Hypertension and Kidney: Choosing the Right Therapeutic Agent for BP Control and Nephroprotection

Studies have indicated that compared with patients with a blood pressure level < 140/90 mm Hg, those with a blood pressure level ≥ 160/95 mm Hg had an average -2.67 mL/min/1.73m 2 greater annual decline in estimated glomerular filtration rate and a 5.21-fold greater risk of early kidney function decline. (4)

While the exact mechanisms of kidney damage in patients with hypertension remain elusive, two complementary pathogenic processes leading to kidney fibrosis and scarring seem plausible. First, changes in systemic and renal macro and microvasculature leading to the loss of renal autoregulation causing elevation of intraglomerular capillary pressure and consequent hyperfiltration-mediated injury. Such hyperfiltration leads to trans glomerular loss of proteins causing the release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells.

Second is endothelial dysfunction and loss of endogenous vasodilators as precipitating factors of hypoxic-ischemic injury. This sequel leads to activation of intrarenal Renin-Angiotensin System (RAS) and an increased release of cytokines and growth factors with recruitment of inflammatory cells, which stimulate apoptosis and cause loss of normal kidney cells, increased matrix production, ultimately leading to progressive glomerular and interstitial fibrosis and scarring. (5) Additionally, the sympathetic nervous system activity is also increased in chronic kidney disease (CKD) (6) . Afferent signals from the diseased kidney are transmitted to the vasomotor control centre in the brain increasing the blood pressure (7) .

The treatment of hypertension has three main goals: blood pressure control; preventing the progression of CKD itself; and reducing the risk of cardiovascular complications (1)

Studies have cited that >75% hypertensive patients require two or more medications to achieve blood pressure goals, with observations supporting that most patients should consider treatment with a renin‐angiotensin system blocker combined with a calcium channel blocker as first‐line therapy or as part of the overall therapeutic regimen (8) with recent global hypertension guidelines also endorsing single-pill combination as initial therapy for effective management of hypertension.

Cilnidipine – a newer generation Calcium Channel Blocker (CCB), possesses both L- and N-type calcium channel blocking activity. Since N-type calcium is distributed along the nerve and in the brain, cilnidipine is anticipated to exert specific action on nerve activity, such as inhibition of the sympathetic nervous system (9) Sympatholytic profiles of cilnidipine have been observed in vitro as well as in clinical practice (10). In a study conducted in 2920 hypertensive patients, treatment with cilnidipine and angiotensin receptor blocker led to significant reductions in heart rate, particularly in patients with a higher baseline heart rate

≥75 beats/min, and was associated with few adverse reactions related to central nervous functions. (11)

The major clinical benefit of N-type calcium channel blocking the activity of cilnidipine is demonstrated in the form of preventing the progression of proteinuria which is superior to amlodipine in patients with hypertension and chronic renal disease when added with a renin-angiotensin system inhibitor (12)

In summary, cilnidipine – dual type (L- and N-type) calcium channel blocker seems to be valuable first-line choice of antihypertensive agent for the management of hypertension as initial therapy for optimising long term – renal and cardiovascular outcomes in these patients.

Adapted from

1 Elsa Morgado and Pedro Leão Neves (2012). Hypertension and Chronic Kidney Disease: Cause and Consequence – Therapeutic Considerations, Antihypertensive Drugs, Prof. Hossein Babaei (Ed.), ISBN: 978-953-51-0462-9, InTech, Available from:

http://www.intechopen.com/books/antihypertensivedrugs/hypertension-in-chronic-kidney-disease-cause-and-consequence-therapeutic-considerations-

2 Schoenborn, C. (2009). Health characteristics of adults aged 55 years and over: United States, 2004–2007. Natl Health Stat Report, Vol. 8, No. 16, (July, 2008), pp. 1-31

3 US Renal data System, USRDS 2010 Annual report: Atlas of Chronic Kidney Disease and End-stage Renal Disease in the United States, NIH, NIDDKD, 2010

4 Suma Vupputuri et al, Effect of Blood Pressure on Early Decline in Kidney Function Among Hypertensive Men, Hypertension. 2003; 42:1144-1149.)

5 Goldblatt, H. (1964). Hypertension of renal origin. Historical and experimental background. American Journal of Surgery, Vol. 107, (January, 1964), pp. 21-25.

6 Converse, R.L. (1992). Sympathetic overactivity in patients with chronic renal failure. N Engl J Med, Vol. 327, No. 27, (December, 1992), pp.1912-1918

7 Rump, L.C. (2000). Sympathetic overactivity in renal disease: a window to understand progression and cardiovascular complications of uremia? Nephrol Dial Transplant 2000; Vol. 15, No. 11, (November, 2000), pp. 1735-1738

8 Brook RD, Kaciroti N, Bakris G, Dahlöf B, Pitt B, Velazquez E, Weber M, Zappe DH, Hau T, Jamerson KA. Prior Medications and the Cardiovascular Benefits From Combination Angiotensin-Converting Enzyme Inhibition Plus Calcium Channel Blockade Among High-Risk Hypertensive Patients. J Am Heart Assoc. 2018 Jan 4;7(1):e006940. doi: 10.1161/JAHA.117.006940. PMID: 29301757; PMCID: PMC5778960.

9 Fujii S, Kameyama K, Hosno M, Hayashi Y, Kitamura K. Effect of cilnidipine, a novel dihydropyridine calcium channel antagonist, on N type calcium channel in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 1997;280:1184e1191

10 Uneyama H, Takahara A, Dohmoto H, Yashimoto R, Inoue K, Akaike N. Blockade of N type calcium current by cilnidipine (FRC 8653) in acutely dissociated rat sympathetic neurones. Br J Pharmacol. 1997;122:37e42

11 Nagahama S, Norimatsu T, Maki T, Yasuda M, Tanaka S. The effect of combination therapy with L/N type calcium channel blocker cilnidipine, & an angiotensin II receptor blocker on blood pressure & heart rate in Japanese hypertensive patients: an observational study conducted in Japan. Hypertens Res. 2007;30:815e822

12 Fujita T, Ando K, Nishimura H, et al. For cilnidipine versus amlodipine randomised trial for evaluation of renal diseases(CARTER) study investigators. Antiproteinuric effect of calcium channel blocker cilnidipine added to rennin angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney Int. 2007;72:1543e1549.The