic presentation of pMN.

Subepithelial deposits with microspherular structures in membranous glomerulonephritis.

Rare cases of membranous glomerulopathy (MGN) with subepithelial deposits consisting of microspherular structures identified by electron microscopy have been described in the literature as either MGN with spherules or podocyte infolding glomerulopathy (PIG). The paucity of available studies shows a strong association with underlying autoimmune disease. To further understand the significance of subepithelial microspherular deposits, we retrospectively identified native kidney biopsies from 10 patients diagnosed as MGN with subepithelial microspherular structures identified by ultrastructural examination at the University of Rochester Medical Center (URMC) during an 11-year period. The majority were Caucasian (80%) with a mean age of 51.3 (±12.9) years. 50% had an autoimmune disorder, of which 80% were SLE. Two SLE cases had concomitant rheumatoid arthritis and Sjogren's syndrome. One additional case had antiphospholipid syndrome and showed lupus-like features on biopsy. 40% were idiopathic and negative for PLA2R, NELL1, and THSD7A. MGN with subepithelial microspherular structures is frequently associated with an underlying autoimmune disease. The majority are negative for markers of primary MGN (PLA2R, THSD7A, and NELL1) and show features suggestive of secondary MGN.

The spectrum of renal diseases with lupus-like features: a single-center study.

BACKGROUND: A subset of patients without overt systemic lupus erythematosus (SLE) present with biopsy findings typically seen in lupus nephritis (LN). Although a minority eventually develops SLE, many do not. It remains unclear how to classify or treat these patients. Our study attempted to further understand the clinical and pathological characteristics of cases with lupus-like nephritis (LLN). METHODS: Among 2700 native kidney biopsies interpreted at University of Rochester Medical Center (URMC) from 2010 to 2019, we identified 27 patients with biopsies showing lupus-like features (LL-fx) and 96 with LN. Of those with LL-fx, 17 were idiopathic LLN and 10 were associated with a secondary etiology (e.g., infection/drugs). RESULTS: At the time of biopsy, the LLN-group tended to be slightly older (44 vs. 35), male (58.8 vs. 17.7%, p = .041), and Caucasian (47.0 vs. 28.1%, p = .005). Chronic kidney disease was the most common biopsy indication in LLN (21.4 vs. 2.8%, p = .001). Both LN and LLN presented with nephrotic-range proteinuria (mean 5.73 vs. 4.40 g/d), and elevated serum creatinine (mean 1.66 vs. 1.47 mg/dL). Tubuloreticular inclusions (TRIs; p < .001) and fibrous crescents (p = .04) were more often seen in LN, while more tubulointerstitial scarring was seen in LLN (p = .011). At mean follow-up of 1684 d (range: 31-4323), none of the LLN patients developed ESRD. A subset of both LN and cases with LL-fx overlapped with other autoimmune diseases. CONCLUSIONS: Lupus-like pathologic features are seen in a wide array of disease processes. The findings suggest that LLN may be a manifestation of an autoimmune process that overlaps with SLE.

Light chain deposition disease masquerading as smoking-associated nodular glomerulosclerosis with deposits identified by electron microscopy only.

Light chain deposition disease (LCDD) is a form of monoclonal gammopathy of renal significance. The diagnosis is based on the immunofluorescence (IF) findings of linear monoclonal light chain staining of basement membranes throughout the kidney, which appear as non-organized, granular punctate to powdery electron dense deposits by electron microscopy (EM). Although "LCDD by IF only" without EM deposits has been well-described, LCDD identified by EM with negative IF is very rare and hardly mentioned in the literature. Herein we describe a case of lambda-type LCDD that appeared negative by IF and showed light microscopic findings of nodular glomerulosclerosis, which was initially attributed to the patient's history of significant tobacco use and uncontrolled hypertension. However, EM later showed powdery electron dense material in focal glomerular and tubular basement membranes and mesangium. Subsequent bone marrow analysis revealed greater than 60% lambda-restricted plasma cells. We report this case to illustrate that within the differential diagnosis of nodular sclerosis, monoclonal immunoglobulin deposition disease (MIDD) should remain in the differential even if immunofluorescence appears negative as EM can prove to be crucial in identifying cases of MIDD.

