Karyomegalic interstitial nephritis, a fascinating histopathologic entity for pathologists: Be watchful of the FAN1 gene mutations.

ABSTRACT: Karyomegalic interstitial nephritis (KIN) is an uncommon autosomal recessive disease, which is characterized by enlarged and hyperchromatic nuclei of the renal tubular epithelial cells. It is associated with mutations in Fanconi anemia-associated nuclease 1 gene, which is responsible for DNA repair, and these pathogenic mutations are responsible for progressive renal failure in young adults. We present a case of a 29-year-old female with end-stage renal disease who had a family history of early-onset renal failure in two of the siblings. Her elder sister with chronic kidney disease stage III was advised to be biopsied to look for any familial causes. Stained sections of renal biopsy revealed normal glomeruli. Tubular epithelial cells showed nuclear changes focally like hyperchromasia, karyomegaly, and anisonucleosis. On direct immunofluorescence, all glomeruli were negative for deposits with all antisera. Based on these findings, a final opinion of KIN was given.

Reporting Trends, Practices, and Resource Utilization in Neuroendocrine Tumors of the Prostate Gland: A Survey among Thirty-Nine Genitourinary Pathologists.

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

C1q Nephropathy in Children with Nephrotic Syndrome: Treatment Strategies and Outcomes.

Introduction: There is a paucity of clinical data on C1q nephropathy (C1qN) in children in India and Southeast Asia. This is the first detailed analysis conducted to elucidate the prevalence, clinicopathological profile, and response to different immunosuppressives in children with C1qN in India. Materials and Methods: Detailed demographic profile, clinical features, urine and blood chemistries, kidney biopsy, and response to different immunosuppressives of the study participants were analyzed between August 2015 and October 2020 for steroid-dependent/-resistant nephrotic syndrome (NS). Results: C1qN was diagnosed in 16 (14.13%) of 113 children who underwent biopsy for steroid-dependent/-resistant NS. The mean age was 44 months (range 18-99 months) and male and female number was 12 (75%) and four (25%), respectively, and mean follow-up was 3.5 years. Eight (50%) had coexistent minimal-change nephrotic syndrome (MCNS) pattern, seven (43.7%) had focal segmental glomerulosclerosis (FSGS), and one (6.2%) had diffuse mesangial hypercellularity. Thirteen children had complete follow-up, of which eight (61.5%) and four (30.7%) cases presented as steroid-dependent and primary steroid-resistant NS, respectively, whereas one (7.6%) had joint pain with rashes. At presentation, seven (53.8%) had hypertension, 12 (92.3%) had nephrotic range proteinuria, and six cases (46.1%) had hematuria. Nine (75%) of 12 cases achieved complete remission with calcineurin inhibitor (CNI) therapy, and two were non responders, one was a partial responder, and one responded to mycophenolate. Of six FSGS cases, four had complete remission, one had partial remission, and one was in non-remission. Of six cases with MCNS, five had complete remission and one was in non-remission. Renal functions remained normal in all except one case who had progression to chronic kidney disease Stage 3. Conclusion: One out of seven children with difficult NS can have underlying C1qN. CNIs are most beneficial to attain and maintain remission. Renal functions remain normal in the majority. Along with C1q deposits, MCNS and FSGS patterns are seen equally and respond almost similarly to CNIs.

Clinical Response to Intestine-targeted Steroid Therapy in Biopsy-proven Immunoglobulin A Nephropathy.

Primary immunoglobulin A (IgA) nephropathy is associated with a dysfunctional mucosal immune system, leading to renal deposition of IgA and injury. Fifty patients with biopsy-proven IgA nephropathy were included. All patients were initiated on renin-angiotensin-aldosterone system (RAAS) inhibitors, polyunsaturated fatty acids, and a controlled release formulation (CRF) of budesonide. All drugs were started together, as isolated RAAS inhibitors will not prevent the immunological damage caused by the ongoing deposition of IgA. Depending on the histology (mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and crescents score), the patients received 9 mg or 12 mg of budesonide. All patients were followed up every 4 weeks to monitor renal function, 24-h urinary protein, and adverse effects. Our primary outcome was a mean change in the estimated glomerular filtration rate (eGFR) and 24-h urinary protein from the baseline to the end of 6 months. The percentage of decline in mean 24-h protein at 6 months from the baseline was 33%. The mean decrease in serum creatinine from the baseline was 0.73 mg/dL. The mean gain in eGFR from the baseline was an increase of 9 mL/min/1.73 m2. Of 50 patients, 11 (22%) achieved complete remission, 20 (40%) achieved partial remission, and 16 (32%) were non-responders. Three patients (6%) were lost to follow-up. The early initiation of CRF budesonide with optimized supportive care led to reductions in proteinuria and improvements in eGFR at 6 months in patients with IgA nephropathy. Early lesions with minimal chronicity showed an excellent response to budesonide.

