In this study, we present a pediatric case with hyperammonemic encephalopathy which occurred due to an episode of metabolic decompensation characterized by repetitive vomiting. To our knowledge, the patient had the highest ever reported serum ammonia level in the context of pediatric distal renal tubular acidosis. Her medical condition required a session of hemodialysis which resulted in rapid clinical improvement.

The relationship between hyperammonemia and distal renal tubular acidosis was first reported by Miller et al. in a 47-day-old female patient clinically diagnosed with distal renal tubular acidosis [3]. This association has been intermittently documented in subsequent reports [4,5,6,7,8]. In distal renal tubular acidosis, impaired distal acidification occurs due to impaired excretion of ammonium (NH4 +) under the stimulus of systemic acidemia. However, hyperammonemia is rarely associated with distal renal tubular acidosis. Ammonia (NH3) and NH4+ are crucial elements in maintaining acid–base balance. Most NH4+ is synthesized in the proximal tubules before moving into the interstitium in the loop of Henle. There, it is converted into NH3 and accumulates in the medullary interstitium. At this point, NH3 enters the acidified distal tubule and medullary collecting ducts, where it acts as a buffer. Chronic metabolic acidosis and hypokalemia both stimulate renal ammoniagenesis. Elevated ammonia production, combined with impaired ammonium excretion caused by distal renal tubular acidosis, leads to the absence of 'diffusion trapping' as NH4 + in the urine. This results in the rediffusion of NH₃ back into the renal medullary interstitium, leading to an accumulation of ammonia in the bloodstream [9]. When the NH3 level exceeds > 100 µmol/L, neurologic findings can be seen and if > 500 µmol/L, coma and convulsions may occur. Prolongation of severe hyperammonemia may result in irreversible neurotoxicity and cerebral necrosis [10].

Hyperammonemia may more commonly occur in association with urea cycle disorders, fatty acid oxidation disorders and some organic acidurias, and can be temporary in neonates [11]. In our patient, the level of glucose, lactate, pyruvate and amino acids in the blood were all within the normal range. In addition, the patient’s urinary ketones, amino acids, and organic acids were all found to be at normal levels, which enabled us to exclude the diagnosis of a metabolic disorder. An underlying hepatic disease and Reye syndrome were also ruled out based on normal serum albumin, bilirubin, coagulation parameters and liver enzymes.

Systematic reviews and pediatric case reports reported hyperammonemia in distal renal tubular acidosis patients more commonly with ATP6V0A4 or occasionally ATP6V1B1 gene mutations [5, 7, 8]. In previously reported cases, the highest ammonia level was 248 mmol/L. Hypokalemia and hypobicarbonatemia were frequently observed concomitantly and were negatively correlated with hyperammonemia. Neurologic findings were usually absent, except for mild confusion noted in some cases. The ammonia level rapidly normalized with alkaline therapy and when potassium levels reached high-normal levels. None of those patients required dialysis [3,4,5,6,7,8]. Our patient also had an underlying ATP6V0A4 gene mutation. However, complaints of repetitive vomiting and poor feeding for a few days resulted in metabolic decompensation, with severely elevated serum ammonia level above 500 µmol/L at admission, accompanied by encephalopathy.

Despite the efforts to normalize metabolic acidosis and hypokalemia via the use of alkaline therapy, potassium supplementation, and non-kidney replacement therapy consisting of nitrogen scavenger agents, ammonia level further increased in our patient and altered consciousness persisted after 6 h of the medical treatment. A recent guideline recommends employing hemodialysis for patients with ammonia levels > 500 mmol/L with clinical signs of severe encephalopathy or those with lower levels if an insufficient clinical response is achieved after 4 h of appropriate medical treatment. It is also stated that the main determinants of neurological outcome are plasma ammonia levels and duration of hyperammonemic coma [12]. Therefore, we believe that initiating dialysis in patients with severely elevated ammonia levels and keeping the duration of hyperammonemia as short as possible should be important management strategies. Considering this literature information, we implemented hemodialysis in our patient.

In the present case, intermittent hemodialysis was preferred over continuous kidney replacement therapy as the dialysis modality. It is reported that within 3–4 h of a treatment session, a 75% decline in blood ammonia levels can be achieved via intermittent hemodialysis [12]. Continuous dialysis modalities are also known to be effective in treating hyperammonemia, whereas continuous venovenous hemodialysis (CVVH) offers relatively better ammonia clearance than continuous venovenous hemodiafiltration (CVVHD). On the other hand, previous pediatric studies showed that intermittent hemodialysis provided a significantly more rapid reduction in serum ammonia levels than CVVHD [10, 13, 14]. Another point was that our patient also had severe metabolic acidosis due to underlying uncompensated distal renal tubular acidosis. It is well-known that severe metabolic acidosis can be more efficiently managed with intermittent hemodialysis compared to continuous kidney replacement therapy options given that the patient is hemodynamically stable [15]. In summary, considering all the above literature information, intermittent hemodialysis was the treatment of choice in our patient. Although rebound hyperammonemia can be seen more often with intermittent hemodialysis, and may necessitate repeated sessions [12], serum ammonia levels rapidly decreased and no rebound increase was detected in our patient. Furthermore, no long-term neurologic sequelae were observed.

The association between distal renal tubular acidosis and hyperammonemia has been demonstrated not only in pediatric cases but also in adult patients. A 69-year-old woman was hospitalized with a reduced level of consciousness, fatigue, generalized weakness, anorexia, and two weeks of polyuria. She was diagnosed with distal renal tubular acidosis which developed secondary to primary hyperparathyroidism and hyperammonemia. Following alkalizing treatment, her ammonia level of 278 µmol/L decreased to normal range, and she was discharged without any residual neurological deficits [16]. Another reported patient was a 72-year-old Japanese man, who had been taking omeprazole for 11 years that was admitted to the hospital due to loss of consciousness and muscle weakness. He was diagnosed with omeprazole-induced hypomagnesemia, leading to possible distal renal tubular acidosis with hypokalemia, hypocalcemia, hyperlactacidemia, and hyperammonemia (ammonia level of 174 µmol/L). After correcting his serum electrolytes and administering alkaline therapy, the patient's muscle weakness and consciousness improved, and his ammonia level normalized. There was no evidence of neurological impairment upon discharge [17].