Vivek Charu

All Publications

• Analysis of Sampling Bias in Large Health Care Claims Databases. JAMA network open Dahlen, A., Charu, V. 2023; 6 (1): e2249804

  Abstract

  This cross-sectional study characterizes variation in sampling in a large health care claims database at the zip code level in 2018 and assesses whether socioeconomic and demographic factors are associated with inclusion.

  View details for DOI 10.1001/jamanetworkopen.2022.49804

  View details for PubMedID 36607640

• A COL4A4-G394S Variant and Impaired Collagen IV Trimerization in a Patient with Mild Alport Syndrome KIDNEY360 Kohler, J., Omachi, K., Charu, V., Miner, J. H., Bhalla, V. 2022; 3 (11): 1899-1908

  Abstract

  Missense variants in COL4A genes are often found in patients with an Alport syndrome-like presentation, but their pathogenicity is not always clear. We encountered a woman with microscopic hematuria and proteinuria at 33 years of age with a diagnosis of thin basement membrane disease who was approaching end stage kidney disease at 59 years of age. We hypothesized that this patient's kidney disease was within the spectrum of Alport syndrome.We used histologic, genetic, and biochemical approaches to investigate the mechanisms of kidney disease. By immunofluorescence, we investigated collagen IV chain composition of the glomerular basement membrane (GBM). We employed targeted sequencing to search for pathogenic variants in COL4A and other relevant genes. We utilized N- and C-terminal split NanoLuciferase assays to determine the effect of a novel COL4A4 variant of uncertain significance (VUS) on collagen IV heterotrimer formation in vitro. We transfected COL4A4 expression constructs with split NanoLuciferase fragment-fused COL4A3 and COL4A5 constructs into human embryonic kidney 293T cells. To assay for α3α4α5(IV) heterotrimer formation and secretion, we measured luminescence in cell lysates and culture supernatants from transfected cells.Immunostaining suggested that the collagen α3α4α5(IV) network was present throughout the patient's GBMs. DNA sequencing revealed a novel homozygous VUS: COL4A4 c.1180G>A (p. Gly394Ser). In the C-terminal split luciferase-based α3α4α5(IV) heterotrimer formation assays, luminescence levels for G394S were comparable to WT, but in the N-terminal tag assays, the extracellular luminescence levels for G394S were decreased by approximately 50% compared with WT.Our cell-based assay provides a platform to test COL4 VUS and shows that G394S impairs assembly of the α3α4α5(IV) N-terminus and subsequent trimer secretion. These data suggest that the COL4A4-G394S variant is pathogenic and causes an atypical mild form of autosomal recessive Alport syndrome.

  View details for DOI 10.34067/KID.0005472022

  View details for Web of Science ID 000889087100013

  View details for PubMedID 36514391

  View details for PubMedCentralID PMC9717634

• Novel CLC-Kb pore mutation associated with defective glycosylation and renal tubulopathy Sharma, Y., Dong, W., Liao, X., Venkataraman, A., Qiao, Y., Francisco, C. V., Maduke, M., Charu, V., Kambham, N., Pochynyuk, O., Govaerts, C., Bhalla, V. OXFORD UNIV PRESS INC. 2022: 1026-1027

  View details for Web of Science ID 000878249700143

• CALIBRATION OF WAITLIST SURVIVAL PREDICTION BY MELD 3.0 IN THE PANDEMIC ERA Wu, W., Chung, N., Vidovszky, A., Mannalithara, A., Melcher, M., Charu, V., Kwong, A. J., Kim, W. WILEY. 2022: S76-S77

  View details for Web of Science ID 000870796600087

• THE WAIST-TO-HIP RATIO ADDS LITTLE TO THE STEATOSIS-ASSOCIATED FIBROSIS ESTIMATOR (SAFE) SCORE IN PREDICTING SIGNIFICANT FIBROSIS AMONG PATIENTS WITH NAFLD Sripongpun, P., Charu, V., Kim, S. H., Kim, W. WILEY. 2022: S792-S793

  View details for Web of Science ID 000870796602258

• MELD 3.0 AS A PREDICTOR OF POST-TRANSPLANT OUTCOMES IN THE COVID ERA Chung, N., Wu, W., Kwong, A. J., Charu, V., Mannalithara, A., Melcher, M., Kim, W. WILEY. 2022: S77-S78

  View details for Web of Science ID 000870796600088

• SPATIAL MULTI-OMIC IMMUNE PROFILING AND FUNCTIONAL CHARACTERIZATION OF HEPATOCELLULAR CARCINOMA (HCC) REVEAL MECHANISMS OF MINIMAL RESIDUAL DISEASE (MRD) Suresh, A., Adeniji, N., Lemaitre, L., Charu, V., Dhanasekaran, R. WILEY. 2022: S1278

  View details for Web of Science ID 000870796604097

• ELEVATED SERUM ALKALINE PHOSPHATASE AS A MARKER OF A DISTINCT PHENOTYPE OF NON-ALCOHOLIC FATTY LIVER DISEASE Sripongpun, P., Charu, V., Kwo, P., Goel, A., Torok, N. J., Kim, W. WILEY. 2022: S866

  View details for Web of Science ID 000870796602357

• Environmental Pollutants are Associated with Irritable Bowel Syndrome in a Commercially Insured Cohort of California Residents. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Okafor, P. N., Dahlen, A., Youssef, M., Olayode, A., Sonu, I., Neshatian, L., Nguyen, L., Charu, V. 2022