Collapsing Glomerulopathy Superimposed on Diabetic Nephropathy.

Diabetic nephropathy (DN) is characterized by progressive increase in proteinuria and decline in renal functions. Various forms of nondiabetic kidney disease may be superimposed on DN, which can alter the progression of DN. Collapsing glomerulopathy (CG) may superimpose on DN, and is characterized by rapid worsening of renal failure and has poor prognosis. In our institute, renal biopsies were performed in diabetic patients for increasing proteinuria or worsening renal functions. There were seven cases of CG superimposed on DN. All patients except one had a history of long standing diabetes mellitus. All patients had nephrotic range proteinuria. Four patients had severe renal failure at presentation. Renal biopsy showed CG superimposed on DN. Six patients progressed to end-stage renal disease during follow-up; one patient is in chronic kidney disease-stage 3b. The development of CG contributes to an increased level or new onset proteinuria in DN, and can lead to rapid worsening of renal failure. The diagnosis of CG superimposed on DN is of prognostic significance.

A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

Recurrence of membranoproliferative glomerulonephritis post transplant - Is this mere recurrence of pattern or recurrence of disease?

Recurrence of membranoproliferative glomerulonephritis (MPGN) is seen in 1965% cases of postrenal transplant resulting in graft loss in up to 35-50% of cases. A 31-year-old female, after 1% years on maintenance hemodialysis, underwent ABO compatible deceased donor kidney transplantation with basiliximab induction. During the immediate posttransplant period, the patient had delayed graft function, but achieved nadir creatinine of 0.9 mg/dL by 10 days. Nine months posttransplant, the patient developed fever, anasarca, and decrease in urine output with albuminuria 3+, active sediments in urine, serum creatinine 3.5 mg/dL, 24-h urine protein 7.5 g, and low C3. The patient underwent graft biopsy. Subsequently, the patient received pulse steroid for three days and five sessions of plasmapheresis. Renal biopsy report was suggestive of MPGN with focal crescents and acute tubular necrosis. Immunofluorescence showed Ig G3+, C3 3+, к 3+, and negative for λ or other immunoglobulins or complements. As her native kidney disease was immune-complex-mediated MPGN with no light chain restriction, paraffin tissue of the native kidney was reexamined for light chain restrictions by immunoperoxidase method, but did not show light chain restriction. The patient underwent extensive workup for paraproteinemias, but results were negative. Subsequently, she received four doses of bortezomib. The patient's serum creatinine got reduced to 0.8 mg/dL and proteinuria reduced to 800 mg/day. Our case is unique as we were not able to demonstrate monoclonal deposits in native kidney sample although there was recurrence of MPGN with monoclonal light chain deposits post transplant. Our findings emphasize the need for thorough evaluation of paraproteinemias in patients with idiopathic MPGN even in the absence of light chain deposition in biopsy.

Hemosiderin tubulopathy-induced acute kidney injury - A rare initial manifestation of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, infections, and thromboembolic complications. Renal abnormalities are rare which occur either due to hemolytic crisis or repeated thrombotic episodes involving small venules. Acute kidney injury (AKI) requiring hemodialysis due to toxic effects of hemoglobinuria, with a stable disease is exceptional. We describe a case of an elderly gentleman presenting with features of severe AKI requiring hemodialysis due to hemosiderin tubulotoxicity as the first manifestation of PNH. The diagnosis was challenging because of the rarity and unfamiliarity with this entity. The outcome was complete recovery of renal function with hemodialysis.

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study.

In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T-antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen-expressing and control cases is intriguing.

Pulmonary thromboembolism as first presentation of childhood membranous nephropathy.

Nephrotic syndrome is associated with an increased risk of thromboembolism. Pulmonary thromboembolism has been described in nephrotic syndrome with or without deep vein thrombosis. In this case report, we describe an unusual first presentation of childhood membranous nephropathy with massive pulmonary thrombus with pulmonary infarction with right renal vein thrombosis.

Fanconi syndrome due to light chain proximal tubulopathy in a patient with multiple myeloma.

