Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice.

BACKGROUND: The SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution. METHODS: To explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA. RESULTS: Nbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects. CONCLUSIONS: The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.

Renal tubular acidosis is highly prevalent in critically ill patients.

INTRODUCTION: Hyperchloremic acidosis is frequent in critically ill patients. Renal tubular acidosis (RTA) may contribute to acidemia in the state of hyperchloremic acidosis, but the prevalence of RTA has never been studied in critically ill patients. Therefore, we aimed to investigate the prevalence, type, and possible risk factors of RTA in critically ill patients using a physical-chemical approach. METHODS: This prospective, observational trial was conducted in a medical ICU of a university hospital. One hundred consecutive critically ill patients at the age ≥18, expected to stay in the ICU for ≥24 h, with the clinical necessity for a urinary catheter and the absence of anuria were included. Base excess (BE) subset calculation based on a physical-chemical approach on the first 7 days after ICU admission was used to compare the effects of free water, chloride, albumin, and unmeasured anions on the standard base excess. Calculation of the urine osmolal gap (UOG)--as an approximate measure of the unmeasured urine cation NH4(+)--served as determinate between renal and extrarenal bicarbonate loss in the state of hyperchloremic acidosis. RESULTS: During the first week of ICU stay 43 of the patients presented with hyperchloremic acidosis on one or more days represented as pronounced negative BEChloride. In 31 patients hyperchloremic acidosis was associated with RTA characterized by a UOG ≤150 mosmol/kg in combination with preserved renal function. However, in 26 of the 31 patients with RTA metabolic acidosis was neutralized by other acid-base disturbances leading to a normal arterial pH. CONCLUSIONS: RTA is highly prevalent in critically ill patients with hyperchloremic acidosis, whereas it is often neutralized by the simultaneous occurrence of other acid-base disturbances. TRIAL REGISTRATION: Clinicaltrials.gov NCT02392091. Registered 17 March 2015.

Metabolic acidosis in hemodialysis patients: a study of prevalence and factors affecting intradialytic bicarbonate gain.

The correction of uremic acidosis is one of the goals of hemodialysis; however, despite acceptable hemodialysis protocols, metabolic acidosis remains a common problem. The prevalence of acidosis and significance of factors affecting bicarbonate flux during hemodialysis were studied. A cohort of 70 stable patients receiving high-efficiency hemodialysis for at least 4 months was studied prospectively over a 1-year period. Twenty patients (28%) had a mean predialysis serum bicarbonate of less than 21 mEq/L. The patients with or without metabolic acidosis had similar mean net ultrafiltration and percent ultrafiltration, but acidotic patients had a higher percent increase in bicarbonate during hemodialysis (35 +/- 12 versus 27 +/- 10 [p = 0.008]). The latter suggests an increased net daily acid gain in patients with metabolic acidosis (1.19 +/- 0.32 mEq/kg versus 1.05 +/- 0.35 mEq/kg [p = 0.04]). A review of factors affecting intradialytic bicarbonate gain showed that predialysis serum bicarbonate (diffusive gradient) was the most significant with a demonstrated linear relationship between these two variables (R2 0.51). The role of dialysance and blood flow, assessed together using percent urea reduction, was minor as was the effect of ultrafiltration. At our level of dialysis delivery, prevalence of metabolic acidosis is low, and dialysis-related factors do not contribute to the persistence of metabolic acidosis. Net daily acid gain was higher in acidotic patients and accounts for the long-term maintenance of metabolic acidosis. For individual dialysis treatments, the diffusive gradient is the most important determinant of bicarbonate gain, with only a minor role being demonstrated for percent urea reduction and ultrafiltration rate.