Robert A. Star, M.D. : NIDDK

Robert A. Star, M.D.

NIDDK, National Institutes of Health
Building 31, Room 9A19C
31 Center Dr.
Bethesda, MD 20892
Tel: 301-496-6325
Fax: 301-402-4874

Research Website:

Education / Previous Training and Experience:
B.A., Harvard, 1976
M.D., Harvard Medical School--MIT, 1980

Research Statement:

The morbidity and mortality of acute renal failure (ARF) have remained high despite numerous attempts at novel therapies. Many agents have worked in animals but failed in clinical trials. Effective treatment likely requires early detection and a better understanding of the pathophysiology of human ARF. Our long_term goals are to find markers to detect ARF and to therapies to treat and prevent ARF. We have recently found:

Therapeutics: Whereas many agents can prevent experimental renal injury when started before the insult, only a few agents are capable of treating ARF in animals. We found that the anti-inflammatory cytokines alpha_melanocyte stimulating hormone (MSH) and interleukin-10 (IL-10) inhibit renal injury in mouse ischemia and cisplatin injury models. "-MSH decreases injury even when given 6 hrs after ischemia; IL-10 is effective when started 1 hr after cisplatin. We initiated a Phase 1 safety trial of "-MSH at UT-Southwestern. Single doses of "-MSH (at levels used in the animal experiments) were safe; the only side effect was that "-MSH increased blood pressure, which might be helpful in ARF. "-MSH inhibits key maladaptive steps such as leukocyte infiltration, induction of IL_8, ICAM_1, inducible NO synthase, activation of Nf-kB and the p38 MAP kinase pathway. Unfortunately, neither "-MSH nor IL-10 protect against mercuric chloride nephrotoxic ARF in mice. However, we recently found that DMSO inhibits mercuric chloride nephrotoxicity, even when DMSO is started 4 hrs after mercury.

Detection of ARF: ARF is diagnosed by a progressive rise in serum creatinine over several days. However, patients are typically volume overloaded which dilutes creatinine and delays diagnosis. Therapeutic agents must be started early; therefore, early detection is critical. By RNA subtraction, we found that one gene, cyr61, was markedly increased 2 hrs in proximal straight tubules but not in other organs after renal ischemia. Cyr61 protein was increased in mouse and rat kidneys within 1 hr, and was detected in urine at 3-6 hrs after ischemia. Cyr61 was not detected volume depletion, which is often difficult to differentiate from ARF. We hypothesize that cyr61, a secreted growth factor-inducible immediate early gene, is rapidly induced in proximal tubules following ischemia and excreted in the urine. Urinary cyr61 might detect subtle renal injury after chemotherapy, transplantation, vascular surgery, multi-organ failure, or in kidney donors.

Non-invasive diagnosis of renal dysfunction. Determining the pathophysiology of human ARF has been difficult because of the paucity of renal biopsies. We developed two magnetic resonance imaging methods for use in mice. The first uses dendrimer-based contrast agents to detect dysfunction of the proximal tubule, the primary site of renal injury. This method has a 160 micron spatial resolution on a 1.5T clinical MRI unit. The gradation of tubular damage as assessed by MRI correlated with renal function. This method can also detect renal damage at two hrs after renal ischemia. We have recently screened a dendrimer library and found several agents that have better pharmacokinetics, but preserved imaging features.

We also developed a MRI method to detect inflamation, which is prominent in animal models of ischemia, but unknown if present in human ARF. We used ultrasmall superparamagnetic iron oxide (USPIO) particles that are engulfed by macrophages. USPIO-enhanced MR imaging could non-invasively detect inflammation in ischemic ARF. USPIO particles appeared as a black band in the outer medulla, the exact location of the inflammation in this model. In contrast, the black band was not detected in normal animals or in a non-inflammatory renal injury model. The change in signal intensity correlated with serum creatinine and the number of iron particle containing cells. This method might be useful to determine the pathogenesis of human ARF and to evaluate the effectiveness of anti-inflammatory agents.

Clinically relevant sepsis model of ARF. Sepsis is one of the leading causes of ARF, and 50% of the patients with sepsis develop ARF. The pathogenesis of sepsis-induced ARF is very poorly understood, and there are no drugs to treat sepsis-induced ARF; in part because of the lack of animal models that mimic the human disease. Therefore, we developed a new mouse model based upon the cecal ligation and puncture model of polymicrobial sepsis which has hyperdynamic and hypodynamic phases typical of human sepsis. To make the model realistic, we gave post-operative fluids and antibiotics. The mice develop biochemical and histological renal injury that is similar to human ARF. We are now characterizing this model and using it to test treatment strategies. We have found one agent that is effective even when started 6 hours after induction of sepsis.

Tool development: Laser Capture Microdissection (LCM). The kidney is an anatomically complex organ with exceptional cellular heterogeneity. We modified LCM for use in kidney tissue and devised an immunofluorescence_LCM technique to allow the microdissection of specifically tagged nephron segments.

Tool development: Frozen protein arrays.Current methods for producing protein arrays require sophisticated equipment or extensive protein modification. We developed an economical method of arraying liquid samples and detecting proteins. Wells made in a frozen block of embedding material were filled with biological samples, which freeze and bond to the surrounding block. The loaded block was cut in a cryostat, and sections were transferred to nitrocellulose slides. The reproducibility, linearity, and sensitivity were excellent. Frozen protein arrays could also detect native tissue proteins, with good correlation with western blotting. Thus, frozen protein arrays are a low cost, moderate size platform for arraying samples. Production of many identical frozen protein arrays is easy, inexpensive, and requires only small sample volumes. 

Clinical Protocols

  • Search for Novel Methods to Detect Acute Renal Failure , 00-DK-0107

Selected Publications:

Yuen PS, Dunn SR, Miyaji T, Yasuda H, Sharma K, Star RA A simplified method for HPLC determination of creatinine in mouse serum. Am J Physiol Renal Physiol (286): F1116-9, 2004. [Full Text/Abstract]

Jo SK, Hu X, Yuen PS, Aslamkhan AG, Pritchard JB, Dear JW, Star RA Delayed DMSO administration protects the kidney from mercuric chloride-induced injury. J Am Soc Nephrol (15): 2648-54, 2004. [Full Text/Abstract]

Hewitt SM, Dear J, Star RA Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol (15): 1677-89, 2004. [Full Text/Abstract]

Kobayashi H, Kawamoto S, Brechbiel MW, Jo SK, Hu X, Yang T, Diwan BA, Waldmann TA, Schnermann J, Choyke PL, Star RA Micro-MRI methods to detect renal cysts in mice. Kidney Int (65): 1511-6, 2004. [Full Text/Abstract]

Kobayashi H, Jo SK, Kawamoto S, Yasuda H, Hu X, Knopp MV, Brechbiel MW, Choyke PL, Star RA Polyamine dendrimer-based MRI contrast agents for functional kidney imaging to diagnose acute renal failure. J Magn Reson Imaging (20): 512-8, 2004. [Full Text/Abstract]

Kobayashi H, Kawamoto S, Choyke PL, Sato N, Knopp MV, Star RA, Waldmann TA, Tagaya Y, Brechbiel MW Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonance lymphangiography. Magn Reson Med (50): 758-66, 2003. [Full Text/Abstract]

Jo SK, Hu X, Kobayashi H, Lizak M, Miyaji T, Koretsky A, Star RA Detection of inflammation following renal ischemia by magnetic resonance imaging. Kidney Int (64): 43-51, 2003. [Full Text/Abstract]

Miyaji T, Hu X, Yuen PS, Muramatsu Y, Iyer S, Hewitt SM, Star RA Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int (64): 1620-31, 2003. [Full Text/Abstract]

Barisoni L, Star RA Laser-capture microdissection. Methods Mol Med (86): 237-55, 2003. [Full Text/Abstract]

Kobayashi H, Kawamoto S, Jo SK, Bryant HL Jr, Brechbiel MW, Star RA Macromolecular MRI contrast agents with small dendrimers: pharmacokinetic differences between sizes and cores. Bioconjug Chem (14): 388-94, 2003. [Full Text/Abstract]

Kobayashi H, Kawamoto S, Star RA, Waldmann TA, Tagaya Y, Brechbiel MW Micro-magnetic resonance lymphangiography in mice using a novel dendrimer-based magnetic resonance imaging contrast agent. Cancer Res (63): 271-6, 2003. [Full Text/Abstract]

Miyaji T Hu X Star RA alpha-Melanocyte-simulating hormone and interleukin-10 do not protect the kidney against mercuric chloride-induced injury. Am J Physiol Renal Physiol (282): F795-801, 2002. [Full Text/Abstract]

Muramatsu Y Tsujie M Kohda Y Pham B Perantoni AO Zhao H Jo SK Yuen PS Craig L Hu X Star RA Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int (62): 1601-10, 2002. [Full Text/Abstract]

Miyaji T Hewitt SM Liotta LA Star RA Frozen protein arrays: a new method for arraying and detecting recombinant and native tissue proteins. Proteomics (2): 1489-93, 2002. [Full Text/Abstract]

Miyaji T, Hewitt SM, Liotta LA, Star RA Frozen protein arrays: a new method for arraying and detecting recombinant and native tissue proteins. Proteomics (2): 1489-93, 2002. [Full Text/Abstract]

Star R Hostetter T Hortin GL New markers for kidney disease. Clin Chem (48): 1375-6, 2002. [Full Text/Abstract]

Kobayashi H Kawamoto S Jo SK Sato N Saga T Hiraga A Konishi J Hu S Togashi K Brechbiel MW Star RA Renal tubular damage detected by dynamic micro-MRI with a dendrimer-based magnetic resonance contrast agent. Kidney Int (61): 1980-5, 2002. [Full Text/Abstract]

Deng J Kohda Y Chiao H Wang Y Hu X Hewitt SM Miyaji T McLeroy P Nibhanupudy B Li S Star RA Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int (60): 2118-28, 2001. [Full Text/Abstract]

Kohda Y Murakami H Moe OW Star RA Analysis of segmental renal gene expression by laser capture microdissection. Kidney Int (57): 321-31, 2000. [Full Text/Abstract]

Murakami H Liotta L Star RA IF-LCM: laser capture microdissection of immunofluorescently defined cells for mRNA analysis rapid communication. Kidney Int (58): 1346-53, 2000. [Full Text/Abstract]

Kohda Y Chiao H Star RA alpha-Melanocyte-stimulating hormone and acute renal failure. Curr Opin Nephrol Hypertens (7): 413-7, 1998. [Full Text/Abstract]

Chiao H Kohda Y McLeroy P Craig L Linas S Star RA Alpha-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils. Kidney Int (54): 765-74, 1998. [Full Text/Abstract]

Star RA Treatment of acute renal failure. Kidney Int (54): 1817-31, 1998. [Full Text/Abstract]

Chiao H Kohda Y McLeroy P Craig L Housini I Star RA Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest (99): 1165-72, 1997. [Full Text/Abstract]

Page last updated: December 17, 2008

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