Fanconi syndrome (FS) in an adult patient is an unusual finding and it merits thorough evaluation. Paraproteinemias are one of the common etiologies in adult FS and need to be ruled out. Among the various forms of renal involvement in multiple myeloma, light chain proximal tubulopathy (LCPT) is the rarest. Usually, it causes proximal tubular dysfunction which is characterized by intracytoplasmic deposition of crystallized, mostly kappa monoclonal light chains in proximal tubules; however, glomerular crystal deposition is unusual. Herein, we are presenting a patient with renal dysfunction and FS. On evaluation, she was found to have multiple myeloma and renal biopsy showed LCPT with extensive crystal deposition in the proximal tubular epithelium along with crystal deposition in the glomerular capillary endothelium. The treatment of the underlying multiple myeloma caused remission of the FS.

Post-infectious glomerulonephritis with crescents in adults: a retrospective study.

BACKGROUND: Crescent formation generally reflects severe glomerular injury. There is sparse literature on post-infectious glomerulonephritis (PIGN) with crescents in adults. This retrospective study looked at nine such cases to see if there is a correlation between the severity of presentation, steroid treatment, histological severity and outcome. METHODS: Biopsy reports of all the adults who underwent kidney biopsy from February 2010 to June 2014 in a tertiary care hospital were screened and all the cases with the diagnosis of PIGN with crescents were selected. Clinical presentation, laboratory data, histology, treatment and outcome were analysed. RESULTS: Six patients had evidence of recent/current infection, but all except two were non-streptococcal. The mean creatinine was 360.67 µmol/L (range 70.72-770.85) and the mean estimated glomerular filtration rate (MDRD eGFR) was 30.28 mL/min/1.73 m(2) (range 6.4-111.1) on presentation. All five patients who were treated with steroids had an excellent response. Among the four patients who did not receive steroids, two were left with significant renal impairment (mean MDRD eGFR 23.5 mL/min/1.73 m(2)) at a mean follow-up of 15.5 months (range 10-21). The mean percentage of glomeruli with crescents was 36.13% (range 11.76-100) and except in one, there was no tubular atrophy or interstitial fibrosis and none had glomerulosclerosis. None of the patients progressed to end-stage renal disease. CONCLUSION: Non-streptococcal infections are more common precipitants. There was no correlation between histological and clinical severity. Patients treated with steroids had better renal outcomes.

Immune mediated crescentic MPGN secondary to HBV infection: A rare presentation for a common infection.

Hepatitis B virus (HBV) infection presenting as crescentic glomerulonephritis in the absence of cryoglobulinemia is an extremely rare phenomenon. We report a case of a 44-year-old male with HBV infection, who underwent kidney biopsy for rapidly progressive renal failure and nephrotic range proteinuria. Histopathological evaluation of the kidney biopsy was consistent with immune complex mediated crescentic membranoproliferative glomerulonephritis (MPGN). The patient achieved complete renal and virological remission with steroids, plasmapheresis and antiviral therapy. This case report summarises the importance of early initiation of immunosuppression and plasmapheresis under antiviral coverage for improved clinical outcomes.

A case of primary renal allograft dysfunction due to myeloma cast nephropathy.

We report a rare case of primary renal allograft dysfunction due to myeloma cast nephropathy in a patient with no overt clinical features of multiple myeloma preceding his transplantation. A 45-year-old man on hemodialysis for six months for end-stage kidney disease due to presumed chronic glomerulonephritis developed immediate graft dysfunction post-transplantation. The graft biopsy was diagnostic of myeloma cast nephropathy. Other criteria for lambda light chain multiple myeloma were fulfilled with immunofixation electrophoresis and bone marrow biopsy. He was treated with plasmapheresis, bortezomib and high-dose dexamethasone. However, the patient succumbed to septicemia on the 37 th post-operative day. This is probably the first report of primary renal allograft dysfunction due to myeloma cast nephropathy diagnosed within the first week post-transplanation in a patient with unrecognized multiple myeloma.

Crystalloid glomerulopathy in monoclonal gammopathy of renal significance (MGRS).

