Current Medical Research & Opinion
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Vol. 31, No. 1, 2015, 177–182
Article RT-0264.R1/960071 All rights reserved: reproduction in whole or part not permitted
2015 Supplement S1: Lercanidipine therapy: New experiences from Eastern Countries Can lercanidipine improve renal function in patients with atherosclerotic renal artery stenosis undergoing renal artery intervention?
Meng Peng* Xiong-jing Jiang* Hui Dong Yu-bao Zou Hui-min Zhang Hai-ying Wu Yuejin Yang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Address for correspondence: Jiang Xiong-jing MD, Department of Cardiology, Fuwai Hospital, Beilishi Road 167, Xicheng District Beijing, 100037, China. [email protected] Keywords: 24-hour urine protein – Lercanidipine – Renal artery stenting – Renal function Accepted: 18 August 2014; published online: 26 November 2014 Citation: Curr Med Res Opin 2015; 31:177–82
Abstract Objective: To investigate the renal-protective effect of lercanidipine in patients undergoing renal artery intervention. Methods: A prospective, single-center, cohort study was conducted and patients, 30–75 years of age, with atherosclerotic renal artery stenosis were consecutively enrolled between September 2011 and October 2012. Lercanidipine (10–20 mg/day) was regularly taken after the intervention. Follow up visits were performed at 3 and 6 months after the intervention. Serum creatinine, clinical blood pressure, 24 hour ambulatory blood pressure, pulse wave velocity, and 24 hour urine protein were assessed. Adverse events were recorded. Results: In total, 55 patients (mean age 63.5 8.9 years) were enrolled and 52 completed the study. Renal function, estimated glomerular filtration rate (eGFR) and 24 hour urine protein at 3 months after the intervention were not statistically different compared with the baseline. At 6 months after the intervention eGFR significantly increased versus baseline (78 23 ml/min/1.73 m2 vs 71 21 ml/min/1.73 m2, p ¼ 0.021); 24 hour urine protein decreased significantly (0.02 g [IQR, 0.01–0.1] vs 0.03 g [IQR, 0.01–0.28], p ¼ 0.042). Blood pressure control improved at 3 months and 6 months after the intervention. The need for antihypertensive drugs decreased; clinical systolic blood pressure, diastolic blood pressure and 24 hour average systolic blood pressure and diastolic blood pressure decreased. The pulse wave velocity decreased after 3 and 6 months. At the end of follow-up, none of the following adverse events occurred: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred. Conclusions: This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention.
Introduction
*Meng Peng and Xiong-jing Jiang equally contribute to the study as first co-author
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Renal vascular disease, one of the most important causes of hypertension and renal insufficiency, is a potentially curable disease. Its prevalence in the hypertensive population is about 1%–3%, and this condition is mainly due to atherosclerosis1. Thanks to the progress of antihypertensive therapy, renal vascular hypertension can be effectively controlled; on the other hand, avoiding renal dysfunction has become a key target of revascularization. Lercanidipine and renal function in renal artery stenosis Peng et al.
177
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January 2015
Although percutaneous renal artery stenting (PRAS) has been widely used in clinical practice as an atherosclerotic renal vascular disease treatment, some studies showed that renal artery stent cannot reverse kidney damage2, suggesting that increased renal blood flow cannot compensate for the unfavorable effects of hypertension and atherosclerosis on renal function. An appropriate antihypertensive treatment may be an important approach to improve the efficacy of renal artery stents. Dihydropyridine calcium channel blockers (DHP CCBs) are very effective in decreasing blood pressure (BP); however, their renal protective effects are uncertain. Lercanidipine is a third-generation DHP CCB and its effect on renal afferent arterioles is similar to that on renal efferent arterioles. The DIAL (Diabete, Ipertensione, Albuminuria, Lercanidipine)3 and ZAFRA (ZAndip en Funcion Renal Alterada)4 studies have shown that the efficacy of lercanidipine in reducing BP and proteinuria is similar to that of ACEIs; in type 2 diabetic nephropathy patients and in patients with renal failure, lercanidipine presents renal protective effects. Recent studies have found that lercanidipine can improve blood vessel elasticity, inhibit the proliferation of vascular smooth muscle, reduce oxidative stress and weaken the inflammatory reaction5. Therefore, we hypothesized that lercanidipine has the potential for protective effects in patients with renal artery stenting and can further improve and stabilize renal function. Based on this background, we conducted a prospective, single-center, cohort study to observe the renal protective effect of lercanidipine in patients undergoing renal artery intervention.
