The Role of Renal Response to Amino Acid Infusion and Oral Protein Load in Normal Kidneys and Kidney With Acute and Chronic Disease

Francis B. Gabbai

Disclosures

Curr Opin Nephrol Hypertens. 2018;27(1):23-29. 

In This Article

Renal Functional Reserve and Amino Acid Infusion in Various Pathologic Conditions

Amino Acid Infusion in the Setting of Experimental Acute Kidney Injury

Studies by Poulsen et al.[24] in normal pigs demonstrated that infusion of amino acids leads to increases in RPF and GFR. Using a similar dose of an intravenous amino acids solution, Vassal et al. tested the hypothesis that infusion of amino acids may prevent the renal vasoconstriction and reduction in GFR associated with administration of Pseudomonas aeruginosa infusion in an experimental model of septic shock.[25] Amino acids infusion in septic pigs led to a paradoxical response with significant reductions in RFP and GFR over time in comparison with the nonamino acid-treated pigs. Amino acid infusion was also associated with significantly higher requirements of epinephrine administration in this goal-directed resuscitation model of sepsis. These recent results are very similar to the ones obtained by Zager and Venkatachalam[26] in 1983 in a rodent model of ischemic AKI, where amino acid infusion led to worsening renal function. The deleterious effect of combined amino acid infusion in the sepsis and ischemic model contrasts with the beneficial effects of glycine infusion in a model of uranyl nitrate administration in rats where a 20% IV glycine infusion prevented the reduction in distal and proximal single nephron GFR associated with intratubular administration of uranyl nitrate.[27] More recently, a multicenter trial in intensive care patients demonstrated that adding 100 g of IV amino acid daily did not improve or shorten renal dysfunction in these patients.[28] Altogether, these results reveal the complexity of infusing single vs. mixed amino acid solution in the setting of AKI and the potential of individual amino acid to alter the specific mechanism(s) involved in AKI.

Renal Functional Reserve and Amino Acid Infusion Postacute Kidney Injury

Although infusion of an amino acid solution during an active episode of AKI may lead to significant deterioration of renal function, there is increasing interest on testing RFR after recovery of an acute episode. This interest is based on the current understanding that an episode of AKI can act as a promotor or accelerator of progression of CKD.[29] In as much as the presence of hyperfiltration and its consequent loss of RFR constitutes a risk for progression as shown by Livi et al.[30] in patients with systemic sclerosis, it becomes important to identify whether a normal serum creatinine/GFR after an episode of AKI constitutes complete recovery of renal function, or partial recovery with the use of the renal reserve to compensate for the loss of functioning nephrons.[31,32,33,34] One potential example is the information provided by Bruno et al.[35] who tested RFR in 33 children aged 2–16 years old with normal renal function and no proteinuria one year after an episode of hemolytic uremic syndrome and demonstrated loss of RFR in 50% of them. Other investigators such as Koratala and Kazory[36] have questioned whether loss of RFR in female patients with recovered AKI are at increased risk of preeclampsia and adverse fetal outcomes, and the potential relationship between these two factors.

Renal Functional Reserve in the Setting of Hypertension

Hypertension has been recognized as a major risk factor for the progression of kidney disease and as such has led to multiple studies analyzing the relationship between hypertension and presence or absence of RFR.[37] Of interest, absence of RFR can precede the development of hypertension as shown by O'Connor et al.[38] in normotensive patients with positive family history of hypertension. Absence of RFR in these individuals correlated with decreased proximal reabsorption as indexed by increased lithium excretion. A reduction in proximal tubular reabsorption with potential activation of the tubuloglomerular feedback system is a universal finding in experimental models with loss of RFR.[11,38] More recently, Gaipov et al.[39] have investigated whether patients with normal GFR and hypertension alone, or hypertension and proteinuria, maintain normal renal reserve. These investigators demonstrated loss of RFR in both groups of patients independent of their normal bGFR. Furthermore, levels of SBP and DBP correlated with RFR and with an increase in the renal resistive index as indexed by sonographic renal blood flow parameters.

Is elevated bGFR enough evidence of hyperfiltration or is loss of RFR required to establish the presence of hyperfiltration (sGFR not different from bGFR)? The detection of hyperfiltration is currently a topic of major interest in the literature.[5**,6*–9*] Several factors are likely to explain this process. The discovery of new antidiabetic agents, such as the Sodium glucose cotransporter2 receptor blockers capable of correcting/lowering GFR in patients with diabetes mellitus is certainly playing a major role.[5] Recent findings establishing a significant correlation between presence of hyperfiltration (high baseline eGFR) and increased overall morbidity and mortality constitute another major driving factor.[6,40] Therefore, separating high bGFR from 'bGFR not different from sGFR', that is, hyperfiltration becomes critical and raises the question: How is the presence of hyperfiltration being established? Is a GFR above a certain target value, alone or after adjustments for age, sex or body weight, and other potential factor(s) enough?[41] Cachat et al.[42] have reviewed the literature in search of various definitions of hyperfiltration and concluded that 30% of the studies they reviewed did not provide adequate justification for the selected threshold and recommended comparison with age and sex-matched control groups but is this enough?

There are several problems trying to establish the presence of hyperfiltration using threshold values based on population studies and estimated GFR (eGFR) values. One problem is the fact that not every patient with hyperfiltration has very high bGFR values as is the case of patients with CKD.[43] Barai et al.[43] measured RFR with amino acid infusion in patients with CKD 1–4 and demonstrated significant reductions in RFR (i.e., hyperfiltration) as bGFR decreased with progression of CKD. Absence of RFR indicating the presence of hyperfiltration is also observed in patients with systemic hypertension and bGFR within the normal range based on population studies.[37]

The opposite situation is observed in pregnancy, a clinical condition where hyperfiltration cannot be based on GFR thresholds derived from population studies. Studies performed in pregnant rats demonstrate that, in the setting of increased bGFR associated with pregnancy, administration of glycine induces renal vasodilation and further increases in GFR.[44] Similar findings have been observed in normal pregnant individuals.[45–47]

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