The Dual Role of the Kidney in Primary Aldosteronism: Key Determinant in Rescue From Volume Expansion and Persistence of Hypertension

Primary aldosteronism is a hypertensive disorder characterized typically by hypokalemia, metabolic alkalosis, suppressed plasma renin, and inappropriately elevated aldosterone secretion resulting from an adrenal adenoma (aldosterone-producing adenoma, APA) or idiopathic adrenal hyperplasia. Recent evidence indicates a greater prevalence of primary aldosteronism among patients with hypertension than the previously accepted estimate of 1%. Such increased prevalence may be the result of more efficient identification of this disease due to the widespread use of the aldosterone-renin ratio as a screening diagnostic test.1 Although primary aldosteronism is considered correctable with either unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists, in many cases, hypertension may persist after treatment.2

Most studies on the effects of treatment of primary aldosteronism on blood pressure have involved patients with APA, and a cumulative analysis of initial case series indicated a rate of hypertension cure of 59% after unilateral adrenalectomy.3 In the majority of these series, however, cure was defined based on achieving a blood pressure < 160/100 mm Hg; more recent evidence indicates that only approximately one-third of patients treated for primary aldosteronism achieve a blood pressure < 140/90 mm Hg without the use of additional antihypertensive agents.3, 4, 5 These estimates were obtained in retrospective investigations and are in keeping with the results of a recent prospective study of primary aldosteronism patients with either APA or idiopathic adrenal hyperplasia, 39% of whom had their blood pressure normalized by adrenalectomy or spironolactone, respectively, whilst the remaining 61% showed significant improvement of hypertension (decrease of blood pressure by more than 20% and/or fewer antihypertensive agents taken to normalize values).6 Many studies have investigated the clinical and laboratory factors associated with resolution of hypertension after treatment of primary aldosteronism and have identified younger age, shorter duration of disease, lack of family history of hypertension, milder preoperative antihypertensive therapy, lower plasma potassium, greater plasma or urinary aldosterone, and lower active renin3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 as such factors.

The study of Wu et al15 in this month's issue of the American Journal of Kidney Diseases reports a retrospective analysis of 150 patients with APA who were included in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database and had undergone unilateral adrenalectomy. In their analysis, the authors investigate whether the presence of mild reduction of preoperative estimated glomerular filtration rate (GFR) was associated with blood pressure outcome after surgery. Two-thirds of patients had their blood pressure normalized by treatment, and increasingly higher frequency of residual hypertension was observed in patients in whom estimated GFR (using the Modification of Diet in Renal Disease [MDRD] Study equation) was greater than 90 mL/min/1.73 m2 (19%), between 60 and 90 mL/min/1.73 m2 (42%), and less than 60 mL/min/1.73 m2 (54%). Preoperative eGFR less than 90 mL/min/1.73 m2, together with duration of hypertension and body mass index, was an independent predictor of residual hypertension, with an odds ratio of 2.7. Strengths of this study include the large cohort size and a long time interval after surgery (mean, 59 months; range, 16-150). Weaknesses include absence of a matched comparison group of patients with primary hypertension, and lack of urinary albumin measurements.

The results of this study do not come as a surprise because the kidney is a target of elevated blood pressure and even early stages of kidney disease may be associated with hypertension. Therefore, in patients with primary aldosteronism, who are commonly diagnosed long after detection of hypertension (more than 7 years in the study of Wu et al), impairment in kidney function might reflect hypertensive kidney damage that does not resolve after appropriate surgical or medical treatment and accounts for more frequent persistence of high blood pressure.

These observations prompt some comments on the role played by the kidney in primary aldosteronism. Although experimental animal studies clearly demonstrate that inappropriate aldosterone levels for sodium status induce extensive kidney damage,16 cross-sectional evaluations of kidney function in patients with primary aldosteronism have shown a high degree of variability in the prevalence of clinically relevant kidney disease.4, 17, 18, 19, 20, 21 Initial kidney biopsy studies demonstrated only moderate damage in patients with primary aldosteronism20 and reported prevalence of decreased kidney function in as little as 7% of patients with primary aldosteronism.20 Similarly, a recent single-center study has reported 24-hour creatinine clearance of < 60 mL/min/1.73 m2 in 7% of 56 patients with primary aldosteronism,22 whereas in the German Conn Registry, increased plasma creatinine concentration was found in a substantially higher percentage of patients.23 Prevalence of overt proteinuria varied from 8% (17) to 24% (21); this disparity might be explained by the differing duration and severity of disease. In a large multicenter Italian study,21 prevalence of microalbuminuria in patients with primary aldosteronism was two-fold that of patients with primary hypertension.

Important information on the role of the kidney in primary aldosteronism was obtained from 2 prospective studies with short-term24 and long-term25 follow-up after treatment. Ribstein et al24 reported a significant decrease in urinary albumin excretion in 25 patients with APA who were reevaluated 6 months after adrenalectomy. In a 9-year follow-up study of patients with either APA or idiopathic adrenal hyperplasia, it was shown that microalbuminuria is more likely to subside to normal levels after either surgical or medical treatment than to progress to overt proteinuria.25 In this study, restoration of normal albumin excretion was more frequent in patients with primary aldosteronism than in matched patients with primary hypertension, and this effect appeared to be independent of blood pressure. Both these studies suggest that albuminuria is a marker of a renal hemodynamic defect. In keeping with the findings of previous studies,26 some of which were conducted in experimental settings,27 these 2 studies also demonstrated the presence of relative glomerular hyperfiltration in patients with primary aldosteronism as compared with appropriately matched patients with primary hypertension. Hyperfiltration was rapidly reversed within the first few months after treatment, an effect that may be explained by several factors, including decreased systemic blood pressure, decreased extracellular fluid volume, recovery of renin activity, postoperative aldosterone suppression, and removal of direct vasodilator effects of aldosterone on intrarenal vessels.28 A very recent analysis of 408 patients with primary aldosteronism (both APA and idiopathic adrenal hyperplasia) who were included in the German Conn Registry23 has confirmed that GFR declines soon after treatment of disease and remains relatively stable thereafter. Moreover, evaluation of intrarenal Doppler velocimetric indices demonstrated decreased intravascular resistance in patients with primary aldosteronism in comparison with patients with primary hypertension and reversal of the abnormal intrarenal hemodynamic pattern 1 year after either surgical or medical treatment.29

Today we know that primary aldosteronism causes a variety of cardiovascular, metabolic, and renal sequelae30 that reflect the capability of inappropriately elevated aldosterone to induce tissue damage in addition to that caused by hypertension itself. However, when we deal with the role of the kidney in primary aldosteronism, 2 distinct aspects need to be considered. On the one hand, there are functional adaptations that are induced by increased tubular sodium reabsorption and lead to expansion of extracellular volume, hypertension, increased renal perfusion pressure, and suppression of renin with decreased intrarenal vascular resistance.29 These intrarenal hemodynamic changes cause glomerular hyperfiltration and increase sodium excretion, with escape from the tubular effect of aldosterone31 and recovery of a steady state. At this stage of disease, the intrarenal hemodynamic adaptation is reversible and, by preventing progressive water and sodium retention, it acts as a rescue mechanism. On the other hand, there is structural damage that involves primarily the intrarenal vessels and results from both persistent hypertensive insult and direct untoward effects of aldosterone.16 This damage may take several years to develop, leading to decreased glomerular perfusion and stimulation of renin release that escapes from suppression by excess plasma aldosterone and subsequent volume expansion.22 In this view, lack of complete renin suppression in patients with primary aldosteronism could be the hallmark of more advanced kidney disease.22 At this stage of disease, the kidney becomes a determinant of the clinical outcome of primary aldosteronism, because kidney function is critical for blood pressure response to treatment, as reported by Wu et al. Once again, these findings underline the importance of appropriate timing in the identification of patients with this form of hypertension to prevent renal complications and optimize the clinical benefits of treatment.