A Urine pH-Ammonium Acid/Base Score and CKD Progression.

INTRODUCTION: Acidosis is associated with exacerbated loss of kidney function in chronic kidney disease (CKD). Currently, acid/base status is assessed by plasma measures, although organ-damaging covert acidosis, subclinical acidosis, may be present before reflected in plasma. Low urine NH4+ excretion associates with poor kidney outcomes in CKD and is proposed as a marker for subclinical acidosis. However, low NH4+ excretion could result from either a low capacity or a low demand for acid excretion. We hypothesized that a urine acid/base-score reflecting both the demand and capacity for acid excretion would better predict CKD progression. METHODS: 24-hour urine collections were included from three clinical studies of patients with CKD stage 3 and 4: A development cohort (n=82), a variation cohort (n=58), and a validation cohort (n=73). A urine acid/base-score was derived and calculated from urinary pH and [NH4+]. Subclinical acidosis was defined as an acid/base-score below the lower limit of the 95% prediction interval of healthy controls. Main outcomes were change in measured GFR after 18 months and CKD progression (defined as ≥50% decline in eGFR, initiation of long-term dialysis or kidney transplantation) during up to 10 years of follow-up. RESULTS: Subclinical acidosis was prevalent in all cohorts (n=54/82, 48/73, and 40/58, ∼67%). Subclinical acidosis was associated with an 18% (95% CI: 2-32) larger decrease of measured GFR after 18 months. During a median follow-up of 6 years, subclinical acidosis was associated with a markedly higher risk for CKD progression. Adjusted hazard ratios were 9.88 (95% CI 1.27-76.7) in the development cohort and 11.1 in the validation cohort (95% CI: 2.88-42.5). The acid/base-score had a higher predictive value for CKD progression than NH4+ excretion alone. CONCLUSIONS: Subclinical acidosis, defined by a new urine acid/base-score, was associated with a higher risk of CKD progression in patients with CKD stage 3 and 4.

Benzamil-mediated urine alkalization is caused by the inhibition of H+-K+-ATPases.

Epithelial Na+ channel (ENaC) blockers elicit acute and substantial increases of urinary pH. The underlying mechanism remains to be understood. Here, we evaluated if benzamil-induced urine alkalization is mediated by an acute reduction in H+ secretion via renal H+-K+-ATPases (HKAs). Experiments were performed in vivo on HKA double-knockout and wild-type mice. Alterations in dietary K+ intake were used to change renal HKA and ENaC activity. The acute effects of benzamil (0.2 µg/g body wt, sufficient to block ENaC) on urine flow rate and urinary electrolyte and acid excretion were monitored in anesthetized, bladder-catheterized animals. We observed that benzamil acutely increased urinary pH (ΔpH: 0.33 ± 0.07) and reduced NH4+ and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K+ diet (ΔpH: 0.74 ± 0.12), a condition when ENaC activity is low. In contrast, benzamil did not affect urine acid excretion in animals kept on a high-K+ diet (i.e., during high ENaC activity). Thus, urine alkalization appeared completely uncoupled from ENaC function. The absence of benzamil-induced urinary alkalization in HKA double-knockout mice confirmed the direct involvement of these enzymes. The inhibitory effect of benzamil was also shown in vitro for the pig α1-isoform of HKA. These results suggest a revised explanation of the benzamil effect on renal acid-base excretion. Considering the conditions used here, we suggest that it is caused by a direct inhibition of HKAs in the collecting duct and not by inhibition of the ENaC function.NEW & NOTEWORTHY Bolus application of epithelial Na+ channel (EnaC) blockers causes marked and acute increases of urine pH. Here, we provide evidence that the underlying mechanism involves direct inhibition of the H+-K+ pump in the collecting duct. This could provide a fundamental revision of the previously assumed mechanism that suggested a key role of ENaC inhibition in this response.

Potassium acts through mTOR to regulate its own secretion.

Potassium (K+) secretion by kidney tubule cells is central to electrolyte homeostasis in mammals. In the K+ secretory "principal" cells of the distal nephron, electrogenic Na+ transport by the epithelial sodium channel (ENaC) generates the electrical driving force for K+ transport across the apical membrane. Regulation of this process is attributable in part to aldosterone, which stimulates the gene transcription of the ENaC-regulatory kinase, SGK1. However, a wide range of evidence supports the conclusion that an unidentified aldosterone-independent pathway exists. We show here that in principal cells, K+ itself acts through the type 2 mTOR complex (mTORC2) to activate SGK1, which stimulates ENaC to enhance K+ excretion. The effect depends on changes in K+ concentration on the blood side of the cells, and requires basolateral membrane K+-channel activity. However, it does not depend on changes in aldosterone, or on enhanced distal delivery of Na+ from upstream nephron segments. These data strongly support the idea that K+ is sensed directly by principal cells to stimulate its own secretion by activating the mTORC2-SGK1 signaling module, and stimulate ENaC. We propose that this local effect acts in concert with aldosterone and increased Na+ delivery from upstream nephron segments to sustain K+ homeostasis.