Naam Esther de Beus
Datum verdediging 29-06-2017
(Co) promotoren prof.dr. M.C. Verhaar, prof.dr. M.L. Bots, dr. P.J. Blankestijn
Titel proefschrift Resistant hypertension: consequences and treatment options

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Samenvatting proefschrift
Resistant hypertension, uncontrolled blood pressure despite use of ≥3 antihypertensives including a diuretic or use of ≥4 antihypertensives regardless of blood pressure (BP), was studied. In this thesis, 1/3 of patients with chronic kidney disease, including kidney transplant patients, is shown to have resistant hypertension. Even intensive guidance by nurse practitioners, aimed at both optimization of antihypertensive drug use and life style adjustments, does not decrease the prevalence during follow-up. Risks of resistant hypertension are very high in this population, with an 1.5-fold increased risk for a composite cardiovascular endpoint and a 2.3-fold increased risk for reaching end stage renal disease. In patients with hypertension and a history of cardiovascular disease, 9% has resistant hypertension. A strong relationship with higher age, and with an adverse cardiovascular risk profile of increased BMI, presence of diabetes mellitus and burden of vascular disease was found. Also, resistant hypertension was significantly more frequent in patients with microalbuminuria or an eGFR below 60 ml/min/1.73m2. Risk for a composite of cardiovascular endpoint was 25% higher in this population, and cardiovascular death 1.5-fold more likely. These risks were similar in resistant hypertensive patients with controlled BP. The role of sympathetic hyperactivity in the pathophysiology of hypertension in chronic kidney disease is reviewed. Experimental studies show that renal denervation can abolish hypertension and have kidney protective effects. Sympathetic activity increases with decrease in kidney function in humans. Therefore, patients with chronic kidney disease are expected to have greater benefit from a new antihypertensive treatment aimed at decreasing sympathetic activity. Antihypertensive drugs have a variable effect on sympathetic activity, with diuretics and calcium channel blockers having a stimulating effect, whereas RAAS inhibitors, beta blockers and central acting drugs have an inhibitory effect. The SYMPATHY trial compared renal denervation (RDN) added to usual care with usual care in patients with resistant hypertension or uncontrolled BP due to intolerance for ≥2 of the major antihypertensive drug classes. The intervention was not found to be effective in decreasing BP, as the daytime systolic blood pressure (primary endpoint) decreased with 6.0 mmHg (95%CI -10.7 to -1.2) in the intervention group as compared with a 7.9 mmHg (95%CI -14.7 to -1.3) decrease in the controls. An interaction term did not show a differential effect with lower eGFR. As a secondary analysis, adherence to antihypertensive drugs, assessed by direct measurement of the compounds, was shown to be strikingly low in these patients. A post-hoc analysis showed that dietary sodium intake cannot be used to select patients with greater effectiveness of RDN. Decrease in salt sensitivity after RDN could not be demonstrated. In the last part of the thesis, a beneficial effect of RDN is found on kidney related pain in patients with polycystic kidney disease and loin pain hematuria syndrome. Overall conclusion is that resistant hypertension is an important issue and both an effective RDN procedure and effective measures to increase adherence to antihypertensive drugs are still to be found. RDN studies should be designed in ways minimizing nonadherence as an important source of bias.