Nephrology Commons^™

Tubular Cell Phenotype In Hiv-Associated Nephropathy: Role Of Phospholipid Lysophosphatidic Acid, K. R. Ayasolla, P. Rai, S. Rahimipour, M. Hussain, A. Malhotra, P. C. Singhal

Journal Articles

Collapsing glomerulopathy and microcysts are characteristic histological features of HIV-associated nephropathy (HIVAN). We have previously reported the role of epithelial mesenchymal transition (EMT) in the development of glomerular and tubular cell phenotypes in HIVAN. Since persistent tubular cell activation of NF kappa B has been reported in HIVAN, we now hypothesize that HIV may be contributing to tubular cell phenotype via lysophosphatidic acid (LPA) mediated downstream signaling. Interestingly, LPA and its receptors have also been implicated in the tubular interstitial cell fibrosis (TIF) and cyst formation in autosomal dominant polycystic kidney disease (PKD). Primary human proximal tubular cells (HRPTCs) were …

Vascular Smooth Muscle Cells Contribute To Apol1-Induced Podocyte Injury In Hiv Milieu, X. Lan, H. Wen, M. A. Saleem, J. Mikulak, A. Malhotra, K. Skorecki, P. C. Singhal

Journal Articles

Clinical reports have demonstrated that higher rates of non-diabetic glomerulosclerosis in African Americans can be attributed to two coding sequence variants (G1 and G2) in the APOL1 gene; however, the underlying mechanism is still unknown. Kidney biopsy data suggest enhanced expression of APOL1/APOL1 variants (Vs) in smooth muscle cells (SMCs) of renal vasculature. Since APOL1 is a secretory protein of relatively low molecular weight (41kDa), SMCs may be a contributory endocrine/paracrine source of APOL1 wild type (WT)/APOL1Vs in the glomerular capillary perfusate percolating podocytes. In the present study, we tested the hypothesis that an HIV milieu stimulated secretion of APOL1 …

Vitamin D Receptor And Epigenetics In Hiv Infection And Drug Abuse, N. Chandel, A. Malhotra, P. C. Singhal

Journal Articles

Illicit drug abuse is highly prevalent and serves as a powerful co-factor for HIV exacerbation. Epigenetic alterations in drug abuse and HIV infection determine expression of several critical genes such as vitamin D receptor (VDR), which participates in proliferation, differentiation, cell death under both physiological and pathological conditions. On that account, active vitamin D, the ligand of VDR, is used as an adjuvant therapy to control infection, slow down progression of chronic kidney diseases, and cancer chemotherapy. Interestingly, vitamin D may not be able to augment VDR expression optimally in several instances where epigenetic contributes to down regulation of VDR; …

An Overlapping Case Of Lupus Nephritis And Igg4-Related Kidney Disease, M. Zaarour, C. Weerasinghe, A. Eter, S. El-Sayegh, E. El-Charabaty

Journal Articles

We report a case of a 71-year-old Filipino female who was admitted to the hospital for abdominal pain, vomiting and diarrhea of 8 days duration. The patient was found to have marked acute kidney injury (AKI), which required hemodialysis in the next 3 days. Extensive workup revealed hematuria, subnephrotic range proteinuria, elevated anti-nuclear antibody (ANA) and elevated total immunoglobulin G (IgG) levels, with normal IgG4 and anti-dsDNA levels. On kidney biopsy, mild membranous glomerulonephritis was found, along with autoimmune tubulointerstitial nephritis (TIN) with a "full-house" pattern of immune deposits. These findings were suggestive of lupus interstitial nephritis. However, IgG4+ plasma …

Presence Of Anti-Glomerular Basement Membrane Antibodies And Myeloperoxidase Anti-Neutrophilic Cytoplasmic Antibodies In A Case Of Rapidly Progressive Glomerulonephritis, G. P. Mavani, M. Pommier, S. Win, M. F. Michelis, J. Rosenstock

Journal Articles

A 69-year-old male had initially presented with low-grade proteinuria, microhematuria, and a positive myeloperoxidase anti-neutrophilic antibody (ANCA). He subsequently developed deterioration of kidney function and developed uremic symptoms. Creatinine was 486.2 mumol/L (5.5 mg/dL). Anti-MPO was positive (titer >8 U, normal

