SDF-1: A Diagnostic and Therapy-Specific Biomarker of AKI and CKD

Va Salt Lake City Healthcare System, Salt Lake City UT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): SIGNIFICANCE and LONG-TERM OBJECTIVE: Acute kidney injury (AKI) is a largely treatment resistant complication encountered after major surgery, shock, sepsis, or administration of nephrotoxic drugs. The frequent progression of AKI to Chronic Kidney Disease (CKD), persistently high mortality rates (>50 %) and treatment costs continue to make AKI a major public health problem, warranting the development of new therapies and diagnostic biomarkers, which is the goal of this proposal. HYPOTHESES: We have shown that mesenchymal stem cells (MSC) in AKI act renoprotectively through complex paracrine actions, and are currently testing this technology in a Phase I Clinical Trial. We showed 1st, that ischemic AKI results in prompt up regulation of the chemokine Stromal Derived Factor-1 (SDF-1 or CXCL12) in the kidney;2nd, urinary SDF-1 levels rise dramatically at 2 hrs post AKI, and decline with recovery;and 3rd, because MSC express CXCR4, the SDF-1 receptor, high SDF-1 levels mediate their homing and thereby their renoprotective actions in AKI. We hypothesize, therefore, (1) that a rise in urinary levels of SDF-1 has utility as a new, early injury marker of AKI or potentially of "unresolved" AKI or progressive CKD;(2) that peak urine levels of SDF-1 after AKI identifies the time point at which MSC thereby is most effective;and (3) that elevated urinary SDF-1 levels, if indicative of persistent injury post AKI or in CKD, similarly signify that MSC therapy may be beneficial. SPECIFIC AIMS: The present work is designed to investigate whether monitoring of the urine for a rise of SDF-1 has utility (1) as a novel, diagnostic biomarker of AKI, and potentially progressive CKD;and (2) as a therapy-specific biomarker for AKI, i.e., for the identification of the time point when MSC therapy would be most effective, and potentially in progressive CKD. RESEARCH DESIGN and METHODS: Specific Aim 1: Utilizing bilateral I/R AKI and 5/6 nephrectomy CKD models in rats, temporal SDF-1 profiles in serum, kidney and urine are defined and correlated with function and NGAL levels. If urinary SDF-1 levels parallel renal SDF-1 levels and function, their monitoring will be sufficient for the early and noninvasive diagnosis of AKI. The influence of MSC therapy on renal SDF-1 and NGAL profiles is assessed. Similarly, in order to determine whether urinary SDF-1 levels can identify ongoing chronic renal injury, SDF-1 and NGAL profiles and renal function are monitored early and late after AKI and 5/6th nephrectomy. Specific Aim 2: Once SDF-1 profiles post AKI have been defined, it will be tested whether MSC therapy at peak urinary SDF-1 levels is most renoprotective, thereby potentially allowing a reduction in the dose of needed MSC. If it is demonstrated that persistently elevated urinary SDF-1 levels correlate with injury due to unresolved AKI or progressive CKD, the utility of MSC therapy in these conditions will be examined.