Alarm off: Maintained kidney tissue oxygen tension when mobilizing GFR reserve

Abstract

In the current issue of Acta Physiologica, Jufar et al¹ address the coupling between changes in glomerular filtration rate and kidney tissue oxygenation. This relation gains increased attention not least due to the demonstration that blocking transepithelial transport in humans by, for example, the loop diuretic furosemide may increase kidney tissue oxygen tension and lower consumption.² The assumption is that sudden increases in GFR would be followed by proportional increases in tubular epithelial transport workload and oxygen consumption. This could potentially lead to lower tissue oxygen tension if not balanced by an increase in renal blood flow and particularly in the medulla where blood supply is limited. Jufar et al¹ elegantly exploit in vivo techniques to directly measure kidney regional oxygen tension in a large animal model (sheep). Infusion of a mixture of amino acids, a classic maneuver to mobilize renal reserve capacity, resulted in an increase in GFR (40%), renal blood flow and oxygen supply accompanied by increased oxygen consumption. Of novelty was the insertion of dual-fiber optic probes in tissue to record tissue O₂ tension, temperature, and flow with validation of placement post hoc. Cortex and medulla tissue oxygenation did not decrease but rather increased in response to amino acid infusion. Authors conclude that in healthy adult sheep, the mobilization of renal reserve capacity, at least by amino acid infusion, with documented increase in sodium reabsorption, does not threaten kidney tissue oxygenation in this acute setting.

As always using a complex in vivo setting, several interpretations and confounders must be taken into consideration before extrapolating safely to more chronic and human settings. The study raises several interesting questions. Renal functional reserve denotes the ability to increase GFR above and beyond baseline. This can be done experimentally and diagnostically in humans by, for example, dopamine infusion, increased protein intake/amino acid infusion (as used here) and is seen, more dramatically, in the remaining kidney following donation of one kidney or cancer nephrectomy. In physiological settings, pregnancy is a situation where GFR increases above normal and in pathophysiology, early diabetes is associated with increased GFR. These situations are quite different but are characterized by different degrees of increased renal blood flow and likely by differential changes in glomerular arteriolar resistances. Amino acid infusion is thought to, at least partially, rely on attenuated tubuloglomerular feedback (TGF), similarly to early diabetes and high protein intake. Increased filtration of amino acids (or glucose in diabetes) will increase proximal reabsorption of Na⁺ and lower tubular NaCl concentration at the macula densa leading to afferent arteriolar dilatation. A specific feature of the amino acid infusion approach, also discussed by authors, is the impact of L-arginine which is substrate for particularly eNOS. This likely leads to an increase in NO formation in vivo but was not addressed by authors. Nitric oxide dilates renal vessels and here of particular interest also medullary resistance vessels³ and such an effect could contribute to the observed stabilization or increase in medullary oxygen tension. This remains a likely situation not least because systemic arterial pressure dropped resulting in increased sympathetic outflow based on increased heart rate.¹ Such a drop is not observed when reserve capacity is mobilized after, for example, unilateral nephrectomy in donors but is typical for healthy pregnancy. It is reassuring that despite arterial pressure drop with increased filtered load, no decrease in oxygen tension is observed across kidney regions. A similar observation was done previously by authors after extracellular volume expansion.⁴ The amino acid infusion approach used by authors is different from the normal physiological absorptive gastrointestinal route for amino acid uptake. Protein-rich meals will initiate the secretion of intestinal incretin hormones GIP/GLP-1 and glucagon that exert effects on the kidneys.

Another relevant but difficult extrapolation is to the chronic setting. A dogma is that glomerular hypertension will lead to kidney injury. However, mobilization of renal functional reserve with hyperfiltration after healthy pregnancy and after family kidney donation (and cancer nephrectomy) is not leading to negative consequences in the long term. Large follow-up studies document that previous healthy kidneys stay healthy in family kidney donation even after many years of hyperfiltration. In fact, the magnitude of reserve capacity recruited in the single remaining kidney is associated with better long-term kidney function.⁵ The present observations should be seen in the context of understanding these complex events and suggest that there is not an obligate coupling between increased tubular workload and lower oxygen tension in healthy kidneys with dynamic increases in flow. This may be very different from chronic kidney disease. A strength of the present investigation despite the few numbers of observations is the invasive approach with catheters placed directly in the tissues combined with the conscious, unstressed, setting and the large-animal model much closer to humans than small rodents.

The author declares no conflicts of interest.