Protein Domains Of Apol1 And Its Risk Variants, X. Q. Lan, H. X. Wen, R. Lederman, A. Malhotra, J. Mikulak, W. Popik, K. Skorecki, P. C. Singhal

Journal Articles

Increasing lines of evidence have demonstrated that the development of higher rates of non-diabetic glomerulosclerosis (GS) in African Americans can be attributed to two coding sequence variants (G1 and G2) in the Apolipoprotein L1 (APOL) gene. Recent studies indicate that the gene products of these APOL1 risk variants have augmented toxicity to kidney cells. However, the biological characteristics of APOL1 and its risk variants are not well elucidated. The APOL1 protein can be divided into several functional domains, including signal peptide (SP), pore forming domain (PFD), membrane address domain (MAD), and SEA-interacting domain. To investigate the relative contribution of each …

Epigenetic Modulation Of Human Podocyte Vitamin D Receptor In Hiv Milieu, N. Chandel, K. S. Ayasolla, X. Lan, M. Sultana-Syed, A. Chawla, R. Lederman, V. Vethantham, M. A. Saleem, A. Malhotra, P. C. Singhal, +1 Additional Author

Journal Articles

HIV (human immunodeficiency virus) has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system; however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors contribute to down regulation of VDR. Kidney cells in HIV transgenic mice and HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhances expression …

Fungal Infections In Renal Transplant Patients, A. Khan, E. El-Charabaty, S. El-Sayegh

Journal Articles

Organ transplantation has always been considered to be the standard therapeutic interventions in patients with end-stage organ failure. In 2008, more than 29,000 organ transplants were performed in US. Survival rates among transplant recipients have greatly improved due to better understanding of transplant biology and more effective immunosuppressive agents. After transplant, the extent of the immune response is influenced by the amount of interleukin 2 (IL-2) being produced by the T-helper cells. Transplant immunosuppressive therapy primarily targets T cell-mediated graft rejection. Calcineurin inhibitor, which includes cyclosporine, pimecrolimus and tacrolimus, impairs calcineurin-induced up-regulation of IL-2 expression, resulting in increased susceptibility to …

Iga-Dominant Post-Infectious Glomerulonephritis Presenting As A Fatal Pulmonary-Renal Syndrome, M. Saad, M. Daoud, P. Nasr, R. Syed, S. El-Sayegh

Journal Articles

Over the last decades, post-infectious glomerulonephritis underwent major changes in its epidemiology, pathophysiology, and outcomes. We are reporting a case of IgA-dominant post-infectious glomerulonephritis (IgA-PIGN) presenting as a fatal pulmonary-renal syndrome. An 86-year-old Filipino man presented with worsening dyspnea, hemoptysis, and decreased urine output over 2 weeks. Past medical history is significant for hypertension, chronic kidney disease stage III, and pneumonia 3 weeks prior treated with intravenous cefazolin for methicillin-sensitive Staphylococcus aureus bacteremia. Physical examination was remarkable for heart rate of 109/min and respiratory rate of 25/min saturating 99% on 3 liters via nasal cannula. There were bibasilar rales in …

At(1)R Blockade In Adverse Milieus: Role Of Smrt And Corepressor Complexes, T. Singh, K. Ayasolla, P. Rai, N. Chandel, S. Haque, R. Lederman, M. Husain, V. Vethantham, A. Chawla, H. Vashistha, M. A. Saleem, G. Ding, P. N. Chander, A. Malhotra, L. G. Meggs, P. C. Singhal

Journal Articles

ANG II type 1 receptor blockade (AT(1)R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT(1)R-BLK provides podocyte protection through regulation of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and vitamin D receptor (VDR) expression under adverse milieus such as high glucose and human immunodeficiency virus infection. Both AT(1)R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT(1)R-BLK-induced VDR complexes contained predominantly unliganded VDR, SMRT, and phosphorylated histone deacetylase 3, whereas VDA-VDR complexes were constituted by liganded VDR …

