Histopathological and Immunohistochemical Study of Acute Tubular Injury in Native Kidney Biopsy.

Background: Acute tubular injury (ATI) is a common diagnosis on renal biopsy. There are no accepted parameters to assess the severity of injury or predict recovery. An objective histologic grading system would be of immense value in clinical practice. The macrophage response to injury involves the MI phenotype which is proinflammatory and M2 which is prorepair. The study of these macrophages could aid in studying the severity and the recovery. Materials and Methods: A total of 58 native kidney biopsies with features of ATI and a minimum follow-up of 12 weeks were graded into mild, moderate and severe, using scores for simplification, sloughing, and mitosis. These scores and the density of macrophages stained with CD68, CD163, and HLA-DR were correlated with serum creatinine at presentation and with recovery. The effect of chronicity index as measured by glomerulosclerosis, tubular atrophy, and interstitial fibrosis and of co-morbidities of age, hypertension, and diabetes on the recovery pattern was also studied. Results: All three histologic scores and the grades of ATI showed positive correlation with the serum creatinine level. The densities of CD 68 + and CD163 + macrophages also showed a significant correlation with serum creatinine level. However, none of these these histological features nor the macrophage densities predicted clinical recovery. Age >60 years, hypertension, diabetes, and chronicity score on biopsy were indicators of partial and delayed recovery. Conclusion: The histopathological semiquantitative scoring system can be used routinely to grade ATI. However none of the studied parameters predicted recovery.

Glomerular Diameter Measurements on Light Microscopy: A New Parameter Available to Pathologists and its Utility in IgA Nephropathy.

Background: With the availability of whole slide digital scanners, fairly accurate glomerular diameter (GD) measurements are now possible on light microscopy. The value of these measurements in prognosis and diagnosis of immunoglobulin A nephropathy (IgAN) have not been studied widely. IgAN is a major cause of end-stage renal disease (ESRD) worldwide, and its progression is currently assessed using Oxford scores, serum creatinine, and 24-h urinary protein. We aimed to correlate the mean and maximum GDs with serum creatinine, 24-h urinary protein, and Oxford scores in patients with IgAN. Materials and Methods: One hundred biopsies of IgAN with a minimum of eight viable glomeruli were collected along with data of their 24-h proteinuria, serum creatinine, and Oxford scores. The slides were scanned using the Philips IntelliSite Pathology Solution-Ultra Fast Scanner. Mean GD of each glomerulus was calculated as the mean of two measurements, that is, the maximal diameter of the glomerulus and the maximal chord perpendicular to the maximal diameter. Maximum GD was also recorded for each case. The Spearman rho/Pearson R correlation coefficient was used to make this correlation. P-values <0.05 were considered statistically significant. Results: The mean age of the patients was 34.67 ± 12.03 years, and they showed a male preponderance. The overall mean GD was 151.82 ± 28.69 µm, and maximum GD was 205.40 ± 32.76 µm. No statistically significant correlation was observed between the mean or maximum GD and the 24-h proteinuria, serum creatinine levels, and Oxford scores. Conclusion: GD in IgAN does not correlate with proteinuria, serum creatinine, or Oxford scores.

Short stature and dysmorphic features in Asian Indian siblings with DAAM2-associated steroid-resistant nephrotic syndrome: Expansion of the phenotypic spectrum or a blended phenotype?

Variants in more than 60 different genes, most of which code for podocyte-related proteins, have been found to be associated with monogenic forms of nephrotic syndrome (NS). Biallelic variants in DAAM2, a member of the formin family, were recently identified to cause autosomal recessive (AR) NS type 24 in four unrelated families with steroid-resistant nephrotic syndrome (SRNS). This case report represents only the fifth reported family of DAAM2-associated NS and the first from India, with two sibs who presented with a complex phenotype characterized by steroid-resistant nephrotic syndrome, short stature, dysmorphic facial features, deep-set toenails, myopia, increased thickness of the calvarium of the skull, and sloping ribs. Both sibs were found to have a homozygous likely pathogenic nonsense variant c.196C>T (p.Arg66Ter; NM_001201427.2) in exon 3 of the DAAM2 gene through whole exome sequencing. The dysmorphic features could possibly be part of the DAAM2-related phenotype which has hitherto not been reported or could represent a blended phenotype, with the extrarenal manifestations resulting from a yet to be identified coexisting genetic condition.

Novel oncogenic transcriptional targets of mutant p53 in esophageal squamous cell carcinoma.

