The National Institute of Diabetes & Digestive & Kidney Diseases

Dr. Kopp graduated from Harvard College (1975), University of Pennsylvania Medical School (1980) and completed training in Internal Medicine and Nephrology at the University of Washington (1987). He came to the NIH in 1987 and has been with the National Institute for Diabetes and Digestive and Kidney Disease since 1995. He is a consulting nephrologist at the NIH Mark Hatfield Clinical Research Center. Dr. Kopp is a Commissioned Officer with the US Public Health Service, holding the rank of Captain. He is an active member of the PHS-1 Rapid Deployment Force, a 105-person medical team that deploys for disasters and public health threats. Honors include the NIDDK Directors Award for service on a medical team in Baton Rouge, Louisiana during Hurricane Katrina Medal and the USPHS Outstanding Service Medal for policy development addressing the needs of dialysis patients following disasters. Dr. Kopp is Adjunct Professor of Medicine at the Uniformed Services University of the Health Sciences. He serves on the Editorial Boards of the American Journal of Nephrology, the American Journal of Physiology (Renal) and Biomed Central Nephrology. He has authored over 160 scientific papers, reviews, and book chapters.

Dr. Kopp leads a translational research group within the Kidney Disease Section, Kidney Diseases Branch, focusing on focal segmental glomerulosclerosis and related podocyte diseases. Recently highlights include the following:

• MYH9 encodes non-muscle myosin heavy chain 9, a component of myosin IIA, which is cellular motor. An MYH9 genetic variant accounts for nearly all the increased risk for FSGS and HIV-associated collapsing glomerulopathy that characterizes African descent individuals. Strikingly, the risk alleles confer a high odds ratio for idiopathic FSGS (approximately 5) and for HIV-associated collapsing glomerulopathy (approximately 7). Further, the risk alleles appear to be the original human allele, with a prevalence of 50-100% in sub-Saharan African populations and 60% in African Americans but only 4% in European Americans and 0% in East Asian populations.

• The anti-fibrotic and cytoprotective drug pirfenidone slows progression of kidney function loss by about 30% in FSGS patients, when used in addition to angiotensin pathway antagonists.

• The HIV-1 protein Vpr, expressed in the glomerular podocytes, is sufficient to reproduce the chief features of HIV-associated collapsing glomerulopathy in transgenic mice.

Current research efforts:

• Defining how MYH9 genetic variation contributes hypertensive kidney disease. We propose that the risk variant results in a fragile podocyte phenotype. We wish to determine whether the risk genotype causes glomerulosclerosis, which leads to hypertension (the glomerulosclerosis-first mode), or alternatively whether essential hypertension acts on a susceptible podocytes to cause glomerulosclerosis (the hypertension-first model).

• Determining whether MYH9 risk alleles are associated with a shorter renal allograft survival and or worse renal donor outcomes (albuminuria, glomerulosclerosis).

• Determining the mechanisms by which MYH9 risk alleles influences podocyte phenotype and confers susceptibility to glomerular disease.

• Determining the prevalence of persistent microalbuminuria among patients with HIV-disease, the histologic correlates, the role of MYH9 genetic variation and the renal outcomes over several years of follow-up.

• An open label phase II trial examining the efficacy of rituximab combined with cyclosporine (for 48 weeks) for treatment refractory podocyte disease.

• An open label phase II trial examining the efficacy of isotretinion (over 24 to 48 weeks) for treatment refractory podocyte disease. Retinoids have been shown to favorably influence the outcome of experiemental glomerular disease and may be trophic for the podocyte. Principle Investigator: Dr. Monqiue Cho.

• Examining the use of cylophosphamide plus plasma exchange for recurrent FSGS following renal transplant and assessment of the role of cardiotrophin-like cytokine 1 as a candidate permeability factor (in collaboration with Dr. Virginia Savin, University of Kansas)

• Developing a deeper understanding of the role of TGF-beta in podocyte injury, including microRNA as mediators of TGF-beta activity and influence on retinoid biology.

Information for patients:

All NIH trials are listed at clinicaltrials.gov

Information about glomerular diseases is available at www2.niddk.nih.gov/NIDDKLabs/Glomerular_Disease_Primer/

Reagents available to the research community:

Transgenic mice

• Podocin promoter/rTTA (reverse tetracycline transactivator) – also available from JAX

• TRE (tet responsive element)/Vpr

• Alb/TGF-beta mice (request permission from Dr. Snorri Thorgeirsson, NCI)

Antibodies

• rabbit polyclonal antibody to Vpr1-50 peptide – also available from AIDS Research and Reference Reagent Program

• rabbit antiserum to human podocin (cross reactive with mouse podocin)

• rabbit antiserum to human nephrin (no cross reactivity with mouse nephrin)

• goat anti-mouse mesangial cell serum, for induction of glomerulonephritis in mice

Podocyte cell lines

• mouse podocytes, immortalized with thermosensitive SV40 T Ag and bearing podocin/rtTA, for expression of genes of interest in cultured mouse podocytes

• same, plus TRE silencer to reduce background expression

• human podocytes, immortalized with hTERT and thermosensitive SV40 T Ag

Please contact us for further details. NIDDK MTAs are available at techdev.niddk.nih.gov/EXPEDITED-MATERIAL-TRANSFERS/ or browse “NIDDK MTA”

Opportunities for research fellowship in the Kidney Disease Section:

• Laboratory research fellowship, for periods of 2-5 years. Research area is podocyte cell biology. Requires a doctoral level degree and substantial laboratory research background.

