Renal tubular acidosis: A ‘basic’ disorder

Abstract

Renal tubular acidosis (RTA) occurs when impaired acid excretion by the kidneys due to varied tubular disorders results in hyperchloremic metabolic acidosis with a normal anion gap. Within human literature, the disease can be classified into types I, II, III or IV, with differences in electrolyte imbalances and cited causes. The disease can be primary (inherited or idiopathic) or secondary to other disease or toxins (Bagga & Sinha, 2020). Drugs that have been associated with RTA include amphotericin B, trimethoprim-sulfamethoxazole, tetracyclines, gentamicin, cephalosporins, carbonic anhydrase inhibitors and lithium carbonate (Arroyo et al., 2020). RTA has limited documentation within horses and has not been reported in donkeys. This case report by Kummer et al. (2025) is the first documentation of occurrence within mules.

Type I, or distal, RTA occurs due to failure of hydrogen ion secretion in the intercalated cells of the distal tubules and collecting duct. This results in failure of urine acidification, reduced ammonium excretion, increased calcium and potassium excretion. The occurrence of hypokalemia is not fully understood but is a hallmark for early recognition of type I RTA (Kunchur et al., 2024). Increased urine calcium that occurs in type I RTA often causes urolithiasis or nephrolithiasis to occur in humans (Alexander et al., 2016), however, to the authors' knowledge, this has not been recorded in horses. The presence of urinary calcium is higher in horses than people, which could explain this pathophysiological difference (Aleman et al., 2001).

Type II, or proximal, RTA results from decreased bicarbonate resorption in the proximal tubules. This, with other proximal tubular absorption deficits, comprises Fanconi syndrome. Fanconi syndrome can be inherited or can occur secondary to other diseases or toxins. A deletion mutation of the Fanconi anaemia-associated nuclease 1 (FAN1) gene has been implicated in the development of Fanconi syndrome in Basenji dogs, resulting in mitochondrial damage in the kidneys (Farias et al., 2024). Transient Fanconi syndrome has been reported in two Quarter Horses, for which an inciting cause was unknown (Ohmes et al., 2014). It has been suggested that Quarter Horses are over-represented in type II RTA, but there have been no genetic links proven (Aleman et al., 2001; Arroyo et al., 2020).

Neither type III nor IV RTA has been reported in horses. Type III RTA in humans is characterised by carbonic anhydrase II deficiency due to an inherited disorder. This produces a mixed RTA which is challenging for practitioners to diagnose and treat. Type IV RTA is caused by aldosterone deficiency or resistance which leads to hyperkalemia and ultimately impaired ammonium excretion (Kunchur et al., 2024).

The mule in this case report presented with lethargy, anorexia, mild signs of colic and decreased faecal output (Kummer et al., 2025). These clinical signs are among those reported previously, which also include lethargy, poor performance and weight loss (Aleman et al., 2001). Limited history was known for this mule, so an inciting cause of RTA cannot be ruled out, though there is little known of RTA causes in equids (Aleman et al., 2001).

RTA was suspected in this case following the detection of severe hyperchloremic metabolic acidosis, hypokalemia, hyponatremia and hypercalcemia with a normal anion gap. Kummer et al. (2025) recognise that urine sample collection before initiating fluid therapy may have provided additional information; however, this appears to be a more helpful diagnostic tool in human RTA, whereby distinguishing acid from alkaline urine helps classify the type of RTA and therefore guides treatment approach. Alkaline urine indicates type I RTA in people, whereas acidic urine indicates type II RTA (Bagga & Sinha, 2020).

Kummer et al. (2025) report increased fractional excretion of sodium and decreased fractional excretion of potassium in this mule case report, but they recognise that prior initiation of fluid therapy could have influenced results. In a previous case report, fractional excretion of sodium was increased, but fractional excretion of potassium was normal (Ohmes et al., 2014). Another case series showed varied fractional excretions to all electrolytes tested (Aleman et al., 2001).

Ammonium chloride load test showed inability to acidify urine, consistent with type I RTA. In a healthy patient, the induced metabolic acidosis would result in excretion of hydrogen ions and formation of ammonium within the collecting duct, leading to acidic urine. However, in this case report, the blood pH only decreased very mildly during the ammonium chloride loading, which therefore may not have yielded sufficient change to cause urine acidification. The presence of metabolic acidosis should ideally be confirmed during the ammonium chloride loading using total carbon dioxide. In humans, the ammonium chloride loading is performed over a 3-day period (Santos et al., 2015), but this extended test has not been utilised in equids. Other functional tests utilised in other species include administering sodium bicarbonate, acetazolamide and furosemide, both with and without fludrocortisone (Santos et al., 2015).

Renal ultrasound appears to have limited diagnostic value; one study showed 50% of horses showed abnormalities (Aleman et al., 2001), whereas other case reports did not support any renal ultrasonographic abnormalities (Ohmes et al., 2014). This mule was reported to have normal renal ultrasound findings (Kummer et al., 2025). The author would be interested to know if a urinalysis would have provided evidence of granular casts, indicative of tubular damage (MacLeay & Wilson, 1998).

The ammonium level in the urine was not reported, which is unsurprising as many laboratories will not measure it. An alternative option could have been measuring the urinary anion gap; a positive urinary anion gap in people with hyperchloremic metabolic acidosis represents inappropriate ammonium excretion, thus confirming RTA (Santos et al., 2015). However, to the authors' knowledge, this test has not been validated in horses.

Treatment of RTA involves supplementation of sodium bicarbonate and potassium chloride, typically intravenously initially and then orally. Additional glucose or dextrose supplementation may stimulate intracellular uptake of potassium (Bayly, 2018). Intravenous glucose was utilised in this case report due to the increased triglyceride reported. This might have had beneficial effects treating the RTA as well as reducing the risk of hyperlipaemia in the mule. Half of the estimated bicarbonate deficit should be addressed within the first 12 h (Arroyo et al., 2020). An improvement in clinical demeanour is expected within the first 12–24 h. Horses may require long-term sodium bicarbonate administration (Bayly, 2018). However, both reported cases of Fanconi syndrome in Quarter Horses were transient; they did not require ongoing sodium bicarbonate supplementation (Ohmes et al., 2014).

RTA, if identified and treated rapidly, has a reasonable prognosis, though little is known of the long-term prognosis (Bayly, 2018). In one case report with a poor short-term outcome, ventricular tachycardia was reported as a potential side effect of RTA (MacLeay & Wilson, 1998). Within the human literature, close monitoring after RTA is recommended (Bagga & Sinha, 2020). Kummer et al. (2025) should be congratulated on the short-term outcome achieved in this case. The author hopes that the long-term outcome will be positive, even if sodium bicarbonate and potassium chloride supplementation is always required. In any case, even if supplementation is discontinued, some equids have relapsed after cessation of treatment (Arroyo et al., 2020).

H. J. Mason: Writing – original draft; writing – review and editing. L. G. Arroyo: Supervision; writing – review and editing.

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No conflicts of interest have been declared.

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