Missense mutations in the DNA binding domain of p53 are observed frequently in esophageal squamous cell carcinoma (ESCC). Recent studies have revealed the potentially oncogenic transcriptional networks regulated by mutant p53 proteins. However, majority of these studies have focused on common "hotspot" p53 mutations while rarer mutations are poorly characterized. In this study, we report the characterization of rare, "non-hotspot" p53 mutations from ESCC. In vitro tumorigenic assays performed following ectopic-expression of certain "non-hotspot" mutant p53 proteins caused enhancement of oncogenic properties in squamous carcinoma cell lines. Genome-wide transcript profiling of ESCC tumor samples stratified for p53 status, revealed several genes exhibiting elevated transcript levels in tumors harboring mutant p53. Of these, ARF6, C1QBP, and TRIM23 were studied further. Reverse transcription-quantitative PCR (RT-qPCR) performed on RNA isolated from ESCC tumors revealed significant correlation of TP53 transcript levels with those of the three target genes. Ectopic expression of wild-type and several mutant p53 forms followed by RT-qPCR, chromatin affinity-purification (ChAP), and promoter-luciferase assays indicated the exclusive recruitment of p53 mutants-P190T and P278L, to the target genes leading to the activation of expression. Several functional assays following knockdown of the target genes revealed a significant suppression of tumorigenicity in squamous carcinoma cell lines. Rescue experiments confirmed the specificity of the knockdown. The tumorigenic effects of the genes were confirmed in nude mice xenograft assays. This study has therefore identified novel oncogenic targets of "non-hotspot" mutant p53 proteins relevant for ESCC besides validating the functional heterogeneity of the spectrum of tumor-specific p53 mutations.

To study the expression of estrogen, progesterone receptor and p53 immunohistochemistry markers in subtyping endometrial carcinoma.

Background: Endometrial cancer is one of the most commonly diagnosed cancers in women worldwide. Aim and Objectives: To study the expression of estrogen receptor (ER), progesterone receptor (PR) and p53 immunohistochemistry (IHC) markers in subtyping endometrial carcinoma. Materials and Methods: A total of 100 cases of carcinoma endometrium submitted during January 2016 to October 2018 were included in our study. The ER, PR and p53 expressions were scored as per the adopted scoring system. Agreement between ER, PR and p53 IHC expression and the consensus HE diagnosis, FIGO grading and tumour staging were assessed using Chi square tests. Results: There was a statistical association between ER, PR and p53 status and tumour histologic type with a P value < 0.01. There was no statistical significance observed between ER and PR expressions and different FIGO grades. Statistical significance (P = 0.036) between p53 and different FIGO grades seen. No statistical significance was observed between ER, PR and p53 expressions and different tumour stages and tumour invasiveness. There was a statistical association between ER and PR status and lymph node metastasis. p53 did not show a statistical significance. Conclusion: Combination of ER, PR and p53 IHC markers can be used to distinguish type 1 and type 2 endometrial cancers. PR expression is more specific than ER in endometrioid carcinomas. p53 expression is more specific in serous carcinoma, however, p53 IHC alone cannot be used to distinguish different grades of endometrioid carcinomas as there is variability of staining in endometrioid carcinomas.

Successful Renal Transplant in Castleman Disease - First Case Report from India.

Castleman disease (CD) comprises a rare group of heterogenous benign lymphoproliferative disorders with pathologic similarities. However, they present with diverse clinical manifestations. Renal involvement is rare in CD and is mainly reported with plasma cell type of multicentric disease. Various glomerular pathologies, interstitial involvement, or thrombotic microangiopathies have all been reported, some of which progress to end-stage renal disease (ESRD). Progression of CD to ESRD is well documented; however, a patient on dialysis developing CD is rare. Moreover, kidney transplantations have seldom been performed on patients with CD. We report a patient with ESRD of unknown etiology who developed multicentric CD while on dialysis. He was treated with four doses of rituximab and later underwent a living kidney transplant with his wife as a donor. He has been clinically well ever since. We believe that this is possibly the first successful case of renal transplantation in CD with ESRD being reported from India.

A Study of Focal and Segmental Glomerulosclerosis according to the Columbia Classification and Its Correlation with the Clinical Outcome.

Introduction Focal and segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome in both adults and children. The "Columbia classification of FSGS" includes five variants; not otherwise specified (NOS), tip, perihilar, cellular, and collapsing variants that may have different prognostic and therapeutic implications. Materials and Methods This is a retrospective study and was carried out in the Department of Histopathology, Apollo Hospitals, Hyderabad. Of a total of 11,691 kidney biopsies over a 7-year period, from 2006 to 2012, 824 cases were diagnosed as FSGS, of which 610 cases in which detailed clinical findings were available were included in this study. FSGS was then categorized according to the Columbia classification. Results FSGS, NOS was the predominant histomorphological variant. Serum creatinine was significantly high in the collapsing variant, followed by NOS. Follow-up data was available for 103 cases,72.8% had complete remission, 10.6% had partial remission, and in 16.5 % there was no remission. Relapses were observed in 6.7% cases, two patients (1.9%) succumbed, and 4.8% cases progressed to chronic kidney disease. Conclusion This study showed that perihilar variant was less prevalent, with tip and cellular variants being more prevalent in Indian subcontinent compared to Western literature. Collapsing variant was also less common.