  Abstract

  BACKGROUND AND AIMS: Prior studies have linked environmental pollutants with gastrointestinal (GI) diseases. Here, we quantify the relationships between seven pollutants and the zip code-level incidence of irritable bowel syndrome (IBS), functional dyspepsia (FD), inflammatory bowel diseases (IBD), and eosinophilic esophagitis (EoE) in California.METHODS: Claims in Optum's Clinformatics Data Mart (CDM) were linked with environmental exposures in California, derived from CalEnviroScreen 3.0. We identified adult patients with new diagnoses of each GI disease, and estimated claims-derived, zip-code level disease incidence rates. Two study periods were considered: 2009-2014 (ICD-9 era) and 2016-2019 (ICD-10 era). Multivariable negative binomial regression models were used to test associations between seven pollutants (ozone, particulate matter <2.5 microns [PM2.5], diesel emissions, drinking water contaminants, pesticides, toxic releases from industrial facilities, traffic density) and zip-code level incidence of the GI diseases along with a negative control outcome, adjusting for numerous potential confounders.RESULTS: Zip code-level IBS incidence was associated with PM2.5 (p<0.001 in both eras) and airborne toxic releases from facilities (p<0.001 in both eras). An increase of 1 microgram/m3 in PM2.5 or 1% in toxic releases translates to an increase in the IBS incidence rate of about 0.02 cases per 100 person-years. Traffic density and drinking water contaminant exposures were also associated with increasing IBS incidence, but these associations were not significant in both eras. Similarly, exposure to PM2.5, drinking water contaminants and airborne toxic releases from facilities were associated with FD incidence, though not in both eras. No significant associations were noted between pollutants and IBD or EoE incidence.CONCLUSION: Exposure to PM2.5 and airborne toxic releases from facilities are associated with higher IBS incidence among a cohort of commercially-insured Californians. Environmental pollutant exposure was not associated with the incidence of IBD and EoE in this cohort.

  View details for DOI 10.1016/j.cgh.2022.09.025

  View details for PubMedID 36202347

• The Utilization of Packed Red Blood Cell Transfusion and Angiography in Pediatric Inpatients after Kidney Biopsy in the United States. Kidney360 Afolabi, H., O'Shaughnessy, M. M., Charu, V. 2022; 3 (8): 1423-1426

  Abstract

  This article contains the largest analysis of pRBC transfusion and renal angiogram in inpatient pediatric patients.We provide accurate estimates of rates of pRBC transfusion and renal angiography after kidney biopsy in inpatient pediatric patients.

  View details for DOI 10.34067/KID.0000022022

  View details for PubMedID 36176649

  View details for PubMedCentralID PMC9416840

• Performance of the Steatosis-Associated Fibrosis Estimator (SAFE) to predict F2 fibrosis and higher in a cohort of South Korean patients with non-alcoholic fatty liver disease (NAFLD) Charu, V., Kwong, A., Mannalithara, A., Yoon, E., Jun, D., Kim, W. ELSEVIER. 2022: S462

  View details for Web of Science ID 000826275102252

• The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (New York, N.Y.) Jones, R. C., Karkanias, J., Krasnow, M. A., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Pisco, A. O., Tan, S. Y., Travaglini, K. J., Xu, C., Alcántara-Hernández, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Crasta, S., Culver, R. N., Cvijović, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kolluru, S., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W. J., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Morri, M., Mrouj, K., Mukherjee, S., Muser, T., Neuhöfer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Pisco, A. O., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L. C., Subramaniam, V. R., Swarup, A., Swift, M., Travaglini, K. J., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgó, E., Martin, B. A., Ozawa, M. G., Silva, O., Tan, S. Y., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Detweiler, A. M., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., de Morree, A., Olivieri, J. E., Park, M., Pisco, A. O., Ravikumar, N., Salzman, J., Stanley, G., Swift, M., Tan, M., Tan, W., Tarashansky, A. J., Vanheusden, R., Vorperian, S. K., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Alcántara-Hernández, M., Antony, J., Chan, C. K., Chang, C. A., Colville, A., Crasta, S., Culver, R., Dethlefsen, L., Ezran, C., Gillich, A., Hang, Y., Ho, P. Y., Irwin, J. C., Jang, S., Kershner, A. M., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Liu, S., Loeb, G. B., Lu, W. J., Maltzman, J. S., Metzger, R. J., de Morree, A., Neuhöfer, P., Perez, K., Phansalkar, R., Qi, Z., Rao, P., Raquer-McKay, H., Sasagawa, K., Scott, B., Sinha, R., Song, H., Spencer, S. P., Swarup, A., Swift, M., Travaglini, K. J., Trimm, E., Veizades, S., Vijayakumar, S., Wang, B., Wang, W., Winkler, J., Xie, J., Yung, A. R., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Krasnow, M., Kuo, C. S., Nguyen, P., Quake, S. R., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wang, B., Wu, A., Wu, S. M., Wyss-Coray, T. 2022; 376 (6594): eabl4896

  Abstract

  Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

  View details for DOI 10.1126/science.abl4896

  View details for PubMedID 35549404

• The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk non-alcoholic fatty liver disease in primary care. Hepatology (Baltimore, Md.) Sripongpun, P., Kim, W. R., Mannalithara, A., Charu, V., Vidovszky, A., Asch, S., Desai, M., Kim, S. H., Kwong, A. J. 2022

  Abstract

  Non-alcoholic fatty liver disease (NAFLD) is common in primary care. Liver fibrosis stage 2 or higher (≥F2) increases future risk of morbidity and mortality. We developed and validated a score to aid in the initial assessment of liver fibrosis for NAFLD in primary care.Biopsy-proven NAFLD patients' data were extracted from the 'NASH CRN' observational study (n = 676). Using logistic regression and machine-learning methods, we constructed prediction models to distinguish ≥F2 from F0/1. The models were tested in participants in a trial ('FLINT', n = 280) and local NAFLD patients with magnetic resonance elastography data (n = 130). The final model was applied to examinees in the National Health and Nutrition Examination Survey III (NHANES, n = 11,953) to correlate with longterm mortality.A multivariable logistic regression model was selected as the Steatosis-Associated Fibrosis Estimator (SAFE) score, which consists of age, body mass index, diabetes, platelets, aspartate and alanine aminotransferases and globulins (total serum protein minus albumin). The model yielded areas under receiver operating characteristic curves ≥0.80 in distinguishing F0/1 from ≥F2 in testing datasets, consistently higher than those of FIB-4 and NAFLD Fibrosis Scores. The negative predictive values in ruling out ≥F2 at SAFE of 0 were 88% and 92% in the two testing sets. In the NHANES III set, survival up to 25 years of subjects with SAFE <0 was comparable to that of those without steatosis (p = 0.34), while increasing SAFE scores correlated with shorter survival with an adjusted hazard ratio of 1.54 (p < 0.01) for subjects with SAFE>100.The SAFE score, which uses widely available variables to estimate liver fibrosis in patients diagnosed with NAFLD, may be used in primary care to recognize low-risk NAFLD.

  View details for DOI 10.1002/hep.32545

  View details for PubMedID 35477908

• Publisher Correction: Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s41587-022-01293-3

  View details for PubMedID 35347330

• Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population. Pediatric nephrology (Berlin, Germany) Miller, P., Lei, L., Charu, V., Higgins, J., Troxell, M., Kambham, N. 2022

  Abstract

  BACKGROUND: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics.METHODS: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed.RESULTS: Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R- (1), NELL1 (1),EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R- adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission.CONCLUSION: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information.

  View details for DOI 10.1007/s00467-022-05503-7

  View details for PubMedID 35333973

• Complement-Binding Donor-Specific Anti-HLA Antibodies: Biomarker for Immunologic Risk Stratification in Pediatric Kidney Transplantation Recipients. Transplant international : official journal of the European Society for Organ Transplantation Sigurjonsdottir, V. K., Purington, N., Chaudhuri, A., Zhang, B. M., Fernandez-Vina, M., Palsson, R., Kambham, N., Charu, V., Piburn, K., Maestretti, L., Shah, A., Gallo, A., Concepcion, W., Grimm, P. C. 2022; 35: 10158

  Abstract

  Antibody-mediated rejection is a common cause of early kidney allograft loss but the specifics of antibody measurement, therapies and endpoints have not been universally defined. In this retrospective study, we assessed the performance of risk stratification using systematic donor-specific antibody (DSA) monitoring. Included in the study were children who underwent kidney transplantation between January 1, 2010 and March 1, 2018 at Stanford, with at least 12-months follow-up. A total of 233 patients were included with a mean follow-up time of 45 (range, 9-108) months. Median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. Fifty-two (22%) formed C1q-binding de novo donor-specific antibodies (C1q-dnDSA). After a standardized augmented immunosuppressive protocol was implemented, C1q-dnDSA disappeared in 31 (58.5%). Graft failure occurred in 16 patients at a median of 54 (range, 5-83) months, of whom 14 formed dnDSA. The 14 patients who lost their graft due to rejection, all had persistent C1q-dnDSA. C1q-binding status improved the individual risk assessment, with persistent; C1q binding yielding the strongest independent association of graft failure (hazard ratio, 45.5; 95% confidence interval, 11.7-177.4). C1q-dnDSA is more useful than standard dnDSA as a noninvasive biomarker for identifying patients at the highest risk of graft failure.

  View details for DOI 10.3389/ti.2021.10158

  View details for PubMedID 35992747

  View details for PubMedCentralID PMC9386741

• EXT1 and NCAM1-associated membranous lupus nephritis in a cohort of patients undergoing repeat kidney biopsies. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Miller, P. P., Caza, T., Larsen, C. P., Charu, V. 2022

  Abstract

  BACKGROUND: EXT1/2 and NCAM1 associated membranous lupus nephritis (MLN) may represent distinct disease phenotypes with prognostic significance.METHODS: We searched our archives for patients with systemic lupus erythematous (SLE) and at least two kidney biopsies demonstrating MLN. Each biopsy was stained for EXT1 and NCAM1 and scored as positive or negative. Histopathologic and clinical data were reviewed.RESULTS: We identified 31 patients with a clinical diagnosis of SLE and at least two kidney biopsies with MLN. 28 patients (90%) showed concordant staining for EXT1 and NCAM1 in both biopsies; 8 (26%) patients were EXT1-positive and NCAM1-negative, 18 (58%) patients were EXT1-negative and NCAM1-negative, and 2 (7%) patients were EXT1-negative and NCAM1-positive. Three patients (10%) had discordant EXT1 staining between their first and last biopsies; two patients (7%) were EXT1-positive in their first biopsy and EXT1-negative in their last biopsy and one patient (3%) was EXT1-negative in their first biopsy and EXT1-positive in their last biopsy. Compared to the EXT1-negative cohort at the time of first biopsy, the EXT1-positive cohort had a higher average eGFR (141 v. 111ml/min/1.73m^2; p=0.04), lower average % global glomerulosclerosis (0.5 v. 12%; p=0.05), lower average interstitial fibrosis and tubular atrophy (2.5 v. 11.7%; p=0.06), and lower average total NIH chronicity scores (0.75 v. 2.33, p=0.05). On long-term follow-up, the rate of change in eGFR did not significantly differ between the two groups (p=0.24). One EXT1-positive patient (12.5%) developed stage 4 CKD or ESKD compared to four patients (20%) in the EXT-negative group and two of the three EXT1-discordant patients (p=0.38).CONCLUSIONS: We performed the largest retrospective repeat-biopsy study to evaluate EXT1 and NCAM1 autoantigens in MLN. Our data demonstrate that EXT1-positivity is associated with better kidney function at the time of diagnosis and raises the possibility that EXT1 status may change throughout the disease course of MLN.

