Professor of Pediatrics, Medicine and Cell Biology; Director Division of Pediatric Nephrology

• Nephrology
• Pathobiology
• Keith A. Hruska Research Lab

The laboratory studies mechanisms of chronic kidney disease (CKD), and its complications. Our focus has been in the bone, cartilage and cardiovascular complications of CKD. We have discovered that chronic kidney diseases directly diminish bone formation and osteoblast number and function leading to an adynamic bone disorder (ABD) despite normal calcium, phosphorus, PTH and vitamin D. Decreased bone formation and the ABD contribute to the development of secondary hyperparathyroidism which is adaptive to the loss of skeletal anabolism. However, secondary hyperparathyroidism becomes maladaptive and causes an osteodystrophy, osteitis fibrosa. A skeletal anabolic factor, BMP-7, reverses the adynamic bone disorder to normal, and it restores the normal osteoblast phenotype in the dystrophic condition, osteitis fibrosis. Thus, BMP-7 holds promise in eliminating renal osteodystrophy from the list of complications of chronic kidney disease. Renal osteodystrophy of both forms 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 causing stimulation of vascular calcification (VC) in CKD. 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. Other studies in basic bone cell biology in the laboratory are focused on the lineage commitment of mesenchymal stem cells and novel mechanisms of osteoclast cytoskeletal regulation.

Education

• B.S., Creighton University, Omaha, Nebraska
• M.D., Creighton University, Omaha, Nebraska, 1969

Training

• Internship and Residency in Medicine, New York Hospital, Cornell University,
  1969-1970
• Second year resident in Medicine, Washington University, Barnes Hospital, St. Louis, Missouri, 1971-1972
• Fellow, Renal Division, Washington University, 1972-1974

Licensure and Board Certification

• Missouri License, 1971; Nebraska License, 1969; Illinois License, 1974
• American Board of Internal Medicine, 1972
• Subspecialty Boards, Nephrology, 1976

Honors

• Alpha Omega Alpha, 1969
• Fellow, National Kidney Foundation, 1974
• Established Investigatorship, American Heart Association, 1979-1984
• American Society of Clinical Investigation
• Association of American Physicians, 1990-present
• Ira M. Lang Chair in Nephrology, 1988-2001

Selected Publications

1. Mathew S, Lund R, Strebeck F, Tustison K,. Geurs T, Hruska KA: Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. J Am Soc Neph 2007; 18:122-130..

2. Hendy GN, Hruska KA, Mathew S, Goltzman D: New insights into mineral and skeletal regulation by active forms of vitamin D. Kidney Int 2006; 69:218-223.

3. Hruska KA, Mathew S, Saab G: Bone morphogenetic proteins in vascular calcification. Circ Res 2005; 97:105-114.

4. Sugatani T, Hruska KA: Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem 2005; 280:3583-3589.

5. Surendran K, Schiavi S, Hruska KA: Wnt-dependent-ß-catenin signaling is activated following unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Neph 2005; 16:2373-2384.