Myeloid bodies is not an uncommon ultrastructural finding.

The presence of myeloid bodies (MBs) is classically associated with Fabry disease (FD). However, MBs are also identified in patients without clinical evidence of FD. We attempt to further understand the clinicopathologic significance of incidental MBs in those without FD. Among the 4400 renal biopsies accessioned at the University of Rochester Medical Center from 2010 to 2021, we identified 32 cases showing MBs, 6 of which had FD. Medications were compared between a non-FG and a control-group of randomly selected cases without MBs (non-MBs). Both Fabry-group (FG) and non-Fabry-group (non-FG) were predominantly middle-aged (mean 48 years vs 56, respectively). Non-FG had slight female predominance (1:4), while all in FG were female. The majority of both non-FG and non-MBs cohort were on the same medications reported to cause phospholipidosis except sertraline and hydralazine (p = .04), which were more frequent in non-FG. Ultrastructurally, non-FG tended to show focal MBs in predominantly podocytes, while FG showed more extensive MBs in not only podocytes but also parietal, tubular, endothelial, and myocyte cells (p = .03). In addition, half of FG had another superimposed renal disease including kappa-light chain deposition disease, thin-basement membrane nephropathy, and lithium-related changes. MBs are encountered not only in FD but in other settings including CADs, toxins, and other inheritable diseases. Although secondary causes of MBs typically show less extensive involvement compared to FD, these features overlap. Given the challenges in diagnosing female carriers, the finding of MBs, though not specific to FD, may be the only clue that leads to further work-up and timely diagnosis, underscoring the importance of considering FD among other etiologies in differential diagnosis.

A rare case of diffuse crescents in fibrillary glomerulonephritis
.

Diffuse crescentic involvement in fibrillary glomerulonephritis (FGN) is very rare. We describe a case of FGN with diffuse crescents in a patient who presented with clinical findings concerning for rapidly progressive kidney failure and pathologic findings suggestive of anti-glomerular basement membrane (GBM) disease. Serologies for anti-neutrophil cytoplasmic antibody (ANCA) and anti-GBM were negative. IgG subtyping showed IgG1 dominance, which has not been described in FGN. We present this unique case to emphasize the importance of considering FGN in biopsies showing diffuse crescentic glomerulonephritis with linear IgG staining of glomerular capillary walls, especially in the absence of other significant proliferative changes.

Segmental membranous nephropathy.

Most cases of membranous nephropathy (MGN) present with global and diffuse distribution of subepithelial deposits. However, segmental MGN, in which there is focal or diffuse segmental subepithelial deposits, are occasionally encountered. The clinical and pathologic significance of segmental MGN is not well understood and thought to be more likely due to either early or resolving phase of the global form of MGN. Several case reports and literature available suggest that it may be a manifestation of secondary causes based on pathologic features such as presence of C1q and mesangial deposits, extra-glomerular deposits involving tubular basement membranes, absence of PLA2R and THSD7A, IgG1 and IgG3 subclass dominance, and the presence of other co-existing renal disease. Other reports, however, suggest that some of these cases may be a variant of the primary form of MGN. In this review, we integrate what is known about segmental MGN in order to better direct interpretation of renal biopsies in which it is identified.

The spectrum of kidney biopsy findings in patients with morbid obesity.

