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.

Plasma cell dyscrasias are a subset of hematological malignancies involving the production of monoclonal immunoglobulins. This spectrum of disorders includes asymptomatic conditions such as monoclonal gammopathy of unknown significance as well as extremely aggressive malignancies such as plasma cell leukemia. Monoclonal gammopathies are occasionally associated with renal failure, which can occur via many pathophysiological processes. The most common of these is light chain cast nephropathy, but many rare renal complications exist, including thrombotic microangiopathy (TMA) and focal segmental glomerulosclerosis (FSGS). Here, we report a patient with new renal failure with features of TMA and FSGS on biopsy and found to be secondary to plasma cell leukemia.

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.

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.

Diffuse crescentic involvement in fibrillary glomerulonephritis (FGN) is very rare. We describe a case of FGN with dif-fuse crescents in a patient who presented with clinical findings concerning for rapidly progressive kidney failure and pathologic findings suggestive of anti-glomerular base -ment 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 impor-tance of considering FGN in biopsies show -ing diffuse crescentic glomerulonephritis with linear IgG staining of glomerular capil-lary walls, especially in the absence of other significant proliferative changes.

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 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.

The objective of this study was to assess the correlation between the objectively measured degree of tissue organization and tensile properties in healthy and aneurysmal aortic tissue. Aneurysmal aortic tissue was obtained during open surgical repair; healthy tissue was obtained from healthy age-matched cadavers. Tissue underwent uniaxial mechanical testing, using a physiologic prestress corresponding to 110 mm Hg, using a sinusoidal ±5% strain at 1 Hz. For histologic analysis, tissue was paraffin-embedded, sectioned, and stained with Verhoeff-Van Gieson. Slides were analyzed using CytoSpectre, an open-source Fourier-transform based program for assessing microscopy images (Fig 1). Averaged circular variances (a measure of structural anisotropy) were taken from both whole aortic walls and from isolated media. Average circular variance of the entire wall demonstrated a moderately strong correlation with Young's modulus (R2 = 0.5467), with a slightly stronger correlation for healthy than diseased tissue (R2 = 0.692 vs 0.6387) (Fig 2). The circular variance of isolated media demonstrated a significantly lower correlation with Young's modulus (R2 = 0.3014). Under high-strain, oscillatory conditions, represented by the dynamic modulus E*, AA, TA, and TAA tissue collectively showed a moderate correlation with whole-wall circular variance (R2 = 0.2397), and a stronger correlation with isolated media (R2 = 0.331), whereas neither the whole wall nor media of abdominal aortic aneurysm tissue showed any correlation with E*. Our results provide evidence that under conditions of low strain, the tensile properties of the aorta arise from the vascular wall in its entirety, whereas under high strain conditions approximating physiologic stresses, the architecture of the media provides a relatively greater contribution. Furthermore, we have demonstrated that abdominal aortic aneurysm tissue, uniquely, demonstrates a lack of coherence between its biomechanical properties and histologic structure.Fig 2Average circular variance vs Young's modulus for healthy and diseased tissue.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

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.

Toxin ingestion can lead to myocardial injury, which may be recoverable. We present a case of cardiogenic shock due to supplement use. A 64-year-old male with no known cardiac disease presented after a motor vehicle accident caused by hypoglycemia. He became progressively hypotensive requiring

Abstract Background: Immune checkpoint inhibitors (ICI) are an effective new tool in the treatment of malignancy by rescuing exhausted T-cells and enhancing anti-tumor immunity. The offset of immune self-tolerance can result in autoimmune adverse effects involving gastrointestinal, pulmonary and endocrine systems. Lung and skin sarcoidosis have been described in association with ICI use. We present the first case of non-PTH medicated hypercalcemia due to cardiac sarcoidosis in the setting of immunotherapy. Case Presentation: A 71-year-old man was referred to endocrinology for hypercalcemia. He had a fourteen-year history of scalp melanoma in remission until February 2019, when routine surveillance scans suggested metastatic disease. Computer tomography of the chest showed mediastinal and hilar lymphadenopathy (largest node 5.2 cm) and numerous pulmonary nodules (largest 1.7 cm). Biopsy of the largest pulmonary nodule and mediastinal lymph node (LN) confirmed BRAF wild-type metastatic melanoma. Ipilimumab/nivolumab (antiCTLA4/antiPD-1) combination therapy was started. After two cycles, hypercalcemia was noted on routine laboratory surveillance. He was asymptomatic and physical exam was unremarkable. Initial workup revealed: calcium 10.6 mg/dL (8.6-10.2), albumin 4 g/dL (3.5 - 5.2), phosphorus 3.8 mg/dL (2.7 - 4.5), PTH <0.6 pg/mL (15.0 - 65.0), PTHrP <2.0 pmol/L (0.0 - 2.3), 25 hydroxyvitamin D 22. 9 ng/mL (30 - 60), vitamin A 0.59 mg/L (0.30 - 1.20). He denied taking calcium-containing supplements. He was treated with hydration and immunotherapy was continued for two cycles, followed by single agent nivolumab. After three months on ICI, the metastatic lesions were reduced in size by 30%. His calcium peaked at 12.5 mg/dL and was treated with 4mg of intravenous Zoledronic acid without resolution. He developed worsening functional status, symptomatic hypotension, and elevated troponins. Cardiac MRI demonstrated myocarditis and nivolumab-induced myocarditis was suspected. Surprisingly, endomyocardial biopsy revealed multiple granulomas suggestive of sarcoidosis. AFB, PAS and Congo red stains were negative. He was treated with supportive care and glucocorticoids with resolution of hypercalcemia and improved cardiac function. Unfortunately, serum 1,25 dihydroxy vitamin D was not successfully measured until after the first dose of prednisone and was found at the upper limit of our reference range 62.0 pg/mL (19.9-79.3). Conclusion: Immune checkpoint inhibitors are effective agents in treating various cancers. Adverse effects due to autoimmunity are common and early recognition of life-threatening complications is critical. Although cutaneous and pulmonary sarcoidosis have been described with ICI, to our knowledge, this is the first case report of ICI-related cardiac sarcoidosis presenting with PTH-independent hypercalcemia.

