Chronic kidney disease (CKD) is the precursor to most end-stage renal failure and is a potent risk factor for cardiovascular disease. Recent interest in CKD has focused on processes of structural change that occur later in the course of CKD when functioning kidney is replaced by scar tissue. We ascribe to the view that these processes begin as adaptive mechanisms, rooted in physiology, to compensate for an earlier injury, then go awry because the means to control them is lost. It is the general purpose of the proposed research to investigate cardinal features of kidney physiology early in the course of CKD by applying renal micropuncture methods in a standard model for early CKD, namely subtotal nephrectomy (STN) in the rat. We have discovered that feeding high NaCl diet to a rat during the first week after STN leads to a reversal of the tubuloglomerular feedback (TGF) response from negative to positive gain. While this will speed up the return to salt balance, it also signifies that the kidney is willing to forego the functional and hemodynamic stability normally conferred by TGF. This shift to anomalous TGF establishes a positive relationship between dietary salt intake and dynamic stretch-relaxation of the glomerular capillary wall, which may explain the nefarious effect of dietary salt in CKD. The upcoming research will determine whether this physiology remains relevant beyond the early stages of adaptation to nephron loss, whether it is a durable process that persists after high NaCl is withdrawn, whether it depends on Na, Cl, or both, and how it interacts with kidney metabolism.

Public Health Relevance

of the Proposed Work to the VA Patient Care Mission: We propose to study kidney physiology because this is prerequisite to understanding chronic kidney disease, which is common among veterans. Chronic kidney disease bears special importance in its own right and because it markedly increases the likelihood of cardiovascular disease. The general purpose of this research is to understand what happens when the diseased kidney is forced to choose between stabilizing its own function and responding to other needs of the body. The proposed research bears clinical relevance for its potential contribution to understanding how to optimize signals that affect kidney function for the benefit of both the kidney and the patient.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Nephrology (NEPH)
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VA San Diego Healthcare System
San Diego
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Singh, Prabhleen; Thomson, Scott C (2014) Salt sensitivity of tubuloglomerular feedback in the early remnant kidney. Am J Physiol Renal Physiol 306:F172-80
Thomson, Scott C; Blantz, Roland C (2012) Biophysics of glomerular filtration. Compr Physiol 2:1671-99
Blantz, Roland C; Singh, Prabhleen; Deng, Aihua et al. (2012) Acute saline expansion increases nephron filtration and distal flow rate but maintains tubuloglomerular feedback responsiveness: role of adenosine A(1) receptors. Am J Physiol Renal Physiol 303:F405-11
Singh, Prabhleen; Blantz, Roland C; Rosenberger, Christian et al. (2012) Aberrant tubuloglomerular feedback and HIF-1? confer resistance to ischemia after subtotal nephrectomy. J Am Soc Nephrol 23:483-93