Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies

Abstract

Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO(3) in the proximal tubule. This is usually manifested as bicarbonate wastage in the urine reflecting that the defect in proximal tubular transport is severe enough that the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments is overwhelmed. More subtle defects in proximal bicarbonate transport likely go clinically unrecognized owing to compensatory reabsorption of bicarbonate distally. Inherited proximal RTA is more commonly autosomal recessive and has been associated with mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1). Mutations in this transporter lead to reduced activity and/or trafficking, thus disrupting the normal bicarbonate reabsorption process of the proximal tubules. As an isolated defect for bicarbonate transport, proximal RTA is rare and is more often associated with the Fanconi syndrome characterized by urinary wastage of solutes like phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins as well as bicarbonate. A vast array of rare tubular disorders may cause proximal RTA but most commonly it is induced by drugs. With the exception of carbonic anhydrase inhibitors which cause isolated proximal RTA, drug-induced proximal RTA is associated with Fanconi syndrome. Drugs that have been recently recognized to cause severe proximal RTA with Fanconi syndrome include ifosfamide, valproic acid and various antiretrovirals such as Tenofovir particularly when given to human immunodeficiency virus patients receiving concomitantly protease inhibitors such as ritonavir or reverse transcriptase inhibitors such as didanosine.

Fig. 1.

Proximal tubule bicarbonate reabsorption. CAII/IV, carbonic anhydrase II/IV; NHE3, Na⁺/H⁺ exchanger 3; NBC1, Na⁺/HCO₃⁻ cotransporter.

Fig. 2.

Differences in urinary pH and plasma bicarbonate in proximal and distal RTA. Adapted from Rodriguez-Soriano and Edelman [144].

Fig. 3.

Band keratopathy of the cornea in the left eye in a patient with autosomal recessive proximal RTA and the R298S mutation in kNBC cDNA. (Source: Igarashi et al. [13]).

Fig. 4.

Schematic model of various mechanisms whereby NBCe1 mutations result in abnormal Na⁺/HCO₃⁻ transport in proximal RTA. (A) Normal, (B) Internal sequestration (R410H, R510H, E 91R,R342S, R881C), (C) decreased function(T485S, G486R), (D) internal sequestration and some mistargeting to both apical membrane and basolateral membrane(S427L).

Fig. 5.

Schematic of IFO-induced nephrotoxicity. CAA, a metabolite of IFO, may inhibit NADH:oxidoreductase following dephosphorylation of AQDQ, an 18 kDa subunit of C-I. The inhibition of C-I disrupts oxidative phosphorylation, leading to multiple metabolic abnormalities, including elevation of NADH, decreased pyruvate dehydrogenase (PDH) and tricarboxylic acid cycle activity. (i) PDH, (ii) PC, (iii) glutamate-aspartate aminotransferase, (iv) glutamate dehydrogenase; C-I, C-II, C-III, C-IV, respiratory chain complexes; C-V, ATP synthetase; Cyt. C, cytochrome c, α-kg, α-ketoglutarate (source: Nissim [87]).

Fig. 6.

Schematic representation of the proximal tubule reabsorption processes perturbed in cisplatin- or gentamcin-induced renal Fanconi-like syndromes that are manifested by the urinary elevation of glucose, NAAs and monocarboxylates. The uptake of glucose, NAA and monocarboxylate into the epithelial cells is mediated by luminal sodium-dependent transporters such as SLC5A1, SLC5A2, SLC6A18 and SLC16A7. The sodium electrochemical gradient across the luminal membrane is provided by the activity of the basolateral sodium/potassium ATPase. The entry of cisplatin (denoted as ‘C’) or gentamicin (denoted as ‘G’) into the tubular epithelial cells results in the transcriptional down-regulation of HNF1R and HNF1, which in turn leads to the reduction of mRNA levels of SLC5A1, SLC5A2 and collectrin. Cisplatin or gentamicin treatment also leads to the reduction of SLC6A18 and SLC16A7 mRNA through unknown transcription factors. Both nephrotoxicants also induce hypoxia in renal tubular cells, which leads to the transcriptional up-regulation and post-translational stabilization of hypoxia-inducible factor HIF1R. An increased amount of HIF1 up-regulates the transcription of basolateral GLUT transporters as one of the adaptive responses to proximal tubule injury. Up-regulated gene names are shown in red color, while down-regulated ones are shown in blue color. For schematic convenience, these regulated genes are shown next to each other, although they are located on different chromosomes inside the nucleus (source: Xu et al. [94]).