Iqgap1 Regulates Actin Cytoskeleton Organization In Podocytes Through Interaction With Nephrin, Y. P. Liu, W. Liang, Y. J. Yang, Y. B. Pan, Q. Yang, X. H. Chen, P. C. Singhal, G. H. Ding

Journal Articles

Increasing data has shown that the cytoskeletal reorganization of podocytes is involved in the onset of proteinuria and the progression of glomerular disease. Nephrin behaves as a signal sensor of the slit diaphragm to transmit cytoskeletal signals to maintain the unique structure of podocytes. However, the nephrin signaling cascade deserves further study. IQGAP1 is a scaffolding protein with the ability to regulate cytoskeletal organization. It is hypothesized that IQGAP1 contributes to actin reorganization in podocytes through interaction with nephrin. IQGAP1 expression and IQGAP1-nephrin colocalization in glomeruli were progressively decreased and then gradually recovered in line with the development of foot …

Exon 4-Encoded Sequence Is A Major Determinant Of Cytotoxicity Of Apolipoprotein L1, A. K. Khatua, A. M. Cheatham, E. D. Kruzel, P. C. Singhal, K. Skorecki, W. Popik

Journal Articles

The apolipoprotein L1 (APOL1) gene (APOL1) product is toxic to kidney cells, and its G1 and G2 alleles are strongly associated with increased risk for kidney disease progression in African Americans. Variable penetrance of the G1 and G2 risk alleles highlights the significance of additional factors that trigger or modify the progression of disease. In this regard, the effect of alternative splicing in the absence or presence of G1 or G2 alleles is unknown. In this study we investigated whether alternative splicing of non-G1, non-G2 APOL1 (APOL1 G0) affects its biological activity. Among seven APOL1 exons, exons 2 and 4 …

Risk Prediction For Chronic Kidney Disease Progression Using Heterogeneous Electronic Health Record Data And Time Series Analysis, A. Perotte, R. Ranganath, J. S. Hirsch, D. Blei, N. Elhadad

Journal Articles

BACKGROUND: As adoption of electronic health records continues to increase, there is an opportunity to incorporate clinical documentation as well as laboratory values and demographics into risk prediction modeling. OBJECTIVE: The authors develop a risk prediction model for chronic kidney disease (CKD) progression from stage III to stage IV that includes longitudinal data and features drawn from clinical documentation. METHODS: The study cohort consisted of 2908 primary-care clinic patients who had at least three visits prior to January 1, 2013 and developed CKD stage III during their documented history. Development and validation cohorts were randomly selected from this cohort and …

Mechanisms Of Mitochondrial Dysfunction In Sepsis-Induced Kidney Injury, Joshua Andrew Smith

MUSC Theses and Dissertations

Mitochondrial dysfunction is a well-characterized pathophysiological feature of acute kidney injury (AKI). Our laboratory has previously implicated suppression of mitochondrial biogenesis, the process by which cells generate new and functional mitochondria, as an important contributor to development of mitochondrial dysfunction in multiple experimental models of AKI. However, relatively little is known about the molecular mechanisms responsible for disruption of biogenesis in renal cells. The primary goals of this project were to define signaling pathways mediating acute suppression of renal cortical mitochondrial biogenesis and to characterize changes in glycolytic metabolism that might support both cellular and organ function following sepsis-induced AKI. …

Ethanol At Low Concentrations Protects Glomerular Podocytes Through Alcohol Dehydrogenase And 20-Hete., Ellen T. Mccarthy, Jianping Zhou, Ryan Eckert, David Genochio, Rishi Sharma, Olurinde Oni, Alok De, Tarak Srivastava, Ram Sharma, Virginia J. Savin, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Clinical studies suggest cardiovascular and renal benefits of ingesting small amounts of ethanol. Effects of ethanol, role of alcohol dehydrogenase (ADH) or of 20-hydroxyeicosatetraenoic acid (20-HETE) in podocytes of the glomerular filtration barrier have not been reported. We found that mouse podocytes at baseline generate 20-HETE and express ADH but not CYP2e1. Ethanol at high concentrations altered the actin cytoskeleton, induced CYP2e1, increased superoxide production and inhibited ADH gene expression. Ethanol at low concentrations upregulated the expression of ADH and CYP4a12a. 20-HETE, an arachidonic acid metabolite generated by CYP4a12a, blocked the ethanol-induced cytoskeletal derangement and superoxide generation. Ethanol at high …

Renal And Hematological Effects Of Clcf-1, A B-Cell-Stimulating Cytokine Of The Il-6 Family., Virginia J. Savin, Mukut Sharma, Jianping Zhou, David Gennochi, Timothy Fields, Ram Sharma, Ellen T. Mccarthy, Tarak Srivastava, Jos Domen, Aurélie Tormo, Jean-François Gauchat

Manuscripts, Articles, Book Chapters and Other Papers

CLCF-1 is a cytokine known for B-cell stimulation and for neurotrophic properties. We have identified CLCF-1 as a potential injurious factor in the human renal disease focal segmental glomerulosclerosis (FSGS). We investigated its effects on renal cells and renal function in in vitro and in vivo studies. Methods include measurement of the effect of CLCF-1 on phosphorylation of target molecules of the JAK/STAT pathway, on cytoskeleton and cell morphology in cultured podocytes, on albumin permeability of isolated rat glomeruli, and on tissue phosphorylation and urine albumin after acute or chronic CLCF-1 injection. In addition, cell sorting was performed to determine …

Cyclooxygenase-2, Prostaglandin E2, And Prostanoid Receptor Ep2 In Fluid Flow Shear Stress-Mediated Injury In The Solitary Kidney., Tarak Srivastava, Uri S. Alon, Patricia A. Cudmore, Belal Tarakji, Alexander Kats, Robert E. Garola, R Scott Duncan, Ellen T. Mccarthy, Ram Sharma, Mark L. Johnson, Lynda F. Bonewald, Ashraf El-Meanawy, Virginia J. Savin, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Hyperfiltration subjects podocytes to increased tensile stress and fluid flow shear stress (FFSS). We showed a 1.5- to 2.0-fold increase in FFSS in uninephrectomized animals and altered podocyte actin cytoskeleton and increased synthesis of prostaglandin E2 (PGE2) following in vitro application of FFSS. We hypothesized that increased FFSS mediates cellular changes through specific receptors of PGE2. Presently, we studied the effect of FFSS on cultured podocytes and decapsulated isolated glomeruli in vitro, and on solitary kidney in uninephrectomized sv129 mice. In cultured podocytes, FFSS resulted in increased gene and protein expression of cyclooxygenase (COX)-2 but not COX-1, prostanoid receptor EP2 …

Severe Tubulointerstitial Nephritis From Acute Epstein-Barr Virus Infection, Craig A. Mackaness Do

Department of Medicine

No abstract provided.

Tps Mutational Status Is A Potential Marker For Risk Stratification In Wilms Tumour With Diffuse Anaplasia, Mariana Maschietto, Richard D. Williams, Tasnim Chagtai, Sergey D. Popov, Neil J. Sebire, Gordan Vujanic, Elizabeth Perlman, James R. Anderson, Paul Grundy, Jeffrey S. Dome, Kathy Pritchard-Jones

Pediatrics Faculty Publications

Purpose

The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whetherTP53 mutational status confers additional prognostic information.

Patients and Methods

We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. …

Predictors Of Hospital Stay And Mortality In Dengue Virus Infection-Experience From Aga Khan University Hospital Pakistan, Muhammad Abdul Mabood Khalil, Jackson Tan, Muhammd Ashhad Ullah Khalil, Safia Awan, Manickam Rangasami

Section of Nephrology

Background: Dengue virus infection (DVI) is very common infection. There is scarcity of data on factor associated with increased hospitalstay and mortality in dengue virus infection (DVI). This study was done to know about factors associated with increased hospital stay and mortality in patients admitted with DVI.

Results: Out of 532 patients, two third (72.6%) had stay ≤3 days while one third (27.4%) had stay greater than 3 days. The mean length of hospital stay was 3.46 ± 3.45 days. Factors associated with increased hospital stay (>3 days) included AKI (acute kidney injury) (Odd ratio 2.98; 95% CI 1.66-5.34), …