Proliferative Glomerulonephritis with Monoclonal Immunoglobulins in a Child with Recurrence in the Allograft.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is among the spectrum of monoclonal protein-associated renal diseases, with only about 15 case reports in children. We report a 7-year-old boy with biopsy-proven crescentic PGNMID who progressed to end-stage renal disease within a few months of presentation. He then received a renal transplant with his grandmother as a donor. Proteinuria was detected at 27 months post-transplant and an allograft biopsy revealed a recurrent disease.

Myoglobinuria-induced Acute Kidney Injury Secondary to CovishieldTM Vaccination.

Vaccination is the best strategy for the development of herd immunity and for the control of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. As the number of immunizations across the globe reaches a record number, random cases of diverse adverse effects of the vaccines are being documented. We report a case of renal biopsy-proven myoglobin-induced acute tubular injury requiring dialytic support post-CovishieldTM vaccination. Awareness of this rare complication is necessary so that it can be recognized early, and renal injury avoided.

Renal Lymphoma Diagnosed on Kidney Biopsy Presenting as Acute Kidney Injury.

Introduction: Renal manifestations associated with hematolymphoid malignancies are known. Primary or secondary involvement of the kidney by lymphomatous infiltration has various clinical presentations. Acute kidney injury is not an uncommon finding in relation to lymphomatous interstitial infiltration proven on kidney biopsy. However, diagnosing it solely on renal biopsy remains a challenge and needs expertise and aid of immunohistochemistry as the prognosis is dismal. Methods: This is a retrospective study of kidney biopsy-proven cases of renal lymphoma presenting with acute kidney injury. Results: The study included 12 patients with ages ranging from 4 to 50 years who presented with serum creatinine ranging 2.1-9.6 mg%. Renal biopsy findings showed interstitial lymphomatous infiltrate. Two cases were diagnosed as primary lymphoma and the other 10 as secondary lymphomas. Among the 12 cases, nine were B-cell non-Hodgkin lymphoma, of which diffuse large B-cell lymphoma was diagnosed in six (50%), low-grade B-cell type in two (16.6%), chronic lymphocytic leukemia in one (8.3%), and three were T-cell-type. Two were acute T-cell lymphoblastic lymphoma and one other was a high-grade T-cell lymphoma. Four patients succumbed. The other four patients are alive; one is on chemotherapy, while two of them are on hemodialysis. Conclusion: Acute kidney injury as a presenting feature with lymphomatous infiltration of renal parenchyma is not uncommon. The patchy involvement makes it challenging on kidney biopsy with definitive diagnosis being made with the help of immunohistochemistry. Appropriate multidisciplinary involvement improves patient outcome.

Fetal sepsis: a cause of stillbirth.

Infection is considered a leading cause of fetal death, responsible for approximately 20% of cases. Such estimates are derived from the frequency of acute histological chorioamnionitis and funisitis in cases of fetal death rather than direct detection of microorganisms in the fetal compartment. We report a case of clinically unexplained fetal death at 38 weeks of gestation in an uncomplicated pregnancy resulting in delivery of an appropriate-for-gestational-age fetus. The mother did not have any clinical signs of infection. Overwhelming bacterial invasion in multiple fetal organs, including the heart, liver, spleen, and kidneys, was observed despite the lack of evidence of maternal clinical infection. The bacteria were visualized by using standard histologic techniques (e.g. H&E/ tissue Gram stain) highlighting the value of autopsy in determining the cause of death.

Whole slide imaging vs eyeballing: The future in quantification of tubular atrophy in routine clinical practice.

Introduction: Histologic assessment of interstitial fibrosis and tubular atrophy is an accepted method of assessing chronic damage to the kidney and correlates with renal function in native and allograft renal biopsies. The challenge, however, is to quantify the interstitial fibrosis and tubular atrophy with accuracy and to minimize the inter-observer variability. Though "eyeballing" on light microscopy is the most commonly practised method used for the quantification of tubular atrophy, it may not be very accurate. To complement this method, Whole Slide Imaging (WSI) techniques that have more accurate results and have a higher reproducibility can be used. There is not much data on the correlation of the results obtained by the 'eyeballing' technique with those by digital WSI. Methods: Tubular atrophy in 151 consecutive adequate native kidney biopsies were graded 0 to III by 'conventional' eyeballing by a single experienced renal pathologist. These results were compared with the grades obtained on the same cases by WSI and digital marking of the atrophy. Results: The concordance of the two groups in the entire cohort was only 66.2% with over grading in 30.4% and under grading in 3.3%. Whilst accuracy of grading was over 74% in all grades, the sensitivity in grades I and II were low at 52% and 47.3% respectively as was the positive predictive value at 32.5 and 44% respectively. Conclusion: Assessment of tubular atrophy on digital images will be the way forward for accurate quantification.

