Keith A. Hruska, M.D.  hruska_k@kids.wustl.edu

Professor of Pediatrics, Department of Medicine
Professor of Pediatrics, Nephrology
Professor of Pediatrics, Cell Biology & Physiology
Cell Biology & PhysiologyNephrologyDepartment of MedicinePathobiology

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Research Interests

The laboratory studies chronic kidney disease (CKD), and mechanisms of its complications. Our focus has been in the high cardiovascular mortality associated with CKD. We have discovered that the skeletal disorder caused by CKD contributes to this mortality. This has lead to the naming of a CKD associated syndrome, the CKD-mineral bone disorder (CKD-MBD). In the CKD-MBD, we have discovered that kidney diseases directly cause vascular calcification and diminish bone formation early in their course despite normal calcium, phosphorus, PTH and vitamin D. Increased tubular fluid phosphate stimulates secretion of fibroblast growth hormone 23 (FGF23), which is a skeletal hormone regulating phosphorus excretion and calcitriol production. Besides stimulation of FGF23, the early pathogenesis of the CKD-MBD, which we have shown in stage 2 CKD, results from release of factors including Wnt inhibitors from the injured kidney during attempted repair. Systemic Wnt inhibition causes vascular disease producing vascular stiffness/calcification, and cardiac hypertrophy. Skeletal anabolic factors, such as neutralization of Wnt inhibition and bone morphogenetic protein 7 (BMP-7), increase bone formation and inhibit vascular calcification in the early CKD. Additionally, BMP-7 restores the normal osteoblast phenotype in the dystrophic condition, osteitis fibrosis. Thus, BMP-7 and skeletal anabolics hold promise in as therapies for the CKD-MBD, and BMP-7, through its renal actions, as a therapy for CKD itself. The CKD-MBD is associated with excess bone resorption which contributes to hyperphosphatemia in CKD. We have shown that hyperphosphatemia is a direct stimulus to osteoblastic differentiation of cells in the neointima of atherosclerotic plaques causing stimulation of vascular calcification (VC) in CKD. This mechanism added to observational studies strongly suggests that phosphorus is a cardiovascular risk factor. We have discovered that members of the bone morphogenetic protein (BMP) family differentially affect lineage allocation of mesenchymal stem cells. While BMP-7 and BMP-2 support endochondral osteogenesis, their actions differ, and BMP-13 favors chondrogenesis. This is critical in the pathogenesis of vascular calcification because BMP-2 is causative of VC, while BMP-7 is therapeutic, capable of reversing established calcification. BMP-7 is a critical renal morphogen. It is expressed in the adult kidney, and its expression is reduced by renal injuries. BMP-7 exhibits therapeutic potential against renal fibrogenesis and diabetic nephropathy, and for vascular calcification and renal osteodystrophy as discussed above. Furthermore, we have discovered that the chondrogenic program represented by autocrine factors, including BMP-13, produced by juvenile chondrocytes is sufficient for the entire differentiation program of the articular cartilage. These data support juvenile articular tissue as potential allograft sources for repair of cartilage injuries. The latter concepts have been taken to clinical trial as have the studies of phosphorus as a cardiovascular risk factor. Other studies in basic bone cell biology in the laboratory are focused on the lineage commitment of mesenchymal stem cells and novel mechanisms of osteoclastogenesis by microRNAs.

Education

  • BS, 1962 - 1965 Undergraduate, Creighton University, Omaha1965
  • MD, Creighton University School of Medicine1969

Training

  • Internship, Cornell University1969 - 1970
  • 1st yr Residency, Cornell University1970 - 1971
  • 2nd year Residency, Washington University, Barnes Hospital 1971 - 1972
  • Fellowship Nephrology, Washington University 1972 - 1974

Licensure and Board Certification

  • NE, 1969
  • MO, 1971
  • American Board of Internal Medicine 1972
  • IL, 1972
  • Subspecialty Boards, Nephrology 1975

Honors

  • Alpha Omega Alpha1969
  • Fellow, National Kidney Foundation1974 - 1974
  • Established Investigatorship, American Heart Association1979 - 1984
  • American Society for Clinical Investigation1981
  • Association of American Physicians (AAP)1985
  • Ira M Lange Chair in Nephrology1988 - 2001
  • Councilor, American Society of Bone and Mineral Metabolism1989 - 1992
  • Best Doctors in America2000 - 2015
  • International Pediatric Nephrology Association2004 - Pres
  • Who's Who in America2004 - 2015
  • Visiting Scientist - Spanish Society of Nephrology2005
  • Secretary/Treasurer - American Society of Bone and Mineral Research2006 - 2008
  • President Elect, American Society of Bone and Mineral Research2010 - 2011
  • President, American Society of Bone and Mineral Research2011 - 2012
  • Past-President, American Society of Bone and Mineral Research2012 - 2013
  • Alumni Achievement Award, Washington University2014
  • Shirley Hohl Service Award, American Bone and Mineral Research Society2014

Selected Publications view all (259)


Publication Co-Authors

1.
Androgens Enhance Male Urinary Tract Infection Severity in a New Model. J Am Soc Nephrol. 2016;27(6):1625-34. PMCID:PMC4884108  PMID:26449605 
2.
The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder. Transplantation. 2016;100(3):497-505. PMCID:PMC4764429  PMID:26356179 
3.
SIRT6 deficiency culminates in low-turnover osteopenia. Bone. 2015;81:168-77. PMCID:PMC4640951  PMID:26189760 
4.
Pathophysiology of the chronic kidney disease-mineral bone disorder. Curr Opin Nephrol Hypertens. 2015;24(4):303-9. doi:10.1097/MNH.0000000000000132  PMCID:PMC4699443  PMID:26050115 
5.
Clinical phenotype of APOL1 nephropathy in young relatives of patients with end-stage renal disease. Pediatr Nephrol. 2015;30(6):983-9. doi:10.1007/s00467-014-3031-0  PMCID:PMC4406792  PMID:25530085 
6.
Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus. Am J Nephrol. 2015;42(6):391-401. doi:10.1159/000443241  PMCID:PMC4732898  PMID:26693712 
7.
Expression of DGCR8-dependent microRNAs is indispensable for osteoclastic development and bone-resorbing activity. J Cell Biochem. 2014;115(6):1043-7. doi:10.1002/jcb.24759  PMCID:PMCID: PMC4079251  PMID:24420069 
8.
CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol. 2014. doi:10.1681/ASN.2013080818  PMCID:PMCID: PMC4116062 [Available on 2015-08-01]  PMID:24578135 
9.
Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int. 2014;85(1):142-50. doi:10.1038/ki.2013.271  PMCID:PMC3836911  PMID:23884339 
10.
Left ventricular mass progression despite stable blood pressure and kidney function in stage 3 chronic kidney disease. Am J Nephrol. 2014;39(5):392-9. doi:10.1159/000362251  PMCID:PMC4066883  PMID:24818573 
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