Response to Letter Regarding Article, “The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio”
We thank Dr Mulatero and colleagues for their comments on the importance of the Spironolactone, Amiloride, Losartan, and Thiazide (SALT) trial, although the question of whether K+-sparing diuretics protect against glucose intolerance is only now being addressed in a collaborative study by the British Hypertension Society. We acknowledge in turn Dr Mulatero’s recognition, using adrenal vein sampling, that normokalemic primary hyperaldosteronism is not rare. Given, however, the need for this technically demanding investigation to be undertaken in tertiary referral centers, the questions are how common is “not rare” and how high, therefore, the index of suspicion should be before patients are referred. The wide range of answers in the literature is due in part to variable definitions of primary hyperaldosteronism; these have been influenced by the degree of clinical improvement required to justify surgery for a benign tumor. Although removal of a functional macroadenoma can usually be justified, cure rates appear to have fallen to only 50% since surgery was extended to patients with adrenal microadenomas.
Like many others, we had previously found that ≈15% of unselected hypertensive patients had elevated aldosterone-renin ratio (ARR) and have not found a minimum level of aldosterone below which even an adrenal macroadenoma can be reliably excluded without further investigation.1 Because plasma renin distribution is log-normal and aldosterone normal, all patients with low renin have a high ARR unless their aldosterone in completely suppressed, as in the monogenic syndromes. The question, therefore, was whether patients with elevated ARR are an artifact of the log-distribution of renin and represent a “rediscovery” of the extreme end of low-renin hypertension or whether they are a distinct subset that needs further investigation to exclude a curable adenoma. For SALT, we wished to frame a question that could be definitively answered by experimental observation and to which the answer was genuinely uncertain in advance: hence, the primary question of whether spironolactone is more effective than thiazide in patients with high ARR. Predicting “yes” at conventional doses of thiazide, we asked the secondary question of whether low-renin patients require higher doses.
We agree with Dr Mulatero that primary hyperaldosteronism leads to resistant hypertension. Our previous study of 850 unselected hypertensive patients in primary care, from whom the SALT patients were drawn, reported more drugs and higher blood pressure in patients at the upper than lower end of ARR distribution.1 Although, at entry to SALT, only background calcium channel blockade was permitted, several patients had a previous systolic blood pressure >140 mm Hg despite also receiving low-dose thiazide and angiotensin-converting enzyme inhibitor. We believe our patients to be sufficiently representative of “real life” to render an aldosterone-secreting adenoma unlikely in most patients with high ARR. Selection of those requiring further investigation remains problematic. Completely suppressed renin, despite blockade of angiotensin feedback, and hypokalemia on low-dose thiazide may be more sensitive clues than an elevated aldosterone level.