Bartter’s and Gitelman’s diseases

Bartter’s and Gitelman’s syndromes are two different genetic renal diseases, but are both characterised by hypokalaemia and metabolic alkalosis. Bartter’s syndrome is characterised by multiple gene mutations (Na–K–2Cl cotransporter; K ⁺channels renal outer medullary potassium channel (ROMK); Cl channels, chloride channel Kb (ClCNKb); regulatory protein Barttin; and Ca ²⁺-sensing receptor, CaSR) at the thick ascending limb of Henle’s loop, while Gitelman’s syndrome is caused by a mutation in the gene encoding the renal thiazide sensitive Na ⁺–Cl ⁻cotransporter, located in the apical membrane of the distal convoluted tubule. The co-existence of hypokalaemia with hypomagnesaemia and hypocalciuria represents the biochemical hallmark of Gitelman’s syndrome that distinguishes it from Bartter’s syndrome. Calcium pyrophosphate deposition (CPPD) including chondrocalcinosis has been frequently reported in association with Bartter’s syndrome. Some authors postulate that these cases were probably due to Gitelman’s syndrome and not due to Bartter’s syndrome as all patients had hypomagnesaemia. This electrolyte disorder seems to induce CCP crystal deposition. To date, no cases of CPPD have been reported in patients who had Bartter’s syndrome without hypomagnesaemia. CPPD may be found in other conditions associated with hypomagnesaemia, such as short bowel syndrome or tacrolimus therapy in liver transplantation patients. As acute CPP crystal arthropathy or pseudogout can be the onset presentation of Gitelman’s syndrome, CPPD should be considered a major feature of this disease. Rheumatologists should be aware of the association between Gitelman’s syndrome and CPPD, and should consider this metabolic disorder when CPPD occurs in younger patients.

Bartter’s syndrome

Bartter’s syndrome, first described in 1962 , is an autosomal-recessive disease characterised by hypokalaemia, metabolic alkalosis, intravascular volume depletion due to renal salt wasting and hyper- or normocalciuria. Typical clinical features presented in infancy or childhood include muscle weakness, anorexia, polydipsia, polyuria, failure to thrive and mental and growth retardation. Patients with Bartter’s syndrome show elevated plasma renin activity, high plasma angiotensin II level, hyperaldosteronism but normal blood pressure and resistance to the pressor effect of angiotensin II – these latter representing a hallmark of the syndrome . Patients may present with the signs and symptoms of the disease as early as the neonatal period. In this case, the clinical presentation is characterised by marked intravascular volume depletion due to salt wasting or tetany, muscular weakness and paraesthesia or seizures because of metabolic alkalosis. Another possible symptom occurring in Bartter’s syndrome includes nephrocalcinosis due to hypercalciuria . Some patients develop mental retardation due to electrolyte abnormalities and end stage renal disease secondary to nephrocalcinosis . The electrolyte abnormalities of Bartter’s syndrome are similar to those observed in patients taking furosemide or other drugs, which inhibit the Na–K–2Cl cotransporter of the thick ascending limb of Henle’s loop. This prompted investigations of the gene NKCC2/SLC12A1 encoding for the Na–K–2Cl cotransporter as a potential site for the presence of potential mutations that could alter its function. These studies showed variants of the coding region of this gene in affected patients and DNA sequence revealed mutations resulting in the loss of cotransporter function. This induces Na ⁺and K ⁺wasting in the thick ascending limb of Henle’s loop and hypovolaemia . The presence of NKCC2 mutations identifies Bartter’s syndrome type I ( Fig. 1 ). In patients where NKCC2 mutations were not detected, targets of the genetic investigations were genes involved in the regulation of NKCC2 activity. In particular, the apical ATP-sensitive K ⁺channel (renal outer medullary potassium channel, ROMK), which recycles K ⁺from the cell back into the lumen and is critical for maintaining NKCC2 activity, presents mutations in some affected patients . The fall of luminal K ⁺shuts down Na–K–2Cl cotransporter activity, therefore resulting in salt wasting and hypovolaemia. The presence of ROMK mutations identifies Bartter’s syndrome type II ( Fig. 1 ).