Morbid obesity, defined as body mass index (BMI) ≥40 kg/m2, affects approximately 8% of United States adults and is a recognized risk factor for chronic kidney disease (CKD). We present the first focused biopsy-based study exploring the range of kidney diseases in this population. Among 3263 native kidney biopsies interpreted at Columbia University in 2017, we identified 248 biopsies from morbidly obese patients. In this cohort with median age of 53.5 years, 56% were female and median BMI was 44.0 kg/m2. Diabetes and hypertension were present in 47% and 81% of patients, respectively. Median estimated glomerular filtration rate (eGFR) was 30 ml/min/1.73 m2, and most patients had nephrotic range proteinuria. Obesity related glomerulopathy (ORG), defined as focal segmental glomerulosclerosis with glomerulomegaly or glomerulomegaly alone, was detected in 73 patients, including 29 with ORG alone and 44 with ORG plus another kidney disease. In contrast, 167 patients had other kidney diseases alone, without ORG, most commonly (in descending order) diabetic nephropathy, acute tubular necrosis, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy, and lupus nephritis. In 49% of patients, kidney biopsy yielded a diagnosis predicted to change patient management. The strongest predictor of non-ORG lesions was eGFR <30 ml/min per 1.73 m2, and presentation with nephrotic syndrome or acute kidney injury (with or without background CKD) was more common in non-ORG than ORG. The findings reveal an unexpectedly broad spectrum of kidney pathology beyond metabolic syndrome-associated disorders and highlight the importance of kidney biopsy to guide management and prognosis in the morbidly obese population.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a young female athlete at 36 weeks gestation: a case report.

A 26year old east African professional athlete presented to the obstetric clinic for a routine visit at 36 weeks gestation. She had a history of Right Ventricular Outflow Tract - Ventricular Tachycardia (RVOT-VT) with an episode of cardiac arrest in the past, and had been treated with ablation 4 years earlier. Her current visit was uneventful, her pregnancy progressing normally. Following the visit she went to a local restaurant where she suffered a cardiac arrest that was unresponsive to therapy. Chest compressions were continued from the time of her collapse until an emergency caesarian section was performed, delivering a healthy female infant. At autopsy a focal area of subtle pallor and myocardial thinning was present at the apex of the right ventricle. Histology showed myocyte degeneration and loss with focal full thickness replacement of myocardium by adipose tissue, consistent with the fatty form of arrhythmogenic right ventricular cardiomyopathy (ARVC). Molecular studies revealed a variant of unknown significance in the MYBPC3 gene, but no variant known to be associated with ARVC. In view of the subtlety of the lesion on gross examination this diagnosis could have been easily missed, emphasizing the importance of performing histologic examination of subtle gross cardiac lesions.

Glomerulopathy in adult recipients of pediatric kidneys.

To compare "for cause" renal biopsies (bx) from adult recipients of pediatric-donor kidneys (PDK) versus adult-donor kidneys (ADKs), we reviewed 103 graft bx from 50 PDK recipients and 85 bx from 49 ADK recipients. PDK bx displayed more frequent glomerular pathology with immune complex-mediated glomerulonephritis present in 11/103 PDK versus 1/85 ADK (p < 0.05). In 15/103 PDK bx and 1/85 ADK (p = 0.001), the association of glomerular sclerosis, expanded mesangium, and halo of prominent podocytes by light microscopy, and ultrastructural glomerular basement membrane lamellation, configured a characteristic glomerulopathy.

The splicing factor SF2/ASF binds to ARS homologs in a human rDNA replication origin.

The function of the relatively well-studied DNA replication origins in the yeast Saccharomyces cerevisiae is dependent upon interactions between origin replication complex (ORC) proteins and several defined origin sequence elements, including the 11 bp ARS consensus sequence (ACS). Although the ORC proteins, as well as numerous other protein components required for DNA replication initiation, are largely conserved between yeast and mammals, DNA sequences within mammalian replication origins are highly variable and sequences homologous to the yeast ACS elements are generally not present. We have previously identified several replication initiation sites within the nontranscribed spacer region of the human ribosomal RNA gene, and found that two highly utilized sites each contain a homologue of the yeast ACS embedded within a DNA unwinding element and a matrix attachment region. Here we examine protein binding within these initiation sites, and demonstrate that these ACS homologues specifically bind the alternate splicing factor SF2/ASF as well as GAPDH in vitro, and present evidence that the SF2/ASF interaction also occurs within the nuclei of intact cells. As the moderate upregulation of SF2/ASF has been linked to oncogenesis through the promotion of alternatively spliced forms of several regulatory proteins, our results suggest an additional mechanism by which SF2/ASF may influence the transformed cell phenotype.