We report a case of monoclonal gammopathy of renal significance in a 63-year-old man who presented with nephrotic-range proteinuria and renal insufficiency. The kidney biopsy showed a membranoproliferative glomerulonephritis pattern with extensive crystalloid deposits in the glomerular capillary endothelial cells and very few in the tubular epithelial cells. The immunoperoxidase staining showed kappa light chain restriction. Subsequently, the bone marrow showed 6% plasma cells which confirmed the diagnosis of monoclonal gammopathy of renal significance. He responded well to bortezomib treatment with resolution of the nephrotic syndrome and normalization of renal function after 7 months.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma. Here we present a detailed study of collecting duct carcinoma (n=39) and renal medullary carcinoma (n=13), characterizing these rare neoplasms and analyzing their interrelationship. Both collecting duct carcinoma and renal medullary carcinoma exhibited significant similarities, such as predilection for the right kidney, tumor mass with an epicenter in the renal medulla, and a mean size of 7 cm. Overall, both tumors exhibited a poorly differentiated adenocarcinoma histology with desmoplastic stromal response (100%), inflammatory infiltrate (100%), frequent perinephric extension (collecting duct carcinoma: 97%; renal medullary carcinoma: 83%), lymphovascular invasion (100%), intraluminal mucin (collecting duct carcinoma: 42%; renal medullary carcinoma: 73%), high nuclear grade (97%), overlapping immunoreactivity for Ulex europaeus agglutinin 1 (collecting duct carcinoma: 75%; renal medullary carcinoma:55%), CK7 (collecting duct carcinoma: 44%; renal medullary carcinoma: 71%), and high-molecular weight cytokeratin (collecting duct carcinoma: 26%; renal medullary carcinoma: 29%), and nonimmunoreactivity for Ksp-cadherin. Histologically, collecting duct carcinoma frequently had tubular, tubulopapillary, or irregular glandular architecture, whereas renal medullary carcinoma commonly demonstrated islands of anastomosing tubules and cords forming irregular microcystic spaces. Multiple metastases to the lymph nodes, lung, bone, and liver were observed in both categories at presentation (collecting duct carcinoma: 17%; renal medullary carcinoma: 36%). Only patients with organ-confined small tumors were disease free beyond the median survival time. Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma. The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma. The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification.

Epithelioid angiomyolipomas (perivascular epithelioid cell tumors) of the kidney are defined as potentially malignant mesenchymal lesions that are closely related to classic angiomyolipoma. Although approximately 120 cases are published, mostly as case reports with variably used diagnostic criteria, the pathologic prognostic predictors of outcome are unknown. We analyzed the clinicopathologic parameters in a large series of 41 cases of pure epithelioid angiomyolipomas of the kidney, which we designate as pure (monotypic) epithelioid PEComas to contrast them from classic angiomyolipomas that are regarded by some as PEComas. We use the terminology "pure" to separate these cases from those that may have variable epithelioid components. The mean age of the patients was 40.7 years (range, 14 to 68 y). The male-to-female ratio was 1:1. Seventy-nine percent of patients were symptomatic at presentation with metastatic disease at onset in 12 cases. Follow-up and/or disease progression information were available for 33 of 41 cases (mean, 44.5 mo and median, 24.5 mo; range, 4 to 240); 9 patients had a history of associated tuberous sclerosis. Recurrence and metastasis were seen in 17% and 49% of patients; 33% of patients died of disease. Lymph node involvement was seen in 24% of patients; the liver (63%), lung (25%), and mesentery (18.8%) were the most common metastatic sites. Clinicopathologic parameters associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis included associated tuberous sclerosis complex or concurrent angiomyolipoma (any metastasis, P=0.046), necrosis (metastasis at diagnosis, P=0.012), tumor size >7 cm (progression, P=0.021), extrarenal extension and/or renal vein involvement (progression, P=0.023), and carcinoma-like growth pattern (progression, P=0.040) (the 5 adverse prognostic parameters for pure epithelioid PEComas). Tumors with <2 adverse prognostic parameters (13 cases) were considered to be low risk for progression tumor, with 15% having disease progression. Tumors with 2 to 3 adverse prognostic parameters (14 cases) were considered to be "intermediate risk," with 64% having disease progression. Tumors with more than 4 or more adverse prognostic parameters (6 cases) were considered to be high risk, with all patients having disease progression. Of tumors with 3 or more adverse prognostic parameters, 80% had disease progression. An exact logistic regression analytic model showed that only carcinoma-like growth pattern and extrarenal extension and/or renal vein involvement were significant predictors of outcome (P=0.009 and 0.033, respectively). Our data of a large series with uniform definitional criteria confirm the malignant potential for pure epithelioid PEComas and provide adverse prognostic parameters for risk stratification in these patients.