Nephrology Research

Faculty interests in nephrology fellowship exhibit considerable diversity, reflecting the distinct areas of expertise held by individual faculty members. Within our program, several notable interests emerge among faculty members:

Transplant Nephrology: Drs. Gallay and Leggat possess extensive expertise in kidney transplantation, encompassing pre-transplant evaluation, immunosuppressive therapy, post-transplant care, and the management of associated complications.

Glomerular Diseases: Dr. Bokhari specializes in the diagnosis and management of glomerular diseases, focusing on conditions such as glomerulonephritis, membranous nephropathy, lupus nephritis, and vasculitis.

Chronic Kidney Disease (CKD): Dr. Devkota's research interests lie in various aspects of CKD, including disease progression, complications, and management strategies, particularly in the context of dialysis and renal replacement therapy. She has also contributed to the field through publications on peritoneal dialysis-related neuropathy and has offered comprehensive lectures on CKD.

Acute Kidney Injury (AKI) and Critical care Nephrology: Dr. Mobeen's expertise lies in the diagnosis, prevention, and management of AKI, with a specific emphasis on critically ill patients.

Hypertension: Dr. Loudis's clinical practice and research focuses on hypertension, encompassing primary and secondary causes, resistant hypertension, and novel therapeutic approaches. He has also garnered recognition within the realm of polycystic kidney disease.

Dialysis: All faculty members possess proficiency in various facets of dialysis, including hemodialysis, peritoneal dialysis, dialysis access management, and the comprehensive management of dialysis-related complications.

Epidemiology and Clinical Research: Dr. Leggat's scholarly pursuits revolve around research methodology, epidemiology, and clinical trials, aimed at advancing knowledge and improving patient care within the nephrology field.

Education and Teaching: Drs. Mobeen, Bokhari, and Devkota exhibit a profound passion for education and mentoring, actively engaging in the guidance and instruction of fellows, residents, and medical students within the fellowship program.

Quality Improvement and Patient Safety: Drs. Bokhari and Habib prioritize the enhancement of care quality and patient safety within nephrology, employing evidence-based practices and implementing quality improvement initiatives.

Kidney Stone Disease: Kidney stone disease, also known as nephrolithiasis, garners significant attention and expertise from Drs. Knohl and Bokhari within our esteemed faculty. Both physicians have developed a keen interest in the field, dedicating their efforts to the management and care of a vast number of patients affected by kidney stones. Dr. Knohl, in particular, has made substantial contributions to the understanding of kidney stone disease throughout his illustrious career, publishing numerous insightful studies and research findings on various aspects of this condition. Their expertise in this area ensures that fellows within our nephrology program receive comprehensive training and exposure to the diagnosis, management, and prevention of kidney stone disease under their guidance.

Geriatric Nephrology: Dr. Devkota specializes in addressing the distinct challenges and considerations associated with kidney disease management in older adults, including age-related changes and comorbidities.

• Michael Lioudis
• Ramya Bhargava
• Kriti Devkota
• W. Clayton Elliott
• Brian Gallay
• Stephen Knohl
• John Leggat
• Haris Mobeen
• Sriram Narsipur

Identifying the Genetic Basis of Kidney Stones and Urinary Calcium

Kidney stones are a serious health and welfare issue for millions of Americans, affecting up to 12% of male Americans and 5% of females. Most stones are formed of calcium salts, and urinary hypercalciuria is the single greatest risk factor of this disorder. Earlier work suggested that nephrolithiatic was an autosomal dominant disorder, but later findings indicate a quantitative, polygenic construction of this disease.

Rodent models have been used for the investigation of this disorder: we are using F2 intercrosses Genetic Hypercalciuric Stone-forming (GHS) rats (a strain developed by our collaborator Dr. David Bushinsky via selection for increased calcium excretion, which resembles all major features of human idiopathic hypercalciuria) with normocalciuric Wistar rats to identify quantitative trait loci (QTL) for increased calcium excretion. We have detected two QTL for urinary calcium, hc1, and hc2, located on rat chromosomes 1 (RNO1; 229 MB) and 4 (RNO4; 51 MB). Both are additive and their expression is partially limited to males, which is evocative of differences in kidney stone rate in male and female humans. Our next objective is to identify gene candidates for these loci using congenic line development and gene expression analysis. Initial analysis using pedigreed QTL mapping confirms the presence of the HC1 QTL in our congenic lines.

Examining the Genetic Basis of Residual Deviations in Phenotype

Nearly the entirety of genetic analysis based on quantitative genetic assays and techniques implicitly assumes the constancy of genetic effects. However, increasing empirical evidence exists that this assumption may be incorrect: model systems using Drosophila, fish, and rodents suggest the presence of genetic effects on residual variance in morphology, physiology, and behavior. We are investigating this phenomenon using a fortuitous rodent model of urinary calcium excretion (GHS rats) and of Attention-Deficit/Hyperactivity Disorder (ADHD), the Spontaneous Hypertensive Rat (SHR); GHS females have higher variance in urinary calcium excretion than male GHS rats, and WKY males higher variance than WKY females. Using our F2 GHS×WKY mapping cohort, we have identified two significant QTL (hcpd1, hcpd2) and several suggestive QTL for individual phenotypic dispersion (PDi) in urinary calcium. Genes with high coefficients of variance (CV) near these QTL include those associated with methylation (Mmadhc, Suv420h2), spliceosome formation (Lsm5, Lsm8, Prpf38b, Tnpo3, Sprk1, Sprk2), serine physiology (serine-rich proteins being critically involved with spliceosome formation: Cdk5, Dkk2, Dmpk, Egf, Galnt11, Riok2, Serpine2, Srpk1, Srpk2, Tnpo3). In particular, Mmadhc and Tra2a were linked to hcpd1 and Lsm5 and two genes in the Fk gene familyFkp506, Fk506to hcpd2; Mmadhc has extreme CVs for expression in both kidney and duodenal tissue (>P3). These results strongly indicate the presence of genes responsible for residual variance and indicate a number of gene candidates in expected pathways: spliceosome formation, methylation, and the regulation of RNA transcription. Several other genes with high CVs linked to our QTL for PDi in urinary calcium were associated with metal ion binding: as a result, we do not know whether the dispersion of phenotype is a general process, ubiquitous to all genes (via general variability in spliceosome induction/mRNA modification/serine protein proportion) or a specific effect on metal ion genes, including those that manipulate Ca2+ physiology and that of associated ions. Sex appears to be a critical element of this process: Tra2a, a key gene in of sexual differentiation linked to hcpd2, also had high CVs in expression; our QTL for PDi are only significantly expressed in female F2 GHS×WKY rats, and previous work in these strains illustrates a marked difference in residual variance according to sex.

The Genetics of Craniosynostosis and Associated Disorders

Craniosynostosis, a relatively common congenital anomaly (1 in 2000 live births), has been linked to fibroblast growth factors (FGF) and FGF receptor mutations, but there is considerable heterogeneity among the various syndromes of craniosynostosis. We have recently discovered a putative spontaneous rat model of craniosynostosis, the spontaneous pug rat (SPR). SPR rats present hypoplasia of the mandible, premaxilla, and maxilla, along with fusion of both the coronal and sagittal sutures. Analysis by our lab indicates that this phenotype is recessive and has a highly negative genetic correlation with body size and a highly positive genetic correlation with calcium excretion. We are attempting to isolate the genetic basis of this phenotype and its connection with calcium excretion physiology.

To learn more about the clinical trials offered by our Nephrology division, click here.