Case 1: A 2-year-old girl born out of consanguineous marriage presented with polyuria, polydipsia and failure to thrive. The X-rays of the child were consistent with rachitic changes. Investigations (Table I) showed normal anion gap hyperchloremic metabolic acidosis, high sodium, low potassium, low phosphate and high alkaline phosphatase. Along with normal serum anion gap; urine anion gap was positive suggesting renal tubular acidosis. Elevated urinary phosphate (Tmp/GFR= 0.04 mg/dL) and glycosuria pointed it to be of proximal i.e. Type 2 variant, which was confirmed by furosemide challenge test wherein urinary pH dropped down to 5.1. Eye examination revealed cystine crystals in the cornea. Although the investigations were suggestive of nephropathic cystinosis; persisting hypernatremia led us to check paired serum and urine osmolality. The urine osmolality was low but serum osmolality was inappropriately elevated and there was no response to vasopressin challenge – confirming NDI. Genetic analysis showed homozygous 5’ splice site mutation in cystinosin gene, further confirming cystinosis to be the underlying cause for the NDI. The child was started on indomethacin, phosphate supplementation, Shohl’s solution along with cysteamine, which is the specific treatment for cystinosis. Repeat urinary osmolality tested three months after treatment was 523 mOsm/kg with a corresponding serum osmolality of 293 mOsm/kg.

TABLE I	Biochemical Parameters of Children with Nephrogenic Diabetis Insipidus. 

Case 2: A 14-month-old girl born out of non-consanguineous marriage presented in a severely dehydrated state with history of increased thirst and passage of excessive urine. Initial investigation (Table I) revealed hyperchloremic normal anion gap metabolic acidosis with hypokalemia along with hypernatremia. In presence of hypernatremia, paired urinary and serum osmolality testing was undertaken which suggested the diagnosis of DI (Table I). This was confirmed to be of renal origin (NDI) after failed vasopressin challenge test. Serum phosphate levels were normal but alkaline phosphatase was high which along with X-ray findings was consistent with presence of underlying rickets. Ultrasound revealed bilateral nephrocalcinosis. Further work-up revealed elevated urinary calcium-creatinine ratio, normal urinary phosphate and positive urinary anion gap. A diagnosis of dRTA was made post furosemide challenge, as the lowest urinary pH post frusemide challenge was only 6. Genetic analysis showed a homozygous mutation of the ATP6V1B1 gene, thus confirming the primary diagnosis of distal RTA with secondary NDI. The child also had moderate bilateral sensori-neural hearing deficiency. Repeat urinary osmolality tested two months after treatment was 769 mOsm/kg with a corresponding serum osmolality of 296 mOsm/kg.

Arginine-vasopressin (AVP) or anti-diuretic hormone (ADH) is synthesized in the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus, and is primarily secreted as a response to an increase in serum osmolality [1]. In its effector organ i.e. the kidneys AVP acts on the V2 (AVPR2) receptors, and relocates the aquaporin 2 (AQP2) channels from intracellular vesicles to the apical plasma membrane. This relocation of the aquaporin 2 channels results in increased water permeability of the collecting ducts, enabling the kidneys to concentrate the urine [1].

Although NDI can occur as a primary phenomenon in young children due to genetic defects in the AVPR2 and AQP2 genes, it can also occur secondary to hereditary tubulo-pathies. In such cases, treating the primary disorder can lead to complete/partial resolution of the NDI and we can avoid serious irreversible damages. We hereby presented two cases of NDI secondary to proximal and distal RTA. The case series highlighted the importance of looking for red flag signs such as hypokalemia, acidosis and or features of rickets in children presenting with NDI. These signs would suggest a secondary cause rather than the classical aquaporin receptor resistance/aquaporin deficiency.

NDI secondary to cystinosis was described more than five decades ago [4,5]. The entrapment of intra-lysosomal cystine crystals can lead to dysfunction of the tubular cells, which although mainly damages the cells in the proximal tubule, can also compromise the function of any other tubular cell, including cells of the collecting duct [6]. Our second case of dRTA with NDI is quite unique, as the entity has not been described in pediatric age group. Kalyanasundaram, et al. [7] did describe a 28-day-old newborn with dRTA who also had features of NDI but unfortunately no mutation study was reported to substantiate the diagnosis [7]. Among adults there are reports of dRTA with NDI, but usually they have a secondary cause such as Sjogren syndrome [8].

It is of utmost importance that whenever we are encountering a child with NDI, we should have a strong suspicion for any underlying secondary etiologies and associated features like rickets; persisting hypokalemia or acidosis should make us look for underlying RTA. Missing this diagnosis can be dangerous for the child as improper management of hypernatremia can have a catastrophic effect on the child’s neurological outcome.

Contributors: DD: collected and analyzed the data and drafted the manuscript; RS: conceptualized the case series, edited the manuscript; SD: conceptualized the case series, edited the manuscript.

Funding: None; Competing Interests: None stated.

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