Vivek Charu, MD

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

View details for Web of Science ID 000518328803371

View details for Web of Science ID 000518328903349

View details for Web of Science ID 000518328903372

View details for Web of Science ID 000518328803348

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

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 beenwell 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 66years 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: 44months; range: 4-145months). 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, whichmay be seen without corresponding anti-PLA2R serum antibodies.

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

View details for PubMedID 32948130

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 israrely 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-, two showed IgG3-, 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

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

View details for DOI 10.1016/j.ekir.2019.07.008

View details for Web of Science ID 000488859300010

View details for Web of Science ID 000478081103084

View details for Web of Science ID 000478081102335

View details for Web of Science ID 000478915501094

View details for Web of Science ID 000478915503209

Abstract

Until recently, the World Health Organization (WHO) estimated the annual mortality burden of influenza to be 250000 to 500000 all-cause deaths globally; however, a 2017 study indicated a substantially higher mortality burden, at 290000-650000 influenza-associated deaths from respiratory causes alone, and a 2019 study estimated 99000-200000 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 389000 (uncertainty range 294000-518000) 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

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

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

View details for DOI 10.1016/j.humpath.2018.06.034

View details for Web of Science ID 000454968800005

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

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 >12months 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 >12months post-RT. Glottic closure significantly worsened, most prominent >12months 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