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Pulse-wave velocity, pulse-wave morphology and dual blockade of the renin-angiotensin system in chronic kidney disease.


Marie Frimodt-Møller


Patients with CKD have a high risk of CV morbidity and mortality, which has been related to anincreased arterial stiffness. By blocking the RAS with an ACEI or an ARB, arterial stiffness isreduced, but in addition it has been shown, that the effects on central BP are larger than seen inperipheral BP. This difference has been translated to an improved CV outcome of RAS inhibitingdrugs. A more complete blockade of the RAS might further reduce arterial stiffness and potentiallyimprove CV survival.Applanation tonometry is a simple non-invasive method to obtain estimates of central BP andarterial stiffness, estimates which have been shown to be strong independent predictors of CVmortality and outcome in patients with CKD.The aim of the present thesis was to examine the effect of dual blockade with ACEI and ARB oncentral BP and arterial stiffness assessed by applanation tonometry in patients with CKD comparedwith mono blockade with ACEI or ARB. Furthermore it was intended to evaluate the tolerance ofdual blockade in CKD patients. Prior to the use in the intervention study, it was aimed to examinethe method of applanation tonometry focusing on examination conditions and reproducibility.In healthy individuals, it was shown that smoking and a high-calorie meal significantly influencedcentral hemodynamics. Furthermore the reproducibility of applanation tonometry was found to behigh in healthy individuals comparable with the reproducibility examined in patients with CKDeven over time. It is concluded, that applanation tonometry may be used as an easy and highlyreproducible method in healthy individuals and in patients with CKD. It is suitable for theassessment of central hemodynamics under standardized examination conditions in long-termclinical trials in patients with CKD.The effects of dual RAS blockade on central BP and arterial stiffness were examined in 67 patientswith CKD. Dual RAS blockade significantly further reduced wave reflection and arterial stiffnesscompared to mono therapy, independently of BP, assessed by applanation tonometry. In additionPP-amplification was further improved, indicating a larger impact of dual blockade on central BPthan observed in brachial BP.RAS-inhibition may induce adverse events in patients with CKD. The tolerance of dual RASblockade was evaluated in 47 CKD patients, who was a subgroup of the larger population in theintervention study. Almost half of these patients did not tolerate full dose dual blockade due to lossof kidney function, symptomatic hypotension or hyperkalemia. Even though hyperkalemia was afrequent problem, it was managed in most cases.To conclude, indices of central BP and arterial stiffness obtained by applanation tonometryperformed under standardized conditions are highly reproducible in healthy individuals and patientswith CKD. It was found that dual RAS blockade had an additive beneficial BP-independent effectcompared to mono RAS blockade on central pulse-wave reflection and arterial stiffness in CKDpatients. Since central BP and arterial stiffness have been shown to be strong independent predictorsof CV mortality and outcome in patients with CKD this further reduction of arterial stiffness by amore complete blockade of the RAS might potentially improve CV survival.