Renal functional reserve: from physiological phenomenon to clinical biomarker and beyond

Abstract

Glomerular filtration rate (GFR) is acutely increased following a high protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in pre-glomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a 'renal reserve' which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in sub-clinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that, once a decline in basal GFR can be detected, renal disease is already well-progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction, before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.

Current Concepts of Pediatric Acute Kidney Injury—Are We Ready to Translate Them into Everyday Practice?

“…The value of basal eGFR and the extent to which it can increase in stress conditions both depend on the intact renal mass. In consequence, return to the baseline eGFR value after a temporary decline in the course of a single episode of AKI can be achieved, although it is reached at the cost of reduced RFR [ 30 ]. Repeat AKI episodes may lead to continuous mobilization of RFR to maintain eGFR.…”

“…These observations urge to describe the phenomenon of hyperfiltration. The hypothetical process has been analyzed in detail in the case of oral protein load or amino acid infusion [ 30 , 34 ]. The major force triggering hyperfiltration in this case is tubuloglomerular feedback.…”

“…Oral protein intake or amino acid infusion result in the increased filtered load of amino acids and their aggravated reabsorption, together with NaCl, by proximal tubules [ 30 ]. In consequence, diminished delivery of NaCl to distal tubules senses macula densa to inhibit the activity of tubuloglomerular feedback and evoke hyperfiltration through vasodilatation of the afferent artery.…”

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“…Similarly, sCr does not immediately decrease when GFR improves [ 18 ]. Lack of renal functional deterioration may also reflect the absence of subtle chronic kidney disease, with an intact renal functional reserve that compensates for a transient subtle injury [ 19 ]. Recent data suggest that early diagnosis of AKI can be made by using a single structural or functional biomarker (or a combination thereof) capable of detecting kidney injury almost in real time [ 6 ].…”

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“…Among the possible diagnostic strategies aimed to better evaluate renal function status, the evaluation of renal functional reserve (RFR) could be clinically useful. RFR represents the ability of the kidney to increase GFR and glomerular filtration in response to stimuli in physiological or pathological conditions [27,28]. RFR allows one to increase the glomerular filtration rate of residual nephrons, vicariously, through the lost function and maintenance of the GFR.…”