Pathologic studies demonstrate that kidney tubule injury, atrophy, and fibrosis are common features of chronic kidney disease (CKD) and are highly predictive of progression to dialysis. Established CKD risk factors including hypertension and advanced age are associated with tubular injury and fibrosis on biopsy. However, current clinical assessment of CKD evaluates only glomerular function (GFR) and glomerular injury (albuminuria), but not kidney tubular dysfunction or injury. The overall hypothesis of this application is that kidney tubular dysfunction and injury are measurable contributors to CKD pathogenesis and prognosis. Dysfunction of the kidney tubules will be assessed by three indices: (1) renal tubule resistance to hormone actions of FGF23 and PTH;(2) acid/base homeostasis;and (3) urine protein reabsorptive capacity. FGF23 and PTH are hormones that induce phosphaturia through effects on kidney tubules. FGF23 can directly cardiac toxicity, however it may also mark kidney dysfunction. In our preliminary work, we have demonstrated that elevated levels of FGF-23 or PTH are more strongly associated with adverse outcomes among persons with concomitantly lower urine phosphorus excretion. These findings suggest that indexing FGF23 and PTH to urine phosphorus identifies individuals with renal tubules that are resistant to these hormonal signals. Abnormal acid/base homeostasis and incomplete reabsorption of filtered proteins from the urine are additional markers of tubule dysfunction that may also be important for prognosis in persons with CKD. In addition, we have investigated several novel urinary proteins that are specific to renal tubular injury. Among community-living individuals without acute kidney injury, we have observed that higher urine concentrations of two markers (KIM-1 and IL-18) are associated with incident development of CKD and risk of death and heart failure, independent of eGFR or albuminuria. Collectively, these results have led us to hypothesize that an assessment of kidney tubular health that incorporates assessments of tubular dysfunction and injury could develop into a major advance in our assessment and management of CKD. Kidney tubular disease would capture a nonglomerular axis of CKD, and could help identify patients at greatest risk for CKD progression and CVD events. To address these objectives, we propose an ancillary study to the SPRINT trial - a large, NIH-sponsored, multi-center randomized clinical trial testing whether intensive (<120 mmHg) vs. standard (<140 mmHg) systolic blood pressure targets result in lower CVD events and rates of CKD progression. Among 2,566 SPRINT participants with eGFR <60ml/min/1.73m2 at baseline, we will: (1) determine the association of kidney tubular dysfunction and injury with risk of CVD events, (2) determine the association of kidney tubular dysfunction and injury with CKD progression, and (3) determine whether randomization to intensive blood pressure management arm of the trial slows progression of kidney tubular dysfunction and injury over time compared with standard blood pressure management.
Currently, clinical assessment of chronic kidney disease (CKD) entails measurement of glomerular function (eGFR) and injury (albuminuria);these markers are strongly associated with CKD progression and cardiovascular disease (CVD) events. However, the kidney has many other non-glomerular functions. Kidney biopsy studies demonstrate that the degree of kidney tubular atrophy and fibrosis are extremely potent prognostic factors not captured by glomerular markers. This study will be conducted within a large multi-center randomized blood pressure trial with long-term follow-up and adjudicated CKD and CVD events. We propose to make non-invasive measurements of kidney tubular function and injury, and to test whether they inform prognosis of CVD events and CKD progression independent of eGFR and albuminuria. In addition, we will test whether randomization to intensive blood pressure management limits progression of tubular injury and dysfunction over time.
|Raphael, Kalani L; Murphy, Rachel A; Shlipak, Michael G et al. (2016) Bicarbonate Concentration, Acid-Base Status, and Mortality in the Health, Aging, and Body Composition Study. Clin J Am Soc Nephrol 11:308-16|
|Kendrick, Jessica B; Zelnick, Leila; Chonchol, Michel B et al. (2016) Serum Bicarbonate Is Associated with Heart Failure in the Multi-Ethnic Study of Atherosclerosis. Am J Nephrol 45:118-126|
|Ix, Joachim H; Biggs, Mary L; Mukamal, Kenneth et al. (2015) Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study. J Am Soc Nephrol 26:2494-503|
|Garimella, Pranav S; Biggs, Mary L; Katz, Ronit et al. (2015) Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. Kidney Int 88:1126-34|
|Driver, Todd H; Shlipak, Michael G; Katz, Ronit et al. (2014) Low serum bicarbonate and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 64:534-41|
|Goldenstein, Leonard; Driver, Todd H; Fried, Linda F et al. (2014) Serum bicarbonate concentrations and kidney disease progression in community-living elders: the Health, Aging, and Body Composition (Health ABC) Study. Am J Kidney Dis 64:542-9|