  View details for DOI 10.1093/ndt/gfac058

  View details for PubMedID 35278072

• Case-control study to identify key residues and domains within hereditary renal disease gene panel to aid in VUS reclassification Vincent, L., Punj, S., Sanapareddy, N., Naik, A., Smart, T., Gray, J., Francisco, R., Charu, V., Keen-Kim, J. ELSEVIER SCIENCE INC. 2022: S202

  View details for DOI 10.1016/j.gim.2022.01.358

  View details for Web of Science ID 000796586200099

• EXT1 and NCAM1-associated Membranous Lupus Nephritis in a Cohort of Patients Undergoing Multiple Renal Biopsies Miller, P., Caza, T., Larsen, C., Charu, V. SPRINGERNATURE. 2022: 1174-1176

  View details for Web of Science ID 000770361803064

• A Diverse Spectrum of Immune Complex-and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma. Kidney international reports Andeen, N. K., Abdulameer, S., Charu, V., Zuckerman, J. E., Troxell, M., Kambham, N., Alpers, C. E., Najafian, B., Nicosia, R. F., Smith, K. D., Kung, V. L., Avasare, R. S., Vallurupalli, A., Jefferson, J. A., Hecox, D., Swetnam, L., Yamashita, M., Lin, M., Bissonnette, M. L., Akilesh, S., Hou, J. 2022; 7 (3): 568-579

  Abstract

  Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL).Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL.Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN).Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

  View details for DOI 10.1016/j.ekir.2021.12.020

  View details for PubMedID 35257069

• EXT1 and NCAM1-associated Membranous Lupus Nephritis in a Cohort of Patients Undergoing Multiple Renal Biopsies Miller, P., Caza, T., Larsen, C., Charu, V. SPRINGERNATURE. 2022: 1174-1176

  View details for Web of Science ID 000770360203064

• Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  Abstract

  Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

  View details for DOI 10.1038/s41587-021-01188-9

  View details for PubMedID 35132263

• Complement-Binding Donor-Specific Anti-HLA Antibodies: Biomarker for Immunologic Risk Stratification in Pediatric Kidney Transplantation Recipients Transpl Int, Sigurjonsdottir, V. K. 2022; 35

  View details for DOI 10.3389/ti.2021.10158

• National and International Kidney Failure Registries: Characteristics, Commonalities, and Contrasts. Kidney international Ng, M. S., Charu, V., Johnson, D., O'Shaughnessy, M., Mallett, A. J. 2021

  Abstract

  Registries are essential for health infrastructure planning, benchmarking, continuous quality improvement, hypothesis generation and real world trials. To date, data from these registries have predominantly been analysed in isolated "silos", hampering efforts to analyse "big data" at the international level, with wide-ranging benefits including enhanced statistical power, an ability to conduct international comparisons, and greater capacity to study rare diseases. This review serves as a valuable resource to clinicians, researchers, and policymakers by comprehensively describing kidney failure registries active in 2021, before proposing approaches for inter-registry research under current conditions and solutions to enhance global capacity for data collaboration. We identified 79 kidney failure registries spanning 77 countries worldwide. International Society of Nephrology exemplar initiatives, including the "Global Kidney Health Atlas" and "Sharing Expertise to support the set-up of Renal Registries (SharE-RR)" continue to raise awareness regarding international healthcare disparities and support the development of universal kidney disease registries. Current barriers to inter-registry collaboration include under-representation of lower income countries, poor syntactic and semantic interoperability, absence of clear consensus guidelines for healthcare data sharing, and limited researcher incentives. This review represents a call to action for international stakeholders to enact systemic change that will harmonise the current fragmented approaches to kidney failure registry data collection and research.

  View details for DOI 10.1016/j.kint.2021.09.024

  View details for PubMedID 34736973

• RNA splicing programs define tissue compartments and cell types at single-cell resolution ELIFE Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10

  View details for DOI 10.7554/eLife.70692.sa2

  View details for Web of Science ID 000715795700001

• Masking by hypokalemia-primary aldosteronism with undetectable aldosterone. Clinical kidney journal Boyle, R. A., Baker, J. E., Charu, V., Rainey, W. E., Bhalla, V. 2021; 14 (4): 1269–71

  Abstract

  Primary aldosteronism is the most common cause of secondary hypertension; however, the dynamic regulation of aldosterone by potassium is less well studied and current diagnostic recommendations are imprecise. We describe a young man who presented with resistant hypertension and severe hypokalemia. The workup initially revealed undetectable aldosterone despite acute potassium repletion. Chronic potassium supplementation eventually uncovered hyperaldosteronism. In situ genetic studies revealed a gain-of-function KCNJ5 mutation within an aldosterone-producing adenoma that was clinically responsive to changes in extracellular potassium. We highlight a unique presentation of Conn's syndrome and discuss the implications for the molecular mechanisms of potassium regulation of aldosterone.

  View details for DOI 10.1093/ckj/sfaa150

  View details for PubMedID 33841871

• Molecular Classification of Endometrial Carcinomas with Long-Term Follow-up Hammer, P., Albro, J., Squires, C., Peters-Schulze, G., Sharp, B., Charu, V., Cessna, M., Howitt, B. SPRINGERNATURE. 2021: 691–93

  View details for Web of Science ID 000629694101264

• Clinicopathologic Features of Non-Lupus Membranous Nephropathy in the Pediatric Population Miller, P., Lei, L., Charu, V., Higgins, J., Sibley, R., Troxell, M., Kambham, N. SPRINGERNATURE. 2021: 1014–15

  View details for Web of Science ID 000629694102179

• Clinicopathologic Features of Non-Lupus Membranous Nephropathy in the Pediatric Population Miller, P., Lei, L., Charu, V., Higgins, J., Sibley, R., Troxell, M., Kambham, N. SPRINGERNATURE. 2021: 1014–15

  View details for Web of Science ID 000629690900842

• Molecular Classification of Endometrial Carcinomas with Long-Term Follow-up Hammer, P., Albro, J., Squires, C., Peters-Schulze, G., Sharp, B., Charu, V., Cessna, M., Howitt, B. SPRINGERNATURE. 2021: 691–93

  View details for Web of Science ID 000629690900575

• Classic Hodgkin lymphoma in Guatemalan children of age less than six years: analysis of immune regulatory pathways and the tumor microenvironment. Leukemia & lymphoma Silva, O., Charu, V., Ewalt, M. D., Metcalf, R. A., Zhao, S., Castellanos, E. M., Orellana, E., Natkunam, Y., Luna-Fineman, S. 2021: 1–13

  Abstract

  Classic Hodgkin lymphoma (cHL) in young children (ages 0-6) is rare in high income countries (HICs) but is more prevalent in low- and middle-income countries (LMICs) like Guatemala. Given that the majority of cHL studies have evaluated adolescent/adults, and the immune system changes with age, we sought to characterize Epstein-Barr virus (EBV) expression, immune regulatory pathway markers and the tumor microenvironment in 42 children ages 0-6 with cHL from Guatemala. We found a very high frequency of EBV expression (97.5%). Hodgkin cells showed increased expression of PD1 ligands and CD137, indicative of shared immune regulatory mechanisms with adult cHL. Pediatric cHL also showed an increase in CD8+ tumor infiltrating lymphocytes and tumor associated macrophages within the tumor microenvironment. Despite 25 having high risk disease, only 4 patients died from progressive disease, relapse or infection.

  View details for DOI 10.1080/10428194.2021.1885666

  View details for PubMedID 33627023

• Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Devereaux, K. A., Weiel, J. J., Pors, J., Steiner, D. F., Ho, C., Charu, V., Suarez, C. J., Renz, M., Diver, E., Karam, A., Litkouhi, B., Dorigo, O., Kidd, E. A., Yang, E. J., Folkins, A. K., Longacre, T. A., Howitt, B. E. 2021

  Abstract

  The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.

  View details for DOI 10.1038/s41379-021-00963-y

  View details for PubMedID 34743187

• Histologic Case Definition of an Atypical Glomerular Immune-Complex Deposition Following Kidney Transplantation. Kidney international reports Chin, K., Charu, V., O'Shaughnessy, M. M., Troxell, M. L., Cheng, X. S. 2020; 5 (5): 632–42

  Abstract

  Introduction: Immune-complex deposition in the transplanted kidney can present as well-phenotyped recurrent or de novo glomerular disease. However, a subset, herein termed immune-complex glomerulopathy not otherwise specified (ICG-NOS), defies classification. We quantified, categorized, and characterized cases of transplant ICG-NOS occurring at a single US academic medical center.Methods: We retrospectively reviewed our single-institution pathology database (July 2007-July 2018) to identify and categorize all cases of immune-complex deposition in kidney allografts (based on immunofluorescence microscopy). We extracted clinicopathologic and outcome data for ICG-NOS (i.e., immune complex deposition not conforming to any well-characterized glomerular disease entity).Results: Of 104 patients with significant immune deposits, 28 (27%) were classified as ICG-NOS. We created 5 mutually exclusive ICG-NOS categories: Full-house, Quasi-full-house, IgA-rich, C1q-rich, and C1q-poor. Overall, 16 (57%) patients met criteria for definite or possible allograft rejection, including 9 (32%) with antibody-mediated rejection (ABMR), 3 (11%) suspicious for ABMR, 1 (4%) with T-cell-mediated rejection (TCMR), and 9 (32%) with borderline TCMR. After a median follow-up of 2.3 (range, 0.1-14.0) years after biopsy, 7 (25%) allografts had failed and an additional 8 (29%) had persistent renal dysfunction (hematuria, 14%; proteinuria, 21%; and estimated glomerular filtration rate<60 ml/min per 1.73 m2, 11%).Conclusion: In contrast to prior studies, our findings suggest that ICG-NOS is not necessarily a benign glomerular process and that there may be an association between ICG-NOS and alloimmunity. Our immunofluorescence-based classification provides a framework for future studies aiming to further elucidate ICG-NOS pathogenesis and prognosis.

  View details for DOI 10.1016/j.ekir.2020.01.022

  View details for PubMedID 32405585

• Progression of Proliferative Glomerulonephritis with Monoclonal IgG Deposits in Pediatric Patients Miller, P., Xiao, A., Kung, V., Sibley, R., Higgins, J., Kambham, N., Charu, V., Lenihan, C., Talley, E., Walavalkar, V., Laszik, G., Arora, N., Nast, C., Troxell, M. NATURE PUBLISHING GROUP. 2020: 1589–90

  View details for Web of Science ID 000518328803371

• Class II HLA Serotype Associations with End-Stage Renal Disease due to Membranous Nephropathy among Caucasians in the United States Charu, V., Tyan, D., Troxell, M., Kambham, N. NATURE PUBLISHING GROUP. 2020: 1569–71

  View details for Web of Science ID 000518328903349

• Progression of Proliferative Glomerulonephritis with Monoclonal IgG Deposits in Pediatric Patients Miller, P., Xiao, A., Kung, V., Sibley, R., Higgins, J., Kambham, N., Charu, V., Lenihan, C., Talley, E., Walavalkar, V., Laszik, G., Arora, N., Nast, C., Troxell, M. NATURE PUBLISHING GROUP. 2020: 1589–90

  View details for Web of Science ID 000518328903372

• Class II HLA Serotype Associations with End-Stage Renal Disease due to Membranous Nephropathy among Caucasians in the United States Charu, V., Tyan, D., Troxell, M., Kambham, N. NATURE PUBLISHING GROUP. 2020: 1569–71

  View details for Web of Science ID 000518328803348

• Multicenter Clinicopathologic Correlation of Kidney Biopsies Performed in COVID-19 Patients Presenting With Acute Kidney Injury or Proteinuria. American journal of kidney diseases : the official journal of the National Kidney Foundation Akilesh, S. n., Nast, C. C., Yamashita, M. n., Henriksen, K. n., Charu, V. n., Troxell, M. L., Kambham, N. n., Bracamonte, E. n., Houghton, D. n., Ahmed, N. I., Chong, C. C., Thajudeen, B. n., Rehman, S. n., Khoury, F. n., Zuckerman, J. E., Gitomer, J. n., Raguram, P. C., Mujeeb, S. n., Schwarze, U. n., Shannon, M. B., De Castro, I. n., Alpers, C. E., Najafian, B. n., Nicosia, R. F., Andeen, N. K., Smith, K. D. 2020

  Abstract

  Kidney biopsy data inform us about pathologic processes associated with SARS CoV-2 infection. We conducted a multi-center evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology in patients with COVID-19 and their association with SARS-CoV-2 infection.Case series.We identified 14 native and 3 transplant kidney biopsies performed for-cause in patients with documented recent or concurrent COVID-19 infection treated at 7 large hospital systems in the United States.Males and females were equally represented in our study cohort, with a higher proportion of Black (n=8) and Hispanic (n=5) patients. All 17 patients had RT-PCR confirmed COVID-19 infection, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (AKI; n=15) and proteinuria (n=11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n=14), collapsing glomerulopathy (n=7) and endothelial injury/thrombotic microangiopathy (n=6) were the most common histologic findings. Two of the three transplant patients developed active antibody-mediated rejection weeks after COVID-19 infection. Eight patients required dialysis, but others improved with conservative management.Small study size and short clinical follow up.Cases of even symptomatically mild COVID-19 infection were accompanied by AKI and/or heavy proteinuria that prompted a diagnostic kidney biopsy. While acute tubular injury was seen among the majority of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.

  View details for DOI 10.1053/j.ajkd.2020.10.001

  View details for PubMedID 33045255

• Membranous nephropathy in patients with HIV: a report of 11 cases. BMC nephrology Charu, V. n., Andeen, N. n., Walavalkar, V. n., Lapasia, J. n., Kim, J. Y., Lin, A. n., Sibley, R. n., Higgins, J. n., Troxell, M. n., Kambham, N. n. 2020; 21 (1): 401

  Abstract

  Membranous nephropathy (MN) has been recognized to occur in patients with human immunodeficiency virus (HIV) infection since the beginning of the HIV epidemic. The prevalence of phospholipase A2 receptor (PLA2R)-associated MN in this group has not been well studied.We conducted a retrospective review of electronic pathology databases at three institutions to identify patients with MN and known HIV at the time of renal biopsy. Patients with comorbidities and coinfections known to be independently associated with MN were excluded.We identified 11 HIV-positive patients with biopsy-confirmed MN meeting inclusion and exclusion criteria. Patient ages ranged from 39 to 66 years old, and 10 of 11 patients (91%) were male. The majority of patients presented with nephrotic-range proteinuria, were on anti-retroviral therapy at the time of biopsy and had low or undetectable HIV viral loads. Biopsies from 5 of 10 (50%) patients demonstrated capillary wall staining for PLA2R. Measurement of serum anti-PLA2R antibodies was performed in three patients, one of whom had positive anti-PLA2R antibody titers. Follow-up data was available on 10 of 11 patients (median length of follow-up: 44 months; range: 4-145 months). All patients were maintained on anti-retroviral therapy (ARV) and 5 patients (52%) received concomitant immunosuppressive regimens. Three patients developed end-stage renal disease (ESRD) during the follow-up period.MN in the setting of HIV is often identified in the setting of an undetectable viral loads, and similar to other chronic viral infection-associated MNs, ~ 50% of cases demonstrate tissue reactivity with PLA2R antigen, which may be seen without corresponding anti-PLA2R serum antibodies.

  View details for DOI 10.1186/s12882-020-02042-x

  View details for PubMedID 32948130

• Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients. Pediatric nephrology (Berlin, Germany) Miller, P. n., Xiao, A. Y., Kung, V. L., Sibley, R. K., Higgins, J. P., Kambham, N. n., Charu, V. n., Lenihan, C. n., Uber, A. M., Talley, E. M., Arora, N. n., Walavalkar, V. n., Laszik, Z. G., Nast, C. C., Troxell, M. L. 2020

  Abstract

  Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain-restricted immunoglobulin and is rarely reported in children.We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition.Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course.Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. Graphical abstract.

  View details for DOI 10.1007/s00467-020-04763-5

  View details for PubMedID 33044675

• A review of non-immune mediated kidney disease in systemic lupus erythematosus: A hypothetical model of putative risk factors. Seminars in arthritis and rheumatism Falasinnu, T., O'Shaughnessy, M. M., Troxell, M. L., Charu, V., Weisman, M. H., Simard, J. F. 2019

  Abstract

  About half of patients with systemic lupus erythematosus (SLE) are diagnosed with lupus nephritis (LN). Patients with SLE are also at increased risk for diabetes, hypertension and obesity, which together account for >70% of end-stage renal disease in the general population. The frequencies of non-LN related causes of kidney disease, and their contribution to kidney disease development and progression among patients with SLE have been inadequately studied. We hypothesize that a substantial, and increasing proportion of kidney pathology in patients with SLE might not directly relate to LN but instead might be explained by non-immune mediated factors such as diabetes, hypertension, and obesity. The goal of the manuscript is to draw attention to hypertension, diabetes and obesity as potential alternative causes of kidney damage in patients with SLE. Further, we suggest that misclassification of kidney disease etiology in patients with SLE might have important ramifications for clinical trial recruitment, epidemiologic investigation, and clinical care. Future studies aiming to elucidate and distinguish discrete causes of kidney disease - both clinically and histologically - among patients with SLE are desperately needed as improved understanding of disease mechanisms is paramount to advancing therapeutic discovery. Collaboration among rheumatologists, pathologists, nephrologists, and endocrinologists, and the availability of dedicated research funding, will be critical to the success of such efforts.

  View details for DOI 10.1016/j.semarthrit.2019.10.006

  View details for PubMedID 31866044

• Percutaneous Kidney Biopsy and the Utilization of Blood Transfusion and Renal Angiography Among Hospitalized Adults KIDNEY INTERNATIONAL REPORTS Charu, V., O'Shaughnessy, M. M., Chertow, G. M., Kambham, N. 2019; 4 (10): 1435–45

  View details for DOI 10.1016/j.ekir.2019.07.008

  View details for Web of Science ID 000488859300010

• Percutaneous Kidney Biopsy and the Utilization of Blood Transfusion and Renal Angiography Among Hospitalized Adults. Kidney international reports Charu, V., O'Shaughnessy, M. M., Chertow, G. M., Kambham, N. 2019; 4 (10): 1435-1445

  Abstract

  Data on percutaneous kidney biopsy (KBx) incidence and frequencies of hemorrhagic complications among inpatients are limited.Using nationally representative US hospitalization discharge data, we report temporal trends in inpatient KBx rates from 2007 to 2014 and estimate frequencies of, and risk factors for, utilization of packed red blood cell (pRBC) transfusion and renal angiography.From 2007 to 2014, rates of native KBx among adult inpatients increased from 8.2 to 10.0 per 100,000, while transplant KBx rates declined from 3.6 to 3.1 per 100,000. We studied 35,183 and 14,266 discharge records with native and transplant KBx. We found that 5.7% (95% confidence interval [CI]: 5.3%-6.0%) of inpatients undergoing native KBx and 4.9% (4.2%-5.5%) of those undergoing transplant KBx received a pRBC transfusion within 2 days of biopsy. Similarly, 0.6% (0.5%-0.7%) of inpatients undergoing native KBx and 0.4% (0.2%-0.5%) undergoing transplant KBx received a renal angiogram within 2 days of KBx. For inpatient native KBx, female sex, older age, higher chronic kidney disease stage, acute renal failure, lupus, vasculitis, cirrhosis, multiple myeloma/paraproteinemia, and anemia of chronic disease were independently associated with increased odds of pRBC transfusion; cirrhosis and end-stage renal disease (ESRD) were associated with increased odds, and nephrotic syndrome was associated with decreased odds, of renal angiography.In this large population-based study of inpatient KBx practices, we demonstrate increasing rates of inpatient native KBx among US adults and provide accurate estimates of the frequencies of, and risk factors for, pRBC transfusion and renal angiography following inpatient KBx.

  View details for DOI 10.1016/j.ekir.2019.07.008

  View details for PubMedID 31701053

  View details for PubMedCentralID PMC6829181

• Long-term Trends and Clinical Outcomes of Inpatient Percutaneous Renal Biopsies in the United States, 2001-2013 Charu, V., O'Shaughnessy, M., Chertow, G., Kambham, N. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081103084

• An analysis of mediastinal B cell lymphomas identifies metachronous occurrence of classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma (PMBL), and mediastinal gray-zone lymphoma (MGZL) Lezama, L., Charu, V., Koo, M., Natkunam, Y. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102335

• An analysis of mediastinal B cell lymphomas identifies metachronous occurrence of classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma (PMBL), and mediastinal gray-zone lymphoma (MGZL) Lezama, L., Charu, V., Koo, M., Natkunam, Y. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915501094

• Long-term Trends and Clinical Outcomes of Inpatient Percutaneous Renal Biopsies in the United States, 2001-2013 Charu, V., O'Shaughnessy, M., Chertow, G., Kambham, N. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915503209

• Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project. Journal of global health Paget, J. n., Spreeuwenberg, P. n., Charu, V. n., Taylor, R. J., Iuliano, A. D., Bresee, J. n., Simonsen, L. n., Viboud, C. n. 2019; 9 (2): 020421

  Abstract

  Until recently, the World Health Organization (WHO) estimated the annual mortality burden of influenza to be 250 000 to 500 000 all-cause deaths globally; however, a 2017 study indicated a substantially higher mortality burden, at 290 000-650 000 influenza-associated deaths from respiratory causes alone, and a 2019 study estimated 99 000-200 000 deaths from lower respiratory tract infections directly caused by influenza. Here we revisit global and regional estimates of influenza mortality burden and explore mortality trends over time and geography.We compiled influenza-associated excess respiratory mortality estimates for 31 countries representing 5 WHO regions during 2002-2011. From these we extrapolated the influenza burden for all 193 countries of the world using a multiple imputation approach. We then used mixed linear regression models to identify factors associated with high seasonal influenza mortality burden, including influenza types and subtypes, health care and socio-demographic development indicators, and baseline mortality levels.We estimated an average of 389 000 (uncertainty range 294 000-518 000) respiratory deaths were associated with influenza globally each year during the study period, corresponding to ~ 2% of all annual respiratory deaths. Of these, 67% were among people 65 years and older. Global burden estimates were robust to the choice of countries included in the extrapolation model. For people <65 years, higher baseline respiratory mortality, lower level of access to health care and seasons dominated by the A(H1N1)pdm09 subtype were associated with higher influenza-associated mortality, while lower level of socio-demographic development and A(H3N2) dominance was associated with higher influenza mortality in adults ≥65 years.Our global estimate of influenza-associated excess respiratory mortality is consistent with the 2017 estimate, despite a different modelling strategy, and the lower 2019 estimate which only captured deaths directly caused by influenza. Our finding that baseline respiratory mortality and access to health care are associated with influenza-related mortality in persons <65 years suggests that health care improvements in low and middle-income countries might substantially reduce seasonal influenza mortality. Our estimates add to the body of evidence on the variation in influenza burden over time and geography, and begin to address the relationship between influenza-associated mortality, health and development.

