Clinical and Physiological Aspects of Salt Sensitive Hypertension

Abstract

Background: Hypertension is a major risk factor for stroke, myocardial infarction, chronic kidney disease and heart failure, and is arguably the most important treatable risk factor for premature death in modern society [1]. Despite being extremely common, the cause of hypertension in most patients is unknown. This limits treatment specificity, and many patients fail to reach blood pressure targets and experience medication side effects [2,3]. It is increasingly recognized however that primary aldosteronism (PA), a specifically treatable and potentially curable form of hypertension, is much more common than previously thought. The diagnostic process for this condition is difficult, and this is particularly true of adrenal vein sampling (AVS), which helps determine treatment options. The optimal approach to AVS is unclear, and the diagnostic criteria are contentious. PA is also now recognised to be associated with blood pressure-independent adverse effects on the cardiovascular system, effects which may be salt dependent. There is additional evidence suggesting a link between PA and obstructive sleep apnoea (OSA). The exact nature of this link is unclear, and it is not known if treating PA will improve OSA.Altered distal renal salt handling plays an important role in most hypertensive states, including PA. The thiazide sensitive sodium chloride cotransporter (NCC) is an important effector of distal sodium handling. Recent advances have uncovered a complex system governing NCC, but the physiology of this system is unclear, particularly in relation to aldosterone. Urinary exosome analysis is a promising technique that allows in vivo assessment of renal tubular constituents, and which might be useful to determine influences of aldosterone on NCC.Aims: There were three aims of this thesis: 1) To investigate two aspects of AVS; the prognostic implications of contralateral suppression for post adrenalectomy outcomes, and the effects of synthetic adrenocorticotropic hormone (ACTH) administration on AVS diagnostic performance 2) To investigate the effects of treatment of PA on OSA parameters 3) To utilize urinary exosome analysis to determine the influence of mineralocorticoids on NCC in humans. Methods and results: All patients who underwent adrenalectomy for PA at the Princess Alexandra Hospital were identified, and post adrenalectomy outcomes were examined with respect to contralateral suppression (CS) at AVS. After surgery, those with CS had lower systolic BP (128mmHg vs. 144mmHg p=0.001), a greater proportion with cure or improvement of hypertension (96% vs. 64%, p=0.0034) and a greater proportion with biochemical cure of PA (43/49 [88%] vs. 4/9 [44%], p=0.002) than those without CS.After a change in protocol to include pre and post ACTH samples, all AVS procedures where ACTH had been used were examined. In 47 procedures the median adrenal/peripheral cortisol gradient increased bilaterally after ACTH (pl0.001 for both). 34/47 studies were diagnostic pre-ACTH (6 failing because of low aldosterone levels bilaterally and 7 failing to cannulate both sides), vs. 44/47 (p=0.011) studies diagnostic post ACTH (failure to cannulate one or both sides in 3). Concordance between diagnostic studies pre and post ACTH was 91%.During the diagnostic workup for PA 44 patients were recruited, from which 34 patients were screened for OSA by polysomnography, and those with OSA had repeat polysomnography g3 months after treatment of PA. At baseline, 21% of the patients had no OSA, 26% had mild, 24% moderate and 29% severe OSA. The apnoea hypopnea index (AHI) correlated with BMI, neck size and urinary sodium excretion. After treatment of PA in 20 patients with at least mild OSA, the median overall AHI fell from 22.5 to 12.3 (fixed effect estimate -8.65, p=0.02), whilst the supine and lateral AHI also reduced significantly.Urinary exosomes were isolated by ultracentrifugation from 26 patients undergoing fludrocortisone suppression testing (FST, in which high doses of the mineralocorticoid, fludrocortisone, are administered over a 4 day period). Abundance of NCC, phosphorylated NCC, 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) were quantified by Western blot. During FST, there was a rise in NCC and pNCC abundance; NCC increased 3.68 fold (pl0.01) and pNCC increased 2.73 fold (pl0.01) relative to baseline. Abundance of WNK4 increased by 3.23 fold (pl0.01) but changes in SPAK were not significant (p=0.14). Plasma potassium was a strong negative correlate to pNCC, NCC and WNK4 abundance (pl0.001 for all), suggesting an important mechanistic link.Conclusions: 1) The presence of contralateral suppression at AVS correlates with good BP and biochemical outcomes from surgery for aldosterone producing adenoma. This suggests that contralateral suppression should be a factor in deciding whether to offer surgery for treatment of PA. 2) The administration of ACTH at AVS results in a reduction in the proportion of non-diagnostic studies with a low proportion of discordance between pre and post-ACTH diagnoses.3) There is a high prevalence of OSA in patients with PA, and OSA parameters improve with specific treatment of PA. A relationship with sodium excretion and the AHI supports a mechanistic link between sodium and fluid retention and OSA.4) In humans mineralocorticoid administration is associated with a rapid increase in abundance of NCC and phosphorylated NCC, possibly via the WNK pathway. The strong negative correlation with potassium suggests these effects may be driven by changes in plasma potassium.