Banff Classification from 1991 to 2019. A Significant Contribution to Our Understanding and Reporting of Allograft Renal Biopsies.

The Banff schema of classification of renal allograft biopsies, first proposed at the meeting in Banff, Canada in 1991 has evolved through subsequent meetings held once in two years and is the internationally accepted scheme of classification which is consensual, current, validated and in clinical use. This review traces the evolution of the classification and our understanding of renal transplant pathology, with emphasis on alloimmune reactions. The proceedings of the meetings and the important studies which have shaped the classification are covered.

Intravascular large B cell lymphoma of prostate, a rare entity.

Intravascular large B cell lymphoma is a rare type of extranodal lymphoma characterized by selective growth of neoplastic cells in small vessels, especially capillaries, sparing larger arteries, veins and surrounding tissue. The absence of intravascular lymphoma in the traditional sites and difference in mode of presentation with no mass forming lesion as compared to other lymphomas, makes it unique and difficult to diagnose early. It is extremely heterogeneous in its clinical presentation depending on the organ involved. Primary intravascular large B cell lymphoma of the prostate is extremely rare and only 8 cases have been reported in English literature till date, limited to single case reports. This is a rare case of a 76 year old male patient, who came with complaints of urinary obstruction and fever of unknown origin since 15 days. Routine investigations were within normal limits including the complete urine examination, complete blood picture and PSA levels. Mild prostatomegaly was noted on radiology. Patient was catheterized and transurethral resection was done. On histopathological examination, prostatic acini and stroma were normal but the vessels in the stroma which were dilated and thin walled lacking a muscular coat, showed sheets of loosely cohesive cells with moderate eosinophilic to clear cytoplasm, vesicular nuclei, with 1 to 3 prominent nucleoli and mitoses, averaging 4-6/hpf. On immunohistochemistry, the tumor cells were positive for CD 20 and MUM 1 with high MIB1 index of about 90% and were negative for CD3, CD10, Bcl6, PSA, P63, CK7, CK20, HMWCK, and Pancytokeratin. CD31 stained and highlighted the endothelial cells of the vessels. Final diagnosis made after correlating light microscopy and immunohistochemistry was a Primary Intravascular large B-cell lymphoma of the prostate.

A Novel Glomerular C4d Scoring System: A Tool to Prognosticate Proliferative Exudative Pattern of Glomerular Injury.

AIM: Proliferative exudative pattern of glomerular injury is usually a manifestation of an infection related or a post-infectious glomerulonephritis (PIGN). Rarely, it may represent a C3 glomerulopathy, which is a dysfunction of the alternative pathway of complement activation, and is then termed an atypical PIGN (aPIGN). C4d deposits in the glomerulus are footprints of the classical and/or lectin pathway of complement activation and hence is expected to be positive in immune-mediated glomerulonephritis (GN) like classical infection-related GN, and could be used to differentiate classical PIGN from atypical PIGN. MATERIALS AND METHODS: We report a novel C4d scoring system based on the intensity and the proportion of glomerular tuft staining, in a series of 104 biopsies with the proliferative exudative pattern of glomerular injury. Using a statistically derived cut-off score of 1.45, the cases were divided into C4d positive and C4d negative groups and compared to IF findings and the follow-up, available in 36 cases. RESULTS: The C4d positive group had a significantly greater proportion of cases with immune complexes compared to the group with C3 deposits alone. In the follow-up, C4d negative group had also a greater number with partial/incomplete response compared to the C4d positive group. CONCLUSIONS: We recommend that the C4d stain be done in all cases with a proliferative exudative pattern of glomerular injury to identify patients who would need a close follow up and further assays of complement function.

Anti-glomerular Basement Membrane Disease with Atypical Associations.

Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating immunoglobulin (Ig) G antibodies to carboxy-terminal, noncollagenous 1 domain of type IV collagen of GBM. Patients typically present with rapidly progressive glomerulonephritis and pulmonary hemorrhage. Anti-GBM disease has been reported to coexist with pauci-immune antineutrophil cytoplasmic autoantibody-positive glomerulonephritis and membranous glomerulopathy. The presentation of anti-GBM disease with thrombotic microangiopathy (TMA) and IgA nephropathy has been rarely described. We herein report two cases of anti-GBM antibody disease, both with crescentic glomerulonephritis and peripheral linear deposits of IgG, one case with clinical and histological findings of associated TMA and other with findings of extensive mesangial IgA deposits. Both the patients were treated with corticosteroid, intravenous cyclophosphamide, and plasma exchange but had poor renal recovery. Association of anti-GBM disease with TMA or IgA nephropathy could open up new pathogenetic mechanism and may help us to prognosticate anti-GBM disease.