  View details for DOI 10.7189/jogh.09.020421

  View details for PubMedID 31673337

  View details for PubMedCentralID PMC6815659

• Immune checkpoint blockade as a potential therapeutic strategy for undifferentiated malignancies. Human pathology Devereaux, K. A., Charu, V., Zhao, S., Charville, G. W., Bangs, C. D., van de Rijn, M., Cherry, A. M., Natkunam, Y. 2018; 82: 39–45

  Abstract

  Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors that pose not only a diagnostic challenge but also a challenge for clinical management. Most tumors in this category are currently treated empirically with nonspecific chemotherapeutic agents that yield extremely poor clinical response. Given that UMs are inherently genetically unstable neoplasms with the potential for immune dysregulation and increased neoantigen production, they are likely to be particularly amenable to immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases previously diagnosed as an "undifferentiated" malignancy and found that 56% (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ hybridization (FISH) was performed on 24 of these cases and demonstrates a genetic gain at both loci in 62.5% of UMs. Genetic alterations at the CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by FISH. Overall, we found that a significant proportion of UMs express PD-L1 and provide molecular support for using checkpoint inhibitors as a treatment approach for this class of tumors.

  View details for PubMedID 30539796

• Immune checkpoint blockade as a potential therapeutic strategy for undifferentiated malignancies HUMAN PATHOLOGY Devereaux, K. A., Charu, V., Zhao, S., Charville, G. W., Bangs, C. D., van de Rijn, M., Cherry, A. M., Natkunam, Y. 2018; 82: 39–45

  View details for DOI 10.1016/j.humpath.2018.06.034

  View details for Web of Science ID 000454968800005

• Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes HUMAN PATHOLOGY Panjwani, P. K., Charu, V., DeLisser, M., Molina-Kirsch, H., Natkunam, Y., Zhao, S. 2018; 71: 91–99

  Abstract

  The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Because efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in more than 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases, respectively, and PD-L1 but not PD-L2 expression correlated with Epstein-Barr virus in tumor cells. PD-L1 staining was detected in 80% of anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and follicular dendritic cell sarcoma; 75% of nodular lymphocyte-predominant Hodgkin lymphoma; 53% of primary mediastinal large B-cell lymphoma; 39% of extranodal NK/T cell lymphoma; 26% of peripheral T-cell lymphoma; 10% of diffuse large B-cell lymphoma; and very rare examples of mantle, marginal zone, and small lymphocytic lymphomas. PD-L2 staining was present in 78% of primary mediastinal large B-cell lymphoma but in fewer cases in all other categories including 40% of follicular dendritic cell sarcoma and 7% of anaplastic large cell lymphoma. Our results confirm and extend prior studies of PD-L1 and provide new data of PD-L2 expression in lymphomas. The differential expression patterns in some tumor types and the expression of PD-L2 in the absence of PD-L1 raise the possibility of targeted therapy for additional subsets of patients with lymphoma.

  View details for PubMedID 29122656

• Evaluating Post-Radiotherapy Laryngeal Function with Laryngeal Videostroboscopy in Early Stage Glottic Cancer. Frontiers in oncology Marciscano, A. E., Charu, V. n., Starmer, H. M., Best, S. R., Quon, H. n., Hillel, A. T., Akst, L. M., Kiess, A. P. 2017; 7: 124

  Abstract

  Dysphonia is common among patients with early stage glottic cancer. Laryngeal videostroboscopy (LVS) has not been routinely used to assess post-radiotherapy (RT) voice changes. We hypothesized that LVS would demonstrate improvement in laryngeal function after definitive RT for early-stage glottic cancer.Blinded retrospective review of perceptual voice and stroboscopic parameters for patients with early glottic cancer and controls.High-volume, single-institution academic medical center.Fifteen patients underwent RT for Tis-T2N0M0 glottic cancer and were evaluated with serial LVS exams pre- and post-RT. Stroboscopic assessment included six parameters: vocal fold (VF) vibration, VF mobility, erythema/edema, supraglottic compression, glottic closure, and secretions. Grade, roughness, breathiness, asthenia, strain (GRBAS) voice perceptual scale was graded in tandem with LVS score. Assessments were grouped by time interval from RT: pre-RT, 0-4, 4-12, and >12 months post-RT.60 LVS exams and corresponding GRBAS assessments were reviewed. There were significant improvements in ipsilateral VF motion (P = 0.03) and vibration (P = 0.001) and significant worsening in contralateral VF motion (P < 0.001) and vibration (P = 0.008) at >12 months post-RT. Glottic closure significantly worsened, most prominent >12 months post-RT (P = 0.01). Composite GRBAS scores were significantly improved across all post-RT intervals.LVS proved to be a robust tool for assessing pre- and post-RT laryngeal function. We observed post-RT improvement in ipsilateral VF function, a decline in contralateral VF function, and decreased glottic closure. These results demonstrate that LVS can detect meaningful changes in VF and glottic function and support its use for post-RT evaluation of glottic cancer patients.

  View details for PubMedID 28660173

  View details for PubMedCentralID PMC5467001