• Senior clinical research fellowship, for periods of 2-5 years. Requires a medical degree, internal medicine or pediatrics residency, nephrology fellowship, and a US medical license. Training is focused on developing translational studies of podocyte diseases including genetic causes and novel therapies. Other mentors include Dr. James Balow and Dr. Howard Austin, whose research program focuses on immune-mediated kidney disease. Most fellows will complete a Masters in Health Sciences degree jointly sponsored by NIH and Duke University – for more details visit www.cc.nih.gov/training/duke.html.

Primary publications

Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Ahuja TS. Berns JS, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Kajiyama H, Winkler CA. Genome wide admixture mapping identifies MYH9 as a major effect risk gene for focal segmental glomerulosclerosis. Nature Genetics 40: 1175-1184, 2008.

Kajiyama J, Titus S, Austin C, Chiotos K, Matsumoto T, Sakairi T, Kopp JB. Tetracyclne-inducible gene expression in conditionally immortalized mouse podocytes. Am J Nephrol 29:153-163, 2008.

Shrivastav S, Kino T, Schubert U, Heinklein P, Chrousos G, Kopp JB. HIV-1 Vpr suppresses the transcriptional activity of PPAR-gamma and inhibits adipocyte differentiation: Implications for HIV-associated lipodystrophy. Mol Endocrinol 22:234-247, 2008.

Cho M, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2:906-13, 2007.

McKenzie LM, Hendrickson SL, Briggs WA, Dart RA, Korbet SM, Mokrzycki MH, Kimmel PL, Ahuja TS, Berns JS, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Cho M, Zhou YC, Binns-Roemer E, Kirk GD, Kopp JB, and Winker CA. Role of NPHS2 variation in sporadic FSGS: A common haplotype is protective and heterozygosity for R138Q is a risk factor. J Am Soc Nephrol, 18: 2987-2995, 2007.

Balasubramanyam A, Mersmann H, Jahoor F, Phillips T, Schubert U, Brar B, Iyer D, Smith EO, Takahashi H, Lu H, Kopp JB. Effects of transgenic expression of HIV-1 protein Vpr on energy metabolism in mice. Am J Physiol 292:E40-48, 2007.

Cho M, Hurley J, Kopp JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis, 49:310-17, 2007

Xu Q, Norman JT, Shrivastav S, Lucio-Cazana J, Kopp JB. Cell-based models of TGF-beta induced fibrogenesis for high-throughput screening of anti-fibrotic agents. Am J Physiol 293:F631-40, 2007.

Reviews and book chapters

Cho ME, Kopp JB. Pirfenidone: an anti-fibrotic and cytoprotective agent as therapy for progressive kidney disease. Expert Opin Invest Drugs, in press.

Kopp JB, Fabian J, Naicker S. HIV infection and the kidney. Comprehensive Clinical Nephrology, RJ Johnson and J Feehally. Third Edition, 2009.

Marasa M, Kopp JB. Monoclonal antibodies as therapy for the podocytopathies: biologic rationale and clinical responses. Nature Clin Pract Nephrol 2009:337-348, 2009.

Barisoni L, Schnaper HW, Kopp JB. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and management. Arch Pathol 133:201-216, 2008.

Waldman M, Marshall V, Whitby D, Kopp JB. Viruses and kidney disease: beyond HIV. Sem Nephrol 28:595-607, 2008.

Woronie R, Kopp JB. Genetics of focal segmental glomerulosclerosis. Pediatr Nephrol 5:638-644, 2007.

Barisoni L, Schnaper HW, Kopp JB. A working classification of podocytopaties integrating morphologic and etiologic criteria. C J Am Soc Nephrol 2:529-542, 2007.

Kopp JB, Ball LK, Cohen A, Kenney RJ, Lempert KD, Miller PE, Muntner P, Qureshi N, Yelton SA. Kidney Patient care in disasters: lessons from the hurricanes and earthquake of 2005. Clin J Am Soc NephroL 2:814-824, 2007.

Kopp JB, Ball LK, Cohen A, Kenney RJ, Lempert KD, Miller PE, Muntner P, Qureshi N, Yelton SA. Kidney Patient care in disasters: Emergency planning for patients and dialysis facilities. Clin J Am Soc Nephrol 2:825-838, 2007.

Waldman M, Kopp JB. Parvovirus B19 and kidney disease. Clin J Am Soc Nephrol 2 Suppl 1:S47-56, 2007.

Waldman M, Kopp JB. Parvovirus B19-associated complications in renal transplant recipients. Nat Clin Pract Nephrol 3:540-550, 2007.