Introduction: Response to anticoagulation varies during management of acute hospitalized pulmonary embolism. We aimed to study thrombus histology in pulmonary embolism samples removed during acute surgical embolectomy to evaluate whether thrombus morphology was similar between patients and whether there was an association with duration of symptoms and/or resolution on follow up imaging. Methods: This was a retrospective observational single center study at the University of Rochester Med-ical Center. We evaluated patients that underwent acute surgical embolectomy and followed up in our clinic 2 - 4 months after the event with Ventilation/Perfusion (V/Q) scan obtained for all regardless of symptoms. Thromboemboli were formalin fixed and processed for light microscopy in the hospital histopathology laboratory. Four-micron thick sections were stained with hematoxylin and eosin, Masson trichrome, and Verhoeff elastic tissue stains. Immunohistochemistry was performed using anti-CD31 and anti-CD68. Slides were independently evaluated for time-dependent microscopic changes using Irniger's classification by two blinded pathologists. Results: Sixteen patients underwent embolectomy with fifteen having V/Q imaging at follow up. The ma-jority of patients were female. Samples showed a generally similar overall architecture that included a central core composed primarily of red blood cells and fibrin and an outer layer of platelets and mono-cytes. Two samples had evidence of fibrosis and recanalization. Conclusions: We found heterogeneous histopathology in samples obtained during acute embolectomy. Further prospective studies should systematically characterize clot morphology and evaluate treatment response and outcomes. Careful thrombus specimen measurement and consistent sampling for sections will be required to draw firm conclusions. (c) 2021 Elsevier Inc. All rights reserved.

Long-term outcomes after acute pulmonary embolism vary from complete resolution to chronic thromboembolic pulmonary hypertension (CTEPH). Guidelines after acute pulmonary embolism are generally limited to anticoagulation duration. We assessed patients with estimated prognosis >1 year in our pulmonary hypertension clinic 2-4 months after treatment for intermediate- or high-risk acute pulmonary embolism. At follow-up, ventilation-perfusion scan and echocardiogram were offered. The aim of this study was to assess for recurrent symptomatic disease, residual imaging defects or right ventricular dysfunction, and functional disability after acute management of pulmonary embolism. After treatment for acute intermediate- or high-risk pulmonary embolism, 104 patients followed up in pulmonary hypertension clinic. Of those, 55% of patients had self-reported limitation in activity. No patients had symptomatic recurrence of pulmonary embolism. Forty-eight percent of patients had residual perfusion defects on perfusion imaging, while 91% of patients had either normal or only mildly enlarged right ventricles. We identified heart failure preserved ejection fraction, iron deficiency, and obstructive sleep apnea as significant contributors to breathlessness. Treatment of these conditions was associated with improvement. Surprisingly, we diagnosed CTEPH in nine patients; for some, chronic thrombus may already have been present at the time of index evaluation. Our findings suggest that follow-up in a dedicated pulmonary hypertension clinic 2-4 months after acute intermediate- or high-risk pulmonary embolism may add value to patient care. We identified treatable comorbidities that could be contributing to post-pulmonary embolism syndrome as well as CTEPH.

Objective:There are few papers regarding repeat mechanical thrombectomy or thrombectomy for Trousseau's related stroke. We present a unique case of repeat thrombectomy due to Trousseau's syndrome affecting the same vessel in a patient with metastatic cancer.Case Presentation:A 47-year-old male presented with a full left middle cerebral artery syndrome and a National Institute of Health Stroke Scale of 17, despite regular apixaban use. He underwent mechanical thrombectomy successfully but developed recurrent symptoms on postoperative day (POD) 6 while on warfarin. He underwent two additional thrombectomies, the final one requiring glycoprotein IIa/IIIb inhibitor for emergent implantation of intracranial stent. Successful recanalization (thrombolysis in cerebral infarction 2b) was achieved, and the patient was discharged home on dual antiplatelet therapy and enoxaparin on POD 10 after last thrombectomy, ambulatory and independent in his activities of daily living. The patient expired as a result of his metastatic disease 109 days after the third procedure and was ambulatory for 91 of those days.Conclusion:This case illustrates the palliative aspects of mechanical thrombectomy and the complexities of anticoagulation management in patients with the metastatic disease Trousseau's syndrome.

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.

Myocarditis is an inflammatory disease of the myocardium with a wide spectrum of symptoms and severity. Fulminant myocarditis is a small cohort of this disease that tends to present with sudden onset acute heart failure, cardiogenic shock, or life-threatening arrhythmias. The most common type, and the one with the best likelihood for recovery, is lymphocytic myocarditis. More rare, and often more fatal, forms are eosinophilic myocarditis and giant cell myocarditis. Delayed recognition and lack of standardized therapy guidelines continue to challenge clinicians treating these critically ill patients. This article will review the most up-to-date literature regarding recognition and recommended treatment for fulminant myocarditis as it pertains to clinical practice.