A Thiazide Test for the Diagnosis of Renal Tubular Hypokalemic Disorders Giacomo Colussi,* † Alberto Bettinelli, ‡ Silvana Tedeschi, § Maria Elisabetta De Ferrari, † Marie Louise Syre ´n, § Nicolo ` Borsa, § Camilla Mattiello, § Giorgio Casari, ¶ and Mario Giovanni Bianchetti** *Unite ´ Operative Nefrologia, Ospedale di Circolo e Fondazione Macchi, Varese, Italy; † Unite ´ Operative Nefrologia, Dialisi e Trapianto Renale, Ospedale Niguarda-Ca’ Granda, Milano, ‡ Unite ´ Operative Pediatria, Ospedale Mandic, Merate (Lecco), § Laboratorio di Genetica Medica, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano,  Istituto di Pediatria e Neonatologia, Universita ` degli Studi di Milano, Milano, and ¶ Unita ` di Genetica Molecolare Umana, DIBIT, Istituto Scientifico San Raffaele, Milano, Italy; and **Servizio di Integratio di Pediatria, Mendrisio e Bellinzona, Switzerland Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with “pseudo-BS” from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping. Clin J Am Soc Nephrol 2: 454-460, 2007. doi: 10.2215/CJN.02950906 M utations of several genes that are involved in Na/ fluid reabsorption along the distal nephron are the cause of tubular disorders that are characterized by chronic hypokalemic alkalosis and normotensive, hyperrenine- mic hyperaldosteronism, including Gitelman syndrome (GS; OMIM 263800) and Bartter syndrome (BS) types I to V (1–3) (OMIM 241200, 601678, 607364, 602522, and 601199). Chronic normotensive hypokalemia and alkalosis may also be acquired as a result of known or unknown diuretic use, anorexia/bu- limia, and laxative abuse (4 – 6). Clinical history and biochem- ical workup may not allow definite diagnosis, especially con- cerning the different types of tubular disorders. Genetic diagnosis is now feasible for all known genes that are respon- sible for GS and BS, but in everyday practice, it remains not easily available for the clinician and, for the geneticist, costly, cumbersome, and time-consuming as a result of the great di- mension of most genes, lack of hot-spot mutations, and the very large number of mutations described. Furthermore, in approx- imately 40% of patients with GS, only a single heterozygous mutation in the SLC12A3 gene is detected (7), so further exam- ination of a second gene is usually necessary. Tests with diuretics have been used in the past to diagnose tubular disorders (8 –12) and nontubular conditions (5); however, genetic confirmation of the supposed diagnosis was rarely, if ever, available. We present the diagnostic yield of a test with the thia- zide diuretic hydrochlorothiazide (HCT) in a large cohort of pa- tients with genetically proven GS and BS types I and III and in three additional patients with nontubular chronic hypokalemia. The results indicate that the thiazide test may correctly character- ize most patients with GS and thereby reduce the need for genetic testing in a substantial fraction of patients. Materials and Methods Patients A total of 51 patients were studied; all had chronic normotensive and hyperreninemic hypokalemia of uncertain origin, and their final diagnosis was GS in 41 patients, BS in seven (type I in five, type III in two), surreptitious diuretic use in two, and alimentary disturbance (vomiting) in one. They were studied and followed up at two adults’ hospitals in Milan and Varese and two children’s hospitals in Milan and Merate, all in Italy. Received September 4, 2006. Accepted January 20, 2007. Published online ahead of print. Publication date available at www.cjasn.org. Address correspondence to: Dr. Giacomo Colussi, U.O. Nefrologia, A.O. Ospedale di Circolo e Fondazione Macchi, Viale Borri, 57, 21100 Varese, Italy. Phone: +39-332-278208; Fax: +39-332-393018; E-mail: giacomo.colussi@ospedale.varese.it Copyright © 2007 by the American Society of Nephrology ISSN: 1555-9041/203–0454