The exclusion criteria were: allergy to DHPs; left ventricular efferent channel block; untreated congestive heart failure; myocardial infarction or unstable angina over the prior 6 months; estimated glomerular filtration rate (eGFR) 530 ml/min/1.73 m2 (eGFR ¼ 186 [SCr]1.154 [Age]0.203 [0.742 if female]); active liver disease or AST/ALT levels greater than three times the upper limit of normality; any known malignancy; past or current evidence of Alzheimer’s disease or mental illness history; alcohol or drug abuse. The study was approved by the local ethics committee; all patients were enrolled in the study after participation acceptance and after specific written informed consent.
Intervention and drug treatment A renal artery balloon dilation and stenting approach was applied to all patients; the method has been previously described by us6. After stent placement, residual stenosis was 530% and no serious complications associated with surgery occurred, which is an index of surgery success. In the preoperative period (7 to 0 day [baseline]), according to the BP of each patient, patients received lercanidipine 10–20 mg, once a day (QD), possibly combined with a beta-blocker (metoprolol 25–50 mg twice a day, BID) and hydrochlorothiazide 12.5–25 mg QD. The BP target was set at 140/90 mmHg. After successful stent implantation, the assigned therapy could be modified on the basis of BP changes: in case of BP 5100/60 mmHg, patients were required to stop or reduce hydrochlorothiazide and metoprolol; if blood pressure increased, study medication doses could have been increased or additional drugs administered.
Patients and methods Subjects
Follow-up
Patients with atherosclerotic renal artery stenosis and successful PRAS, within the age range 30–75 years, were consecutively enrolled in this study, between September 2011 and October 2012 at Fu Wai Hospital (Beijing, China); patients had no contraindications for using lercanidipine after intervention. The inclusion criteria on the basis of renal artery stenting were as follows: (1) renal artery or main branch diameter stenosis 60%, if diameter was 60% to 75% it was required that the proximal to distal arterial pressure was 30 mmHg or positive captopril renography; (2) uncontrolled hypertension by three-drug therapy (including one diuretic), or in patients not taking antihypertensive drugs systolic blood pressure 180 mmHg and/or diastolic blood pressure 110 mmHg; (3) longitudinal renal length of the kidney with a stenosed artery.
All patients were invited to our institute for follow up visits at 3 and 6 months after the intervention. Serum creatinine, clinical BP, 24 hour ambulatory BP, pulse wave velocity (measured as carotid–femoral with a single measurement/patient), and 24 hour urine protein were assessed. Adverse events were recorded.
178
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Statistical analysis SPSS17.0 software was used to analyze the data derived from the subjects who completed the treatment. Data were analyzed by descriptive statistics; paired t test (normal distribution) or Wilcoxon (non-normal distribution) were used for intra-patient comparisons. A two-tailed p-value 50.05 was considered statistically significant. www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
110
eGFR (m1 × m in−1 × 1.73m−2)
∗ 100 90 80 70 60 50 baseline
3 months
6 months
Figure 1. eGFR. *p50.05 vs baseline. eGFR: estimated glomerular filtration rate. 4
24-hour urine protein
A total of 55 subjects were enrolled; 3 patients were withdrawn as lercanidipine treatment was interrupted for BP normalization; therefore, 52 patients completed the study. The demographic and clinical features of study subjects are shown in Table 1. Twenty-one subjects had bilateral renal artery stenosis (40.4%), 70 proximal or ostial lesions, 3 lesions in the middle; renal artery stenosis rate was 84.1 8.3%, and stent implantation was performed in 71 renal arteries. As for renal function, eGFR (75 27 ml/min/1.73 m2 vs 71 21 ml/min/1.73 m2, p ¼ 0.266) or 24 hour urine protein (0.055 [0.01–0.225] g vs 0.03 [0.01–0.28] g, p ¼ 0.742) at 3 months after the intervention were not different compared with baseline values (Figures 1 and 2). At 6 months after the intervention, eGFR significantly increased (78 23 ml/min/1.73 m2 vs 71 21 ml/min/ 1.73 m2, p ¼ 0.021) and 24 hour urine protein significantly decreased (0.02 g [IQR 0.01–0.1] vs 0.03 g [IQR 0.01– 0.28], p ¼ 0.042). BP control was more effective at 3 and 6 months after intervention than during the preoperative period (baseline). At 3 months, the number of different antihypertensive drugs administered to patients had significantly decreased (1.8 0.8 vs 2.3 0.7; p ¼ 0.001; in most cases, diuretics were suspended), as well as clinical and 24 hour systolic and diastolic BP (clinical systolic BP: 143 15 mmHg vs 158 17 mmHg, p50.001; clinical diastolic BP 77 11 mmHg vs 86 12 mmHg, p50.001; 24 hour systolic BP 133 15 mmHg vs 143 20 mmHg, p ¼ 0.001; 24 hour diastolic BP 71 9 mmHg vs 80 11 mmHg, p50.001) (Figures 3 and 4). At 6 months, the number of antihypertensive drugs
January 2015
significantly decreased (1.6 0.9 vs 2.3 0.7, p50.001), clinical systolic BP 136 15 mmHg vs 158 17 mmHg (p50.001), diastolic BP 73 9 mmHg vs 86 12 mmHg (p50.001) and 24 hour average systolic BP
3
∗ 2
1
Table 1. Baseline characteristics of the study population (n ¼ 55). 0
Males Mean age Previous (smoking cessation more than 6 months before enrolment) or current smokers Duration of hypertension Prior antihypertensive therapies Diabetes Hyperlipidemia Coronary heart disease Heart rate Body mass index preoperative serum creatinine Blood urea nitrogen High sensitivity C-reactive protein Erythrocyte sedimentation rate Total cholesterol Triglycerides HDL LDL Hemoglobin Left ventricular ejection fraction
37 (71.1%) 63.5 8.9 years 30 (57.7%) 14.8 12.5 years 2.3 0.7 10 (19.2%) 32 (61.5%) 16 (30.8%) 69 9 pulse/min 25.3 2.8 kg/m2 1.1 0.4 mg/dl 7.5 2.5 umol/L 3.4 2.8 mg/L 14 14 mm/h 5 1 mmol/L 1.0 0.7 mmol/L 1.1 0.2 mmol/L 2.7 1.0 mmol/L 134.2 17.6 g/L 63 5%
HDL: high-density lipoprotein; LDL: low-density lipoprotein.
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baseline
3 months
6 months
Figure 2. 24 hour urine protein. *p50.05 vs baseline.
170
∗
150 BP (mmHg)
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Results
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130 110
∗
SBP DBP
∗
90
∗
70 50 baseline
3 months
6 months
Figure 3. Clinical blood pressure. *p50.05 vs baseline. SBP: systolic blood pressure; DBP: diastolic blood pressure.
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170 150
∗
∗
∗
∗
3 months
6 months
BP (mmHg)
130 SBP DBP
110 90
50 baseline
Figure 4. 24 hour blood pressure. *p50.05 vs baseline. SBP: systolic blood pressure; DBP: diastolic blood pressure. 26
∗
24 pulse wave velocity (m/s)
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70
∗
22 20 18 16 14 12 10 baseline
3 months
6 months
Figure 5. Pulse wave velocity. *p50.05 vs baseline.
122 23 mmHg vs 143 20 mmHg (p50.001), and diastolic BP 69 10 mmHg vs 80 11 mmHg (p50.001) significantly decreased (Figure 3 and 4). Pulse wave velocity was significantly decreased at both 3 and 6 months compared with baseline (from 19.8 5.1 to 18.6 4.2 and then to 16.9 4.3 m/s; p50.05 vs baseline for both comparisons; the fact that a single measurement was taken should be considered) (Figure 5). No differences at 6 months versus 3 months were disclosed in any parameter. At the end of follow-up, none of the following adverse events occurred to study patients: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred.
Discussion If not properly treated, renal excretion of large amounts of protein can damage the kidney, with a consequent progression to chronic kidney disease7. Research is indeed 180
Lercanidipine and renal function in renal artery stenosis Peng et al.
interested in the understanding of the mechanisms for reducing urine protein secretion and the related progress to glomerular sclerosis. At present, only few works report the impact of renal artery intervention on protein secretion in urine in patient with renal artery stenosis. Coen et al. reported that in 27 patients with unilateral renal artery stenosis, urinary protein significantly increased at 1 year after stenting compared with baseline values8. Our outcomes show that, already after 6 months since intervention, urine protein is significantly lower than values at baseline. Some studies evaluating eGFR reported that, in the 6 months after stenting, the eGFR did not change significantly compared with preoperative values9,10. On the contrary, in our study, 6 months after intervention, eGFR was significantly raised by 6 ml/min/1.73 m2. Considering our results regarding eGFR increase and urine protein decrease after the intervention, it can be speculated that both parameters may be related to the effect of lercanidipine. Animal experiments showed that, in rat models, lercanidipine can significantly improve renal function, reducing proteinuria11. In a randomized, double-blind clinical trial, 277 hypertensive patients with diabetes and microalbuminuria reported a decrease in the rate of urinary albumin secretion with lercanidipine, the same effect shown with ramipril3. Studies described that low doses of lercanidipine, even without exerting any antihypertensive effect, result in kidney protection12. The mechanisms of this improved renal function and reduced proteinuria with lercanidipine may be related to the following aspects: first, lercanidipine is the latest generation calcium antagonist and the expansion of renal afferent arterioles artery effect is similar to the expansion of renal efferent arterioles; secondly, lercanidipine may reduce the concentration of intracellular calcium, inhibit the angiotensin-induced protein kinase C (PKC)-a and d activation, reduce inflammation and fibrosis, and can increase the biological effects of nitric oxide11. A possible relationship has also been hypothesized between increased PKC-a activity and enhanced endothelial cell layer protein leakage, with important consequences in proteinuria, cardiac hypertrophy and fibrosis, and heart failure control13–16. Lercanidipine may improve blood vessel elasticity, inhibit proliferation of vascular smooth muscle, reducing oxidative stress5, inhibit cell proliferation, reduce expression of glomerular endothelial cell adhesion molecules, and reduce tissue inflammation and renal tubule interstitial fibrosis11. Last, another possible renoprotective mechanism of lercanidipine is by offsetting platelet-derived growth factors and platelet-activating factors17. Collectively, these changes in the kidneys will reduce proteinuria and improve renal function. These renoprotective effects were also noted when lercanidipine was administered in a fixeddose combination with enalapril18. In the present study, BP was effectively controlled at 3 and 6 month after intervention compared with baseline; www.cmrojournal.com ! 2015 Informa UK Ltd
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one of the reasons – in addition to the antihypertensive effect of lercanidipine – is that PRAS plays a positive role in BP control19. This study also showed a modest incidence of adverse events (only one patient experienced mild lower extremity edema) in patients under lercanidipine after intervention. This outcome is in line with the report by Barrios et al., who reported that lercanidipine has a good antihypertensive effect, and fewer adverse events occurred in comparison with other CCBs20. A significant decrease of pulse wave velocity (an important indicator of arterial elasticity response) was observed, although on the basis of a single measurement. This may be due to lercanidipine which can reduce oxidative stress, inhibit proliferation of vascular smooth muscle and improve blood vessel elasticity5. Moreover, renal artery stenosis activates the renin–angiotensin–aldosterone system, aldosterone increase determines arterial function and structural changes, accumulation collagen and growth factors in vascular smooth muscle cells, leading to an increase in pulse wave velocity21. Renal artery interventional surgery can reduce the renin–angiotensin–aldosterone activation level, thus improving the elasticity of blood vessels, and therefore reducing pulse wave velocity. The cohort study design could be considered as a limiting factor, while a randomized controlled study versus an active comparator should be considered as the best option to better investigate the renal-protective effect of lercanidipine in the same study population (for a comprehensive review of this topic, see Burnier22). Notably, other factors (e.g., conditions which induce renal damage such as diabetes or renal protection exerted by other therapies such as pioglitazione in diabetic patients) may be considered confounding factors. In addition, this is a single site study, and a multicenter trial could allow confirmation of our initial results and their reliability. Therefore, we are planning a multicenter randomized controlled trial to evaluate the renal protection role of lercanidipine and ACEIs in patients with atherosclerotic renal artery stenosis who will undergo stent implantation.
Conclusion This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention. Considering that lercanidipine has also showed great efficacy in hypertension control with good tolerability, it might be considered as an elective therapy for patients with hypertension and renal impairment.
Transparency Declaration of funding Editorial support for this manuscript was funded by Recordati.
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Declaration of financial/other relationships M.P., X.-j.J., H.D., Y.-b.Z., H.-m.Z., H.y.W., and Y.Y. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose. Acknowledgments Editorial assistance was provided by Chiara Mossali PhD and Luca Giacomelli PhD of Content Ed Net.
References 1. Safian RD, Textor SC. Renal-artery stenosis. New Engl J Med 2001;344: 431-42 2. Wheatley K, Ives N, Gray R, et al. Revascularization versus medical therapy for renal-artery stenosis. New Engl J Med 2009;361:1953-62 3. Dalla Vestra M, Pozza G, Mosca A, et al. Effect of lercanidipine compared with ramipril on albumin excretion rate in hypertensive type 2 diabetic patients with microalbuminuria: DIAL study (diabete, ipertensione, albuminuria, lercanidipina). Diabetes Nutr Metab 2004;17:259-66 4. Robles NR, Ocon J, Gomez CF, et al. Lercanidipine in patients with chronic renal failure: the ZAFRA study. Ren Fail 2005;27:73-80 5. Wu JR, Liou SF, Lin SW, et al. Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling. Pharm Res 2009;59:48-56 6. Jiang XJ, Wu HY, Ming GH, et al. Clinical results of stent revascularization as treatment for renal artery stenosis during 6 months of follow-up. Zhonghua Xin Xue Guan Bing Za Zhi 2005;33:224-7 7. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992;19:403-18 8. Coen G, Moscaritolo E, Catalano C, et al. Atherosclerotic renal artery stenosis: one year outcome of total and separate kidney function following stenting. BMC Nephrol 2004;5:15 9. Sapoval M, Tamari I, Goffette P, et al. One year clinical outcomes of renal artery stenting: the results of ODORI Registry. Cardiovasc Surg Radiol 2010;33:475-83 10. Takumi T, Mathew V, Barsness GW, et al. The association between renal atherosclerotic plaque characteristics and renal function before and after renal artery surgery. Mayo Clin Proc 2011;86:1165-72 11. Menne J, Park JK, Agrawal R, et al. Cellular and molecular mechanisms of tissue protection by lipophilic calcium channel blockers. FASEB J 2006;20:994-6 12. Sabbatini M, Vitaioli L, Baldoni E, et al. Nephroprotective effect of treatment with calcium channel blockers in spontaneously hypertensive rats. J Pharmacol Exp Ther 2000;294:948-54 13. Menne J, Park JK, Boehne M, et al. Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes 2004;53:2101-9 14. Muth JN, Bodi I, Lewis W, et al. A Ca(2þ)-dependent transgenic model of cardiac hypertrophy: A role for protein kinase C alpha. Circulation 2001;103:140-7 15. Hahn HS, Marreez Y, Odley A, et al. Protein kinase C alpha negatively regulates systolic and diastolic function in pathological hypertrophy. Circulation Res 2003;93:1111-19 16. Braz JC, Gregory K, Pathak A, et al. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med 2004;10:248-54 17. Robles NR. Calcium antagonists and renal failure progression. Ren Fail 2008;30:247-55 18. Egan CG, Pontremoli R. Role of the fixed-dose combination lercanidipine– enalapril in renal protection. J Nephrol 2011;24:428-37
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metabolic syndrome: results from the TOLERANCE study. Int J Clin Pract 2008;62:723-8 21. Rosa J, Somloova Z, Petrak O, et al. Peripheral arterial stiffness in primary aldosteronism. Physiol Res 2012;61:461-8 22. Burnier M. Renal protection with calcium antagonists: the role of lercanidipine. Curr Med Res Opin 2013;29:1727-35
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19. Nordmann AJ, Woo K, Parkes R, et al. Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials. Am J Med 2003;114:44-50 20. Barrios V, Escobar C, de la Figuera M, et al. High doses of lercanidipine are better tolerated than other dihydropyridines in hypertensive patients with
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0300-7995 doi:10.1185/03007995.2014.960071
Vol. 31, No. 1, 2015, 177–182
Article RT-0264.R1/960071 All rights reserved: reproduction in whole or part not permitted
2015 Supplement S1: Lercanidipine therapy: New experiences from Eastern Countries Can lercanidipine improve renal function in patients with atherosclerotic renal artery stenosis undergoing renal artery intervention?
Meng Peng* Xiong-jing Jiang* Hui Dong Yu-bao Zou Hui-min Zhang Hai-ying Wu Yuejin Yang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Address for correspondence: Jiang Xiong-jing MD, Department of Cardiology, Fuwai Hospital, Beilishi Road 167, Xicheng District Beijing, 100037, China. [email protected] Keywords: 24-hour urine protein – Lercanidipine – Renal artery stenting – Renal function Accepted: 18 August 2014; published online: 26 November 2014 Citation: Curr Med Res Opin 2015; 31:177–82
Abstract Objective: To investigate the renal-protective effect of lercanidipine in patients undergoing renal artery intervention. Methods: A prospective, single-center, cohort study was conducted and patients, 30–75 years of age, with atherosclerotic renal artery stenosis were consecutively enrolled between September 2011 and October 2012. Lercanidipine (10–20 mg/day) was regularly taken after the intervention. Follow up visits were performed at 3 and 6 months after the intervention. Serum creatinine, clinical blood pressure, 24 hour ambulatory blood pressure, pulse wave velocity, and 24 hour urine protein were assessed. Adverse events were recorded. Results: In total, 55 patients (mean age 63.5 8.9 years) were enrolled and 52 completed the study. Renal function, estimated glomerular filtration rate (eGFR) and 24 hour urine protein at 3 months after the intervention were not statistically different compared with the baseline. At 6 months after the intervention eGFR significantly increased versus baseline (78 23 ml/min/1.73 m2 vs 71 21 ml/min/1.73 m2, p ¼ 0.021); 24 hour urine protein decreased significantly (0.02 g [IQR, 0.01–0.1] vs 0.03 g [IQR, 0.01–0.28], p ¼ 0.042). Blood pressure control improved at 3 months and 6 months after the intervention. The need for antihypertensive drugs decreased; clinical systolic blood pressure, diastolic blood pressure and 24 hour average systolic blood pressure and diastolic blood pressure decreased. The pulse wave velocity decreased after 3 and 6 months. At the end of follow-up, none of the following adverse events occurred: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred. Conclusions: This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention.
Introduction
*Meng Peng and Xiong-jing Jiang equally contribute to the study as first co-author
! 2015 Informa UK Ltd www.cmrojournal.com
Renal vascular disease, one of the most important causes of hypertension and renal insufficiency, is a potentially curable disease. Its prevalence in the hypertensive population is about 1%–3%, and this condition is mainly due to atherosclerosis1. Thanks to the progress of antihypertensive therapy, renal vascular hypertension can be effectively controlled; on the other hand, avoiding renal dysfunction has become a key target of revascularization. Lercanidipine and renal function in renal artery stenosis Peng et al.
177
Curr Med Res Opin Downloaded from informahealthcare.com by State U of Ny at Buffalo on 01/21/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 1
January 2015
Although percutaneous renal artery stenting (PRAS) has been widely used in clinical practice as an atherosclerotic renal vascular disease treatment, some studies showed that renal artery stent cannot reverse kidney damage2, suggesting that increased renal blood flow cannot compensate for the unfavorable effects of hypertension and atherosclerosis on renal function. An appropriate antihypertensive treatment may be an important approach to improve the efficacy of renal artery stents. Dihydropyridine calcium channel blockers (DHP CCBs) are very effective in decreasing blood pressure (BP); however, their renal protective effects are uncertain. Lercanidipine is a third-generation DHP CCB and its effect on renal afferent arterioles is similar to that on renal efferent arterioles. The DIAL (Diabete, Ipertensione, Albuminuria, Lercanidipine)3 and ZAFRA (ZAndip en Funcion Renal Alterada)4 studies have shown that the efficacy of lercanidipine in reducing BP and proteinuria is similar to that of ACEIs; in type 2 diabetic nephropathy patients and in patients with renal failure, lercanidipine presents renal protective effects. Recent studies have found that lercanidipine can improve blood vessel elasticity, inhibit the proliferation of vascular smooth muscle, reduce oxidative stress and weaken the inflammatory reaction5. Therefore, we hypothesized that lercanidipine has the potential for protective effects in patients with renal artery stenting and can further improve and stabilize renal function. Based on this background, we conducted a prospective, single-center, cohort study to observe the renal protective effect of lercanidipine in patients undergoing renal artery intervention.
The exclusion criteria were: allergy to DHPs; left ventricular