Increased arterial stiffness does not respond to renal denervation in an animal model of secondary hypertension

Abstract

Renal denervation is a novel device based therapy promoted to reduce high blood pressure. We examined the impact of renal denervation on systolic blood pressure, renal function, and arterial stiffness in the Lewis Polycystic Kidney disease (LPK) rodent model of kidney disease. Animals were subjected to bilateral renal denervation or sham surgeries at age 6 and 12 weeks. Systolic blood pressure was monitored by tail-cuff plethysmography and renal function by urinalysis and creatinine clearance. At age 16 weeks, beat-to-beat aortic pulse wave velocity as a functional indicator of arterial stiffness was determined. Renal denervation produced an overall reduction in blood pressure in the LPK [(denervated 164±4 vs. sham-operated 180±6 mmHg, n = 6 per group, P=0.003)] and delayed, but did not prevent, the decline in renal function. Aortic pulse wave velocity was markedly elevated in the LPK compared with Lewis and was not altered by renal denervation in the LPK however a reduction was seen in the control Lewis animals. These results support the hypothesis that renal nerves contribute to secondary hypertension in conditions such as kidney disease.

Hypertension in chronic kidney disease: What lies behind the scene

“…As an earlier study from our group has demonstrated, chronic administration of the ACEi, perindopril to the LPK rat causes a reduction in the PWV index of arterial stiffness and enhances central artery compliance ( Ng et al, 2011 ). These results were not achieved by renal denervation of our animals ( Yao et al, 2017 ), and whether this is the case in different CKD animal models or humans with kidney diseases has not been fully investigated. Hence, further research in this area is required in order to establish a clear ground on the clinical outcome of RAS antagonism versus that of renal denervation.…”

“…Several trials have been conducted ( Krum et al, 2009 ; Investigators, 2010 ; Esler et al, 2012 ; Kandzari et al, 2012 ; Bakris et al, 2014 ; Bhatt et al, 2014 ; Liu et al, 2017 ; Sievert et al, 2017 ; Böhm et al, 2020 ), however to date, there is no global census or legislative approval of renal denervation as a clinical procedure for the treatment of hypertension non-pharmacologically. Although renal denervation has played an ameliorating role in reducing elevated BP and preserving renal function in diseased kidneys in humans ( Hering et al, 2012 ; Ott et al, 2015 ) and rats ( Yao et al, 2017 ) with CKD, other factors contributing to BP elevation remain, that are unalterable by renal denervation. For example, in our studies, we have shown that despite a reduction in BP and urinary protein of our CKD rat model, renal denervation did not fix the problem of increased arterial stiffness as assessed by pulse wave velocity (PWV), a hallmark of BP derived risk factor for morbidity ( Yao et al, 2017 ).…”

“…Although renal denervation has played an ameliorating role in reducing elevated BP and preserving renal function in diseased kidneys in humans ( Hering et al, 2012 ; Ott et al, 2015 ) and rats ( Yao et al, 2017 ) with CKD, other factors contributing to BP elevation remain, that are unalterable by renal denervation. For example, in our studies, we have shown that despite a reduction in BP and urinary protein of our CKD rat model, renal denervation did not fix the problem of increased arterial stiffness as assessed by pulse wave velocity (PWV), a hallmark of BP derived risk factor for morbidity ( Yao et al, 2017 ). To date, the renal denervation field is challenged by: 1) a lack of trained personnel and professionals performing the procedure; 2) an unavailability of strict requirements for operation specifications; 3) nil available methods for measuring the effectiveness of denervation procedures; 4) a lack of definition with regards to which patients are optimal candidates for the denervation; 5) reported controversy in clinical outcomes, especially in relation to office or ambulatory BP readings, and GFR protection versus worsening; 6) the extent of the denervation process required; 7) nerve anatomical variations among patients; 8) the issue of re-denervation or renal nerves convergence ( Yao et al, 2017 ) after a period of time following the procedure; 9) variation in timing and follow-up during the trials (for example, 2–36 months); (10) the presence of good representative sham-controls; and 11) the complications that arise following the procedures, which may range from minor adverse effects, to hematoma, renal artery narrowing or stenosis or dissection, acute renal failure, or even death ( Sata et al, 2018 ; Ku et al, 2019 ; Liang et al, 2020 ).…”