Inherited tubulopathies: SAQ

This neonate has antenatal Bartter syndrome. The polyhydramnios from fetal polyuria, the prematurity, the hypokalaemic hypochloraemic metabolic alkalosis, the raised urine calcium-to-creatinine ratio and the medullary nephrocalcinosis together are the classical presentation of an inherited defect of salt reabsorption in the thick ascending limb of the loop of Henle. The low blood pressure confirms a salt-losing rather than a sodium-retaining tubulopathy. [1]

Question 1 (10 marks)

Outline your immediate neonatal management and your medium-term surveillance plan for this child. [1]

The immediate priority is to correct the volume, potassium and magnesium deficits safely. I would establish intravenous access and give cautious fluid and salt replacement with normal saline, because the salt wasting is the driver of the polyuria and the alkalosis. I would correct the hypokalaemia with potassium chloride and check and replace the magnesium, because the potassium will not correct and stay corrected if the magnesium is low. I would monitor weight, strict fluid input and output, and serial electrolytes frequently, because the salt and potassium losses in antenatal Bartter are large and dynamic. [1]

The defining medical therapy for antenatal Bartter is a prostaglandin synthesis inhibitor, because the salt-losing state drives a marked prostaglandin E2 excess that worsens the polyuria, the salt wasting and the fever. I would start indometacin or ibuprofen at 1 to 3 mg per kg per day once the ductal and renal status is assessed, titrated to the response, and I would add a potassium-sparing diuretic such as amiloride or spironolactone to reduce the potassium wasting. Oral potassium chloride and magnesium would replace the ongoing losses. [5]

For the medium-term surveillance, I would confirm the diagnosis genetically with a Bartter gene panel covering SLC12A1, KCNJ1, CLCNKB and BSND, because the subtype determines the prognosis and the extrarenal features. I would arrange a hearing assessment, because the BSND subtype carries sensorineural deafness. I would monitor growth closely, because growth failure is the marker of under-treatment, and the renal ultrasound for nephrocalcinosis and stone formation. Serial electrolytes, the urine calcium-to-creatinine ratio, and blood pressure would guide the titration of the potassium, magnesium and prostaglandin synthesis inhibitor through growth, and I would involve the paediatric nephrology team for long-term care. [3]

Question 2 (10 marks)

Contrast Gitelman syndrome with Liddle syndrome, explaining how the blood pressure, the renin and aldosterone, the urine calcium and the serum magnesium distinguish them, and how the definitive treatment differs. [2]

Gitelman and Liddle both produce a hypokalaemic metabolic alkalosis, but they diverge at the blood pressure. Gitelman syndrome is a salt-losing tubulopathy from failure of the thiazide-sensitive sodium chloride cotransporter NCC in the distal convoluted tubule, encoded by SLC12A3, so the patient runs a normal or low blood pressure. Liddle syndrome is a gain-of-function of the epithelial sodium channel ENaC in the collecting duct, encoded by SCNN1B or SCNN1G, so the patient retains sodium and develops early-onset, often severe hypertension. The blood pressure is the single most reliable discriminator between them. [4]

The renin and aldosterone confirm the mechanism. In Gitelman the salt loss contracts the extracellular volume and drives secondary hyperaldosteronism, so both renin and aldosterone are raised. In Liddle the constitutive ENaC activity expands the volume and suppresses the renin and aldosterone, so both are low. This is the key biochemical separation, and it also distinguishes Liddle from primary hyperaldosteronism, in which the aldosterone is high and the renin is suppressed. [2]

The urine calcium and the serum magnesium further characterise Gitelman. Gitelman runs hypocalciuria, a low urine calcium-to-creatinine ratio, because the distal convoluted tubule defect increases proximal calcium reabsorption, and a characteristically low serum magnesium, because the NCC-dependent transport sustains the gradient for magnesium reabsorption. These two findings, hypocalciuria and hypomagnesaemia, are the signature of Gitelman and separate it from Bartter, which runs hypercalciuria. Liddle does not share these features. [3]

The definitive treatment differs because the broken segment differs. Gitelman is treated with oral magnesium salts as the chloride, lactate or aspartate in divided doses, potassium chloride, and a potassium-sparing diuretic such as amiloride or eplerenone, with a liberal salt intake. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are avoided because they can precipitate hypotension. Liddle is treated with amiloride, which blocks the epithelial sodium channel directly and corrects both the hypertension and the potassium loss. Spironolactone and eplerenone are ineffective in Liddle, because they act through the mineralocorticoid receptor and the aldosterone is already suppressed. [4]