Medicine and Health Sciences Commons^™

Text Messaging For Disease Monitoring In Childhood Nephrotic Syndrome., Chia-Shi Wang, Jonathan P. Troost, Larry A. Greenbaum, Tarak Srivastava, Kimberly Reidy, Keisha Gibson, Howard Trachtman, John D. Piette, Christine B. Sethna, Kevin Meyers, Katherine M. Dell, Cheryl L. Tran, Suzanne Vento, Krishna Kallem, Emily Herreshoff, Sangeeta Hingorani, Kevin Lemley, Gia Oh, Elizabeth Brown, Jen-Jar Lin, Frederick Kaskel, Debbie S. Gipson

Manuscripts, Articles, Book Chapters and Other Papers

Introduction: There is limited information on effective disease monitoring for prompt interventions in childhood nephrotic syndrome. We examined the feasibility and effectiveness of a novel text messaging system (SMS) for disease monitoring in a multicenter, prospective study.

Methods: A total of 127 patientsresults, symptoms, and medication adherence were sent to a designated caregiver (n = 116) or adolescent patient (n = 3). Participants responded by texting. Feasibility of SMS was assessed by SMS adoption, retention, and engagement, and concordance between participant-reported results and laboratory/clinician assessments. The number of disease relapses and time-to-remission data captured by SMS were compared …

Health-Related Quality Of Life In Glomerular Disease., Pietro A. Canetta, Jonathan P. Troost, Shannon Mahoney, Amy J. Kogon, Noelle Carlozzi, Sharon M. Bartosh, Yi Cai, T Keefe Davis, Hilda Fernandez, Alessia Fornoni, Rasheed A. Gbadegesin, Emily Herreshoff, John D. Mahan, Patrick H. Nachman, David T. Selewski, Christine B. Sethna, Tarak Srivastava, Katherine R. Tuttle, Chia-Shi Wang, Ronald J. Falk, Ali G. Gharavi, Brenda W. Gillespie, Larry A. Greenbaum, Lawrence B. Holzman, Matthias Kretzler, Bruce M. Robinson, William E. Smoyer, Lisa M. Guay-Woodford, Bryce Reeve, Debbie S. Gipson, Curegn Consortium

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There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep …

The Copy Number Variation Landscape Of Congenital Anomalies Of The Kidney And Urinary Tract., Miguel Verbitsky, Rik Westland, Alejandra Perez, Krzysztof Kiryluk, Qingxue Liu, Priya Krithivasan, Adele Mitrotti, David A. Fasel, Ekaterina Batourina, Matthew G. Sampson, Monica Bodria, Max Werth, Charlly Kao, Jeremiah Martino, Valentina P. Capone, Asaf Vivante, Shirlee Shril, Byum Hee Kil, Maddalena Marasà, Jun Y. Zhang, Young-Ji Na, Tze Y. Lim, Dina Ahram, Patricia L. Weng, Erin L. Heinzen, Alba Carrea, Giorgio Piaggio, Loreto Gesualdo, Valeria Manca, Giuseppe Masnata, Maddalena Gigante, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E Van Wijk, Marijan Saraga, Domenico Santoro, Giovanni Conti, Pasquale Zamboli, Hope White, Dorota Drozdz, Katarzyna Zachwieja, Monika Miklaszewska, Marcin Tkaczyk, Daria Tomczyk, Anna Krakowska, Przemyslaw Sikora, Tomasz Jarmoliński, Maria K. Borszewska-Kornacka, Robert Pawluch, Maria Szczepanska, Piotr Adamczyk, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, Mark G. Dobson, John M. Darlow, Prem Puri, David E. Barton, Susan L. Furth, Bradley A. Warady, Zoran Gucev, Vladimir J. Lozanovski, Velibor Tasic, Isabella Pisani, Landino Allegri, Lida M. Rodas, Josep M. Campistol, Cécile Jeanpierre, Shumyle Alam, Pasquale Casale, Craig S. Wong, Fangming Lin, Débora M. Miranda, Eduardo A. Oliveira, Ana Cristina Simões-E-Silva, Jonathan M. Barasch, Brynn Levy, Nan Wu, Friedhelm Hildebrandt, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Feng Zhang, Hakon Hakonarson, Virginia E. Papaioannou, Cathy L. Mendelsohn, Ali G. Gharavi, Simone Sanna-Cherchi

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Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, …

An Eqtl Landscape Of Kidney Tissue In Human Nephrotic Syndrome., Christopher E. Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T. Mcnulty, Nephrotic Syndrome Study Network (Neptune), Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G. Sampson, Tarak Srivastava

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Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map …

Hla-Dqa1 And Apol1 As Risk Loci For Childhood-Onset Steroid-Sensitive And Steroid-Resistant Nephrotic Syndrome., Adebowale Adeyemo, Christopher Esezobor, Adaobi Solarin, Asiri Abeyagunawardena, Jameela A. Kari, Sherif El Desoky, Larry A. Greenbaum, Margret Kamel, Mahmoud Kallash, Cynthia Silva, Alex Young, Tracey E. Hunley, Nilka De Jesus-Gonzalez, Tarak Srivastava, Rasheed Gbadegesin

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Background: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association.

Study design: Case-control study.

Setting & participants: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium.

Factor: Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles.

Outcomes: SSNS …

Role Of Biomechanical Forces In Hyperfiltration-Mediated Glomerular Injury In Congenital Anomalies Of The Kidney And Urinary Tract., Tarak Srivastava, Ganesh Thiagarajan, Uri S. Alon, Ram Sharma, Ashraf El-Meanawy, Ellen T. Mccarthy, Virginia J. Savin, Mukut Sharma

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Congenital anomalies of the kidney and urinary tract (CAKUT) including solitary kidney constitute the main cause of progressive chronic kidney disease (CKD) in children. Children born with CAKUT develop signs of CKD only during adolescence and do not respond to renin-angiotensin-aldosterone system blockers. Early cellular changes underlying CKD progression to end-stage renal disease by early adulthood are not well understood. The mechanism of maladaptive hyperfiltration that occurs from loss of functional nephrons, including solitary kidney, is not clear. We re-examine the phenomenon of hyperfiltration in the context of biomechanical forces with special reference to glomerular podocytes. Capillary stretch exerts tensile …

Multiple Targets For Novel Therapy Of Fsgs Associated With Circulating Permeability Factor., Virginia J. Savin, Mukut Sharma, Jianping Zhou, David Genochi, Ram Sharma, Tarak Srivastava, Amna Ilahe, Pooja Budhiraja, Aditi Gupta, Ellen T. Mccarthy

Manuscripts, Articles, Book Chapters and Other Papers

A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A …

Renal And Cardiovascular Morbidities Associated With Apol1 Status Among African-American And Non-African-American Children With Focal Segmental Glomerulosclerosis., Robert P. Woroniecki, Derek K. Ng, Sophie Limou, Cheryl A. Winkler, Kimberly J. Reidy, Mark Mitsnefes, Matthew G. Sampson, Craig S. Wong, Bradley A. Warady, Susan L. Furth, Jeffrey B. Kopp, Frederick J. Kaskel

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BACKGROUND AND OBJECTIVES: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children.

DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.

RESULTS: A total of 140 AA children in the CKiD study were genotyped. High …

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

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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 …

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

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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 …

American And Brazilian Children With Primary Urolithiasis: Similarities And Disparities., Maria Goretti Moreira Guimarães Penido, Marcelo De Sousa Tavares, Milena Maria Moreira Guimarães, Tarak Srivastava, Uri S. Alon

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Objectives. Considering the differences in location, socioeconomic background, and cultural background, the aim of this study was to try to identify possible factors associated with the increased incidence of urolithiasis by comparing American and Brazilian children with stones.
Methods. Data of 222 American and 190 Brazilian children with urolithiasis were reviewed including age, gender, body mass index, imaging technique used (ultrasound and computed tomography), and 24-hour urine volume and chemistries.
Results. There were no differences between age and gender at diagnosis. Brazilian children were leaner but in no population did obesity rate exceed that of the general population. Ultrasound was …

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 …

Lps And Pan-Induced Podocyte Injury In An In Vitro Model Of Minimal Change Disease: Changes In Tlr Profile., Tarak Srivastava, Mukut Sharma, Kok-Hooi Yew, Ram Sharma, R Scott Duncan, Moin A. Saleem, Ellen T. Mccarthy, Alexander Kats, Patricia A. Cudmore, Uri S. Alon, Christopher J. Harrison

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Minimal change disease (MCD), the most common idiopathic nephrotic syndrome in children, is characterized by proteinuria and loss of glomerular visceral epithelial cell (podocyte) ultrastructure. Lipopolysaccharide (LPS) and puromycin aminonucleoside (PAN) are used to study podocyte injury in models of MCD in vivo and in vitro. We hypothesized that LPS and PAN influence components of the innate immune system in podocytes such as the Toll-Like Receptor (TLRs), TLR adapter molecules, and associated cytokines. Our results show that cultured human podocytes constitutively express TLRs 1-6 and TLR-10, but not TLRs 7-9. LPS (25 μg/ml) or PAN (60 μg/ml) caused comparable derangement …

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

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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 …

Prostaglandin E(2) Is Crucial In The Response Of Podocytes To Fluid Flow Shear Stress., Tarak Srivastava, Ellen T. Mccarthy, Ram Sharma, Patricia A. Cudmore, Mukut Sharma, Mark L. Johnson, Lynda F. Bonewald

Manuscripts, Articles, Book Chapters and Other Papers

Podocytes play a key role in maintaining and modulating the filtration barrier of the glomerulus. Because of their location, podocytes are exposed to mechanical strain in the form of fluid flow shear stress (FFSS). Several human diseases are characterized by glomerular hyperfiltration, such as diabetes mellitus and hypertension. The response of podocytes to FFSS at physiological or pathological levels is not known. We exposed cultured podocytes to FFSS, and studied changes in actin cytoskeleton, prostaglandin E(2) (PGE(2)) production and expression of cyclooxygenase-1 and-2 (COX-1, COX-2). FFSS caused a reduction in transversal F-actin stress filaments and the appearance of cortical actin …