Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes

Abstract

Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO absorption or new renal HCO generation; (3) changes in renal NH, Ca, K, and HO homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.

Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead

“…In addition, these mice develop proximal renal tubular dysfunction with defective endocytic trafficking, proteinuria, and phosphaturia, which has not been reported in humans 33. This may be due to compensatory changes in the a1, a2, and a3 subunits in the proximal tubules of dRTA patients with the ATP6V0A4 mutation 17,34…”

“…Mutations in three transporter genes expressed in A-ICs have been identified as causes of dRTA, including the B1 ( ATP6V1B1 ) and a4 ( ATP6V0A4 ) subunits of H + -ATPase and the AE1/ SLC4A1 16. However, because mutations in these genes are identified in only 70%–80% of patients with dRTA,4,5 dRTA is also likely to be caused by mutations in other genes 3,17. In addition to its genetic component, dRTA can also be acquired 7…”

“…dRTA caused by AE1 gene mutations can occur with either an AD or AR transmission (Table 1). 1,6 AE1 mutations are rare and usually have an AD transmission in Caucasians, while AR dRTA is common in Asians 17. The clinical symptoms are more severe and the age of onset is earlier in patients with AR dRTA compared to patients with AD dRTA 7.…”

Kidney Tubular Acidosis: Causes, Symptoms, Diagnostics, Treatment (Literature Data and the Authors’ Own Observations)

“…The loss of a large amount of calcium with alkaline urine, hypocitraturia, is the cause of the oxalate and calcium phosphate calculus deposition in the kidneys. By the age of 3-5 years, bilateral nephrocalcinosis occurs [9,10,11]. This creates the conditions for the onset of a secondary urinary tract infection.…”

A molecular dual carriageway

“…For example, the central role ammonium plays in the global nitrogen cycle makes them important both for improving crop yields and for the breakdown of pollutants ( Li et al, 2017 ; Fowler et al, 2013 ). Human ammonium transporters are essential for kidney function, and mutations have been implicated in various diseases ( Kurtz, 2018 ; Huang and Ye, 2010 ). For those interested in other membrane transport processes, the idea of using selective protonation or deprotonation of small, ionisable solutes, or even the amino acid side chains of larger protein molecules, is compelling ( Jiang et al, 2015 ; Wiechert and Beitz, 2017 ).…”