Proximal renal tubular acidosis with and without Fanconi syndrome

Abstract

Proximal renal tubular acidosis (RTA) is caused by a defect in bicarbonate (HCO 3 − ) reabsorption in the kidney proximal convoluted tubule. It usually manifests as normal anion-gap metabolic acidosis due to HCO 3 − wastage. In a normal kidney, the thick ascending limb of Henle’s loop and more distal nephron segments reclaim all of the HCO 3 − not absorbed by the proximal tubule. Bicarbonate wastage seen in type II RTA indicates that the proximal tubular defect is severe enough to overwhelm the capacity for HCO 3 − reabsorption beyond the proximal tubule. Proximal RTA can occur as an isolated syndrome or with other impairments in proximal tubular functions under the spectrum of Fanconi syndrome. Fanconi syndrome, which is characterized by a defect in proximal tubular reabsorption of glucose, amino acids, uric acid, phosphate, and HCO 3 − , can occur due to inherited or acquired causes. Primary inherited Fanconi syndrome is caused by a mutation in the sodium-phosphate cotransporter (NaP i -II) in the proximal tubule. Recent studies have identified new causes of Fanconi syndrome due to mutations in the EHHADH and the HNF4A genes. Fanconi syndrome can also be one of many manifestations of various inherited systemic diseases, such as cystinosis. Many of the acquired causes of Fanconi syndrome with or without proximal RTA are drug-induced, with the list of causative agents increasing as newer drugs are introduced for clinical use, mainly in the oncology field.

Renal Tubular Acidosis and Management Strategies: A Narrative Review

“…Isolated proximal type 2 RTA is characterized by defects in the reabsorption of filtered HCO 3 – in the proximal tubule without defects in the transport of other solutes (Table 1 ) [ 33 , 34 ]. The threshold serum concentration for HCO 3 – reabsorption (normally approximately 25 mmol/L) is reduced, leading to delivery of larger quantities of filtered HCO 3 – to the distal nephron (which has a low capacity for HCO 3 – reabsorption) and urinary HCO 3 – wastage [ 33 , 34 ]. Reductions in serum HCO 3 – cause acidosis; however, the urine pH remains alkaline because of the presence of urinary HCO 3 − [ 34 ].…”

“…When serum HCO 3 – concentrations decrease below the lower threshold (16–20 mmol/L), a new steady state is reached, whereby all filtered HCO 3 – is reabsorbed. At this point, the urine contains no HCO 3 – and is maximally acidic [ 33 ].…”

“…Proximal RTA may occur as an isolated defect in HCO 3 – reabsorption, but more typically occurs in association with Fanconi syndrome, characterized by a widespread proximal tubular dysfunction resulting in the loss of phosphate, glucose, uric acid, amino acids, and low molecular weight proteins, as well as HCO 3 – [ 33 , 34 ]. Although proximal RTA is not associated with nephrolithiasis or nephrocalcinosis, patients with proximal RTA and Fanconi syndrome may develop skeletal abnormalities, such as osteomalacia [ 38 – 41 ].…”

Protective Role of Vitamin D in Renal Tubulopathies

“…Primary inherited Fanconi syndrome is provoked by a mutation in the NaP i -II in the proximal tubule. Recent studies have established new causes of Fanconi syndrome due to mutations in the EHHADH and the HNF4A genes [108].…”

A Neglected Case of Wilson’s Disease Presenting as Symptomatic Urolithiasis and Proteinuria

“…Although infrequent, Fanconi's syndrome is a significant cause of hypophosphatemic rickets. It is described as proximal RTA when presented with other proximal tubular defects such as aminoaciduria, phosphaturia, glucosuria, and uricosuria (6).…”