Nephrology Commons^™

Efficacy Of Galactose And Adalimumab In Patients With Resistant Focal Segmental Glomerulosclerosis: Report Of The Font Clinical Trial Group., Howard Trachtman, Suzanne Vento, Emily Herreshoff, Milena Radeva, Jennifer Gassman, Daniel T. Stein, Virginia J. Savin, Mukut Sharma, Jochen Reiser, Changli Wei, Michael Somers, Tarak Srivastava, Debbie S. Gipson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Patients with resistant focal segmental glomerulosclerosis (FSGS) who are unresponsive to corticosteroids and other immunosuppressive agents are at very high risk of progression to end stage kidney disease. In the absence of curative treatment, current therapy centers on renoprotective interventions that reduce proteinuria and fibrosis. The FONT (Novel Therapies for Resistant FSGS) Phase II clinical trial (NCT00814255, Registration date December 22, 2008) was designed to assess the efficacy of adalimumab and galactose compared to standard medical therapy which was comprised of lisinopril, losartan, and atorvastatin.

METHODS: Key eligibility criteria were biopsy confirmed primary FSGS or documentation of a causative …

Hla-Dqa1 And Plcg2 Are Candidate Risk Loci For Childhood-Onset Steroid-Sensitive Nephrotic Syndrome., Rasheed A. Gbadegesin, Adebowale Adeyemo, Nicholas J A Webb, Larry A A. Greenbaum, Asiri Abeyagunawardena, Shenal Thalgahagoda, Arundhati Kale, Debbie Gipson, Tarak Srivastava, Jen-Jar Lin, Deepa Chand, Tracy E. Hunley, Patrick D. Brophy, Arvind Bagga, Aditi Sinha, Michelle N. Rheault, Joanna Ghali, Kathy Nicholls, Elizabeth Abraham, Halima S. Janjua, Abiodun Omoloja, Gina-Marie Barletta, Yi Cai, David D. Milford, Catherine O'Brien, Atif Awan, Vladimir Belostotsky, William E. Smoyer, Alison Homstad, Gentzon Hall, Guanghong Wu, Shashi Nagaraj, Delbert Wigfall, John Foreman, Michelle P. Winn, Mid-West Pediatric Nephrology Consortium

Manuscripts, Articles, Book Chapters and Other Papers

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were …

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 …

Fluid Flow Shear Stress Over Podocytes Is Increased In The Solitary Kidney., Tarak Srivastava, Gianni E. Celsi, Mukut Sharma, Hongying Dai, Ellen T. Mccarthy, Melanie Ruiz, Patricia A. Cudmore, Uri S. Alon, Ram Sharma, Virginia A. Savin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Glomerular hyperfiltration is emerging as the key risk factor for progression of chronic kidney disease (CKD). Podocytes are exposed to fluid flow shear stress (FFSS) caused by the flow of ultrafiltrate within Bowman's space. The mechanism of hyperfiltration-induced podocyte injury is not clear. We postulated that glomerular hyperfiltration in solitary kidney increases FFSS over podocytes.

METHODS: Infant Sprague-Dawley rats at 5 days of age and C57BL/6J 14-week-old adult mice underwent unilateral nephrectomy. Micropuncture and morphological studies were then performed on 20- and 60-day-old rats. FFSS over podocytes in uninephrectomized rats and mice was calculated using the recently published equation …

Cinacalcet As Adjunctive Therapy For Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets., Tarak Srivastava, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Secondary hyperparathyroidism from inadequate calcium absorption in the gut, is the underlying pathophysiology for rachitic changes in hereditary vitamin D-resistant rickets (HVDRR). We describe a novel use of Cinacalcet to treat a child with HVDRR in whom conventional modes of therapy had to be discontinued. Cinacalcet therapy with high-dose oral calcium effectively normalized the metabolic abnormalities and bone condition. The relative ease of administration of the calcimimetic as a once- or twice-daily oral preparation, compared with traditional intravenous calcium administration, should encourage its move to the frontline of treatment of the disorder.

The Adipose Tissue Production Of Adiponectin Is Increased In End-Stage Renal Disease., Maria P Martinez Cantarin, Scott A Waldman, Cataldo Doria, Adam M Frank, Warren R Maley, Carlo B Ramirez, Scott W Keith, Bonita Falkner

Department of Medicine Faculty Papers

Adiponectin has antidiabetic properties, and patients with obesity, diabetes, and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end-stage renal disease. Here we determine whether adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end-stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared with 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis …

Renal Function And Proteinuria After Successful Immunosuppressive Therapies In Patients With Fsgs., Ronald J. Hogg, Aaron Friedman, Tom Greene, Milena Radeva, Milos N. Budisavljevic, Jennifer Gassman, Debbie S. Gipson, J Ashley Jefferson, Eunice G. John, Frederick J. Kaskel, Asha Moudgil, Marva Moxey-Mims, Luis A. Ortiz, Jeffrey R. Schelling, William Schnaper, Tarak Srivastava, Howard Trachtman, V Matti Vehaskari, Craig Wong, Robert P. Woronieki, Scott K. Van Why, Anna Zolotnitskaya

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined.

DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout …

A Kidney For Christmas, Stephen Scholand

The Medicine Forum

When Asmar Lawrence first walked into the small examining room in the Jefferson Hospital Ambulatory Practice (JHAP) Clinic, we both had no idea what the future would hold. It was July, 1998 and I was fresh from medical school. Each week, I looked forward to the JHAP experience to develop my clinical skills and follow patients longitudinally. No longer was my learning prescribed from a textbook, this was the 'real world' of medicine where anything could happen and I was supposed to be in control of it. The long white coat probably helped perpetuate some of that illusion. Fortunately our …

Novel Napi-Iic Mutations Causing Hhrh And Idiopathic Hypercalciuria In Several Unrelated Families: Long-Term Follow-Up In One Kindred., Y Yu, S R. Sanderson, M Reyes, A Sharma, N Dunbar, Tarak Srivastava, H Jüppner, C Bergwitz

Manuscripts, Articles, Book Chapters and Other Papers

Homozygous and compound heterozygous mutations in SLC34A3, the gene encoding the sodium-dependent co-transporter NaPi-IIc, cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate-wasting resulting in hypophosphatemia, elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, rickets/osteomalacia, and frequently kidney stones or nephrocalcinosis. Similar albeit less severe biochemical changes are also observed in heterozygous carriers, which are furthermore indistinguishable from those encountered in idiopathic hypercalciuria (IH). We now searched for SLC34A3 mutations (exons and introns) in two previously not reported HHRH kindreds, which resulted in the identification of three novel mutations. The affected members of kindred A were compound heterozygous …

A Phase I/Iia Clinical Trial Of A Recombinant Rho Protein Antagonist In Acute Spinal Cord Injury., Michael G Fehlings, Nicholas Theodore, James Harrop, Gilles Maurais, Charles Kuntz, Chris I Shaffrey, Brian K Kwon, Jens Chapman, Albert Yee, Allyson Tighe, Lisa Mckerracher

Department of Neurosurgery Faculty Papers

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or …

Serum 25-Hydroxyvitamin D Level And Acute-Phase Reaction Following Initial Intravenous Bisphosphonate., Tarak Srivastava, Hongying Dai, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets With Alopecia Resulting From A Novel Missense Mutation In The Dna-Binding Domain Of The Vitamin D Receptor., Peter J. Malloy, Jining Wang, Tarak Srivastava, David Feldman

Manuscripts, Articles, Book Chapters and Other Papers

The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3) or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone X-rays normalized …

Atorvastatin May Have No Effect On Acute Phase Reaction In Children After Intravenous Bisphosphonate Infusion., Tarak Srivastava, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Intravenous bisphosphonate therapy is associated with acute phase reaction characterized by fever and musculoskeletal pain. Bisphosphonates have been shown in vitro to activate gammadeltaT-cells to proliferate and produce cytokines, suggesting a role in acute phase reaction, which can be effectively blocked by statins. We conducted a double-blind randomized crossover placebo controlled study in 12 children (12.1 +/- 4.2 yr; 10 girls and 2 boys) receiving intravenous bisphosphonates to evaluate whether statins can be used to prevent acute phase reaction associated with therapy. Children received two cycles given 3-4 mo apart of intravenous bisphosphonate given on 2 consecutive days in each …

Time To Renal Disease And End-Stage Renal Disease In Profile: A Multiethnic Lupus Cohort, Graciela S. Alarcón, Gerald Mcgwin, Michelle Petri, Rosalind Ramsey-Goldman, Barri J. Fessler, Luis M. Vilá, Jeffrey C. Edberg, John D. Reveille, Robert P. Kimberly

Faculty, Staff and Student Publications

BACKGROUND: Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).

METHODS AND FINDINGS: PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic-demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of …

Cell-Cycle Regulatory Proteins In The Podocyte In Collapsing Glomerulopathy In Children., Tarak Srivastava, Robert E. Garola, H K. Singh

Manuscripts, Articles, Book Chapters and Other Papers

Podocyte is a terminally committed cell in G1 arrest of cell cycle, and is unable to overcome G1/S transition phase in children with minimal change disease (MCD) and classic focal segmental glomerulosclerosis (FSGS), in contrast to dysregulated proliferative phenotype of idiopathic collapsing glomerulopathy (CGN) in adults. Forty-two kidney biopsies, MCD (14), FSGS (12), CGN (4), and normal (CON) (12), were evaluated by immunohistochemistry using dual staining for expression of p27, p21, and p57, and cyclins D and A, in podocytes of children with CGN. On light microscopy, all podocytes expressed p27, whereas p21 and p57 expression was seen in a …

Cell-Cycle Regulatory Proteins In Podocyte Cell In Idiopathic Nephrotic Syndrome Of Childhood., Tarak Srivastava, Robert E. Garola, J M. Whiting, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The podocyte cell is believed to play an important role in idiopathic nephrotic syndrome (INS) of childhood. In adults with cellular and collapsing focal segmental glomerulosclerosis (FSGS), the expression of cell-cycle regulatory proteins such as p27, p57, and cyclin D is decreased and expression of cyclin A, Ki-67, and p21 is observed in podocyte cells suggestive of a dysregulated podocyte phenotype. We investigated for alterations in the expression of cyclin kinase inhibitors, p27, p57, p21, and cyclins D and A in the podocyte cell of children with INS.

METHODS: Forty-two kidney biopsies were investigated; 14 with minimal-change disease (MCD), …