Podocyte Infolding Glomerulopathy (PIG) in a Patient With Undifferentiated Connective Tissue Disease: A Case Report.

Podocyte infolding glomerulopathy (PIG) is a recently described pathologic entity characterized by diffuse podocyte infolding into the glomerular basement membrane (GBM) associated with ultrastructurally demonstrable microspherular aggregates. The clinical features, significance, and pathogenesis of this condition are still not well delineated because only a few cases have been documented to date, all from Japan. We report a case of PIG associated with undifferentiated connective tissue disease in an Indian woman who presented with nephrotic syndrome while undergoing treatment for an autoimmune disorder. Ultrastructural analysis of the kidney biopsy specimen revealed unusual subepithelial aggregates of microspherules admixed with few microtubules alongside extensive infolding of podocyte foot processes into the underlying GBMs. Characteristic clustering of these microparticles near the invaginated tips of podocyte foot processes in the GBM was observed on transmission electron microscopy. The patient's clinical condition responded favorably to immunosuppressive therapy. The clinical, light microscopic, and diagnostic electron microscopic features of this condition are highlighted in this report in an attempt to contribute some insights into the possible pathogenetic mechanisms of this obscure entity.

Cancer stem cells in hepatocellular carcinoma--an immunohistochemical study with histopathological association.

BACKGROUND & OBJECTIVES: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection. METHODS: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour. RESULTS: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other ( P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC. INTERPRETATION & CONCLUSIONS: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs.

Podocyte Infolding Glomerulopathy Masquerading as Membranous Nephropathy - A Shared Pathogenesis?

Podocyte infolding glomerulopathy (PIG) is a rare pathological entity, diagnosed by electron microscopic demonstration of diffuse infolding of the podocytes into the glomerular basement membranes. We report the first case from United Kingdom exhibiting typical ultrastructural features of PIG in a male with Type II diabetes mellitus, hypertension and common variable immune deficiency. Renal biopsy revealed phospholipase A2 receptor (PLA2R) immunostain positive membranous nephropathy (MN) but no serum PLA2R antibodies. Diffuse infolding of the podocytes into the glomerular basement membranes along with pathognomonic microspherular and microtubular intra basement membrane clusters distributed diffusely and globally were noted on electron microscopy, diagnostic of PIG. We postulate a shared pathomechanistic link between PIG and MN, highlighting the overlapping features of both conditions.

Crystals, crystals everywhere but not a clue till late Light chain crystalline proximal tubulopathy with concomitant myeloma cast nephropathy.

The renal diseases commonly associated with myeloma include primary amyloidosis, cast nephropathy, and light chain deposition disease. Less frequent forms of renal involvement encountered in the course of myeloma are crystalline and non-crystalline proximal tubulopathies, neoplastic plasma cell infiltration, and immunoglobulin crystallization in interstitial histiocytes and glomerular cells including podocytes. Light chain proximal tubulopathy (LCPT) caused by aggregation of non-crystalline and rarely crystalline deposits of monoclonal light chains in the cytoplasm of proximal tubular epithelial cells, accounts for less than 5% of monoclonal gammopathy-associated kidney diseases. We report the case of a 48-year-old Indian woman with multiple myeloma, who presented with acute kidney injury and nephrotic syndrome, in whom the renal biopsy revealed widespread crystalline inclusions in extraglomerular and glomerular compartments. We present illustrative light microscopic (LM) and diagnostic electron microscopic (EM) findings of this case which enabled a diagnosis of crystalline LCPT, crystal storing histiocytosis, and crystalline podocytopathy occurring synchronously with myeloma cast nephropathy. While documenting this unique juxtapositioning of multicompartmental paraproteinemic renal injury in multiple myeloma, diagnosed after EM analysis of the patient's renal biopsy, we discuss the pathogenetic pathways of this condition along with the clinical implications. Due to intrinsic structural properties of the crystals, they frequently escape detection by routine LM, necessitating EM analysis for their diagnosis. Given the prognostic implications of tubulopathies complicating myeloma, LCPT is a critically important diagnosis, highlighting the need for a comprehensive renal biopsy evaluation inclusive of EM for the practice of precision medicine in such scenarios.

Collagenofibrotic glomerulopathy - A rare disease diagnosed with the aid of transmission electron microscopy.

Collagenofibrotic glomerulopathy (CFG) is a rare idiopathic kidney disease characterized by abnormal deposition of atypical Type III collagen fibers in the glomerulus causing subendothelial and mesangial expansion, manifesting as progressive renal dysfunction accompanied by proteinuria. The majority of CFG cases reported in literature are from Japan where this disease entity was initially recognized. There is an increased awareness and diagnosis of this rare renal disease in India with the recent increase in utilization of electron microscopy (EM) in clinical diagnostic settings. We describe a 28-year-old Bangladeshi woman who presented with hypertension and nephrotic range proteinuria not amenable to treatment with steroids and cyclophosphamide, whose renal biopsy demonstrated diagnostic ultrastructural features of CFG. This illustrative case is presented to highlight the role of EM analysis for diagnostic accuracy in renal biopsy evaluation in addition to demonstrating the unusual renal biopsy findings of this rare entity.

Nephropathic cystinosis presenting with uveitis: Report of a "Can't See, Can't Pee" situation.

Nephropathic cystinosis is a rare autosomal recessive lysosomal disease characterized by accumulation of pathognomonic cystine crystals in renal and other tissues of the body. Cystinosis is caused by mutant cystinosin, the cystine transport protein located in lysosomal membranes, leading to systemic deposits of cystine and resultant end organ damage. Cystinosis is rarer in Asians than Caucasians with only a handful of cases reported from India to date. Due to its extreme rarity and clinically insidious presentation in contrast to the infantile form, the diagnosis of juvenile nephropathic cystinosis is frequently delayed or overlooked. Moreover, routine processing and sectioning of paraffin embedded tissues dissolves cystine crystals, making it difficult to diagnose this condition on light microscopic examination alone, mandating electron microscopic (EM) analysis of renal biopsies for an accurate diagnosis of this condition. We describe a case of juvenile nephropathic cystinosis presenting with uveitis and photophobia in a 17-year-old Indian male, diagnosed after EM examination of the patient's renal biopsy for evaluation of nephrotic syndrome. While highlighting the diagnostic utility of EM, we describe a few histopathologic clues which can prompt inclusion of EM analysis of renal biopsies in this setting.

Fibrillary glomerulonephritis in a human immunodeficiency virus-positive, hepatitis C-negative Indian patient: Expanding the profile of renal involvement in human immunodeficiency virus infection.

Highly active anti retroviral therapy (HAART) has dramatically improved life expectancy of human immunodeficiency virus (HIV) infected patients, converting HIV infection into a chronic illness with associated changes in its attendant renal complications. The past two decades have witnessed a decrease in the prevalence of HIV associated nephropathy (HIVAN), traditionally considered to be the hall mark of renal involvement in HIV infection. Simultaneously a host of other glomerular and tubulo-interstitial diseases have emerged, expanding the spectrum of HIV associated renal diseases, predominant among which is HIV associated immune complex mediated kidney diseases (HIVICK). Of the diverse glomerular diseases constituting HIVICK, fibrillary glomerulonephritis (FGN) remains a rarity, with only two existing reports to date, confined to patients co-infected with Hepatitis C virus (HCV). The pathogenetic role of HIV in these patients remains under a cloud because of previously well established association of HCV infection and FGN. We report a case of FGN in a HIV seropositive, HCV negative Indian patient, highlighting the diagnostic electron microscopy (EM) findings of FGN and strengthening the causal association of HIV with FGN. In view of increasing heterogeneity of renal complications in HIV infection, the diagnostic utility of a comprehensive renal biopsy evaluation inclusive of EM is emphasized for appropriate selection of treatment modalities.

Unmasking and successful management of light chain deposition disease of kidney in pregnancy: a complex case, mirroring the complex needs of pregnancy with kidney disease in India.

Pregnancy offers a precious window of opportunity to diagnose previously undetected or new onset kidney diseases in emerging countries like India, where access to medical, educational and health care facilities are not equitably distributed across varied sections of society. We report a case of a 33 year-old primi gravida who had a successful pregnancy following what was initially considered to represent preeclampsia at 38 weeks of gestation, in whom a subsequent kidney biopsy for persistence of pregnancy-related acute kidney injury (Pr-AKI) revealed light chain deposition disease (LCDD). The etiological evaluation of LCDD led to the detection of an underlying plasma cell dyscrasia which was treated effectively with chemotherapy and autologous stem cell transplant. In this report, we explore the hitherto uncharted pathophysiological relationship between LCDD and pregnancy-related kidney injury by transmission electron microscopic (TEM) studies of endothelial injury in this setting, and underscore the benefits of medical care in a multidisciplinary environment which yielded gratifying results in preservation of maternal kidney health and fetal outcome.

Protocol and rationale for the first South Asian 5-year prospective longitudinal observational cohort study and biomarker evaluation investigating the clinical course and risk profile of IgA nephropathy: GRACE IgANI cohort.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney disease. Unlike the slowly progressive course seen among Caucasian and East Asian subjects (actuarial survival 80-85% over 10 years), in India about 30-40% of patients have nephrotic syndrome and renal dysfunction at presentation and a 10-year renal survival of 35%, as reported from a retrospective registry. These observations cannot be entirely attributed to a lack of uniform screening protocols or late referral and attest to the probability that IgAN may not be the same disease in different parts of the world. Methods: We will prospectively recruit 200 patients with IgAN (the GRACE IgANI- Glomerular Research And Clinical Experiments- Ig A Nephropathy in Indians-cohort) and stratify them into low and high risk of progression based on published absolute renal risk scores. We will test the validity of this risk score in an unselected Indian IgAN population over a 5-year follow-up period. In parallel, we will undertake extensive exploratory serum, urine, renal and microbiome biomarker studies, firstly, to determine if the underlying pathogenic pathways are the same in Indian IgAN compared to those reported in Caucasian and East Asian IgAN. Secondly, we will systematically assess the value of measuring selected biomarkers and adding this data to traditional measures of risk in IgAN to predict kidney failure. We ultimately hope to generate a composite IgAN risk score specific for the Indian population. Ethics and data dissemination: Approval was obtained from the Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College, Vellore, India (Ref. No. IRB Min. No. 8962 [Other] dated 23.07.2014 and IRB Min. No. 9481 [Other] dated 24.06.2015). It is anticipated that results of this study will be presented at national and international meetings, with reports being published from late 2018.

Immunoglobulin G4-related tubulointerstitial nephritis: A not to be missed diagnosis.

Immunoglobulin G4-related tubulointerstitial nephritis (IgG4-TIN) is a newly recognized clinicopathological entity characterized by a dense interstitial infiltrate of IgG4-positive plasma cells accompanied by fibrosis and obliterative phlebitis causing acute or chronic renal dysfunction amenable to corticosteroid therapy. IgG4-TIN is the dominant manifestation of renal involvement in IgG4-related disease (IgG4-RD) which is a novel, immune-mediated, fibroinflammatory and multiorgan disorder. We describe a case of IgG4-TIN with isolated renal involvement in an elderly male patient with poor response to corticosteroid therapy. The distinctive serological, histopathological, and ultrastructural features of this condition which can facilitate differential diagnosis of TIN are highlighted to emphasize the need for early diagnosis and preservation of kidney function.

Aspiration cytology of sarcomatoid carcinoma of the breast: Report of a case with cystic change.

Sarcomatoid/metaplastic carcinomas of the breast are rare breast malignancies that show a myriad of cytohistologic patterns in aspirates. These poorly differentiated invasive carcinomas contain both ductal and mesenchymal elements with transitional forms displaying either spindle, squamous, chondroid, or osseous differentiation. We describe such a neoplasm in a 68-yr-old woman, the diagnosis of which was missed at the initial fine-needle aspiration (FNA) due to cystic change. Extensive cystic change in a sarcomatoid carcinoma is unusual and is reported for the first time in the English literature.

Diagnostic value of eosinophils in pleural effusion: a prospective study of 26 cases.

Eosinophilic pleural effusions (EPFs), defined as the presence of 10% or more eosinophils in the pleural fluid, are relatively rare. Their diagnostic and prognostic significance, however, remains controversial, as most of the studies are based almost entirely on retrospective case studies. This prospective study examines 26 eosinophilic pleural effusions from among 444 consecutive pleural effusions investigated at this tertiary health care center from October 1999 to April 2002. This study was attempted to unravel the diagnostic and prognostic significance of these eosinophilic effusions and assess their clinical implications, if any. Koss and Light's criteria were applied in the analysis, which comprised macroscopic, biochemical, cytological, and microbiological examinations. Of the 26 EPFs studied, five were associated with tuberculosis and three with metastatic disease. Nineteen patients had significant associated lymphocytosis. Twenty-four patients have been followed up and are in good health to date and have had no recurrence of effusion. Thus, EPF could be associated with inflammatory, benign, and malignant conditions. Hence, a closer search for a definite etiological agent is warranted in the setting of such an effusion, especially in populations endemic for tuberculosis, as in a developing country like India and in populations with a high prevalence of malignancy.

Cancer stem cells in hepatocellular carcinoma - an immuno- histochemical study with histopathological association.

Background & objectives: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection. Methods: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour. Results: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other (P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC. Interpretation & conclusions: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs.