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.
Project Narrative: Relevance to Veterans'Health A growing number of veterans require dialysis for the treatment of acute kidney injury (AKI) sustained during surgery, trauma, crush injuries, sepsis or from nephrotoxic dyes and drugs. The associated morbidity and mortality remains high and functional recovery, if it occurs, may take from days to weeks, thus consuming enormous resources. It is imperative that more effective therapeutic tools be developed to help prevent and combat this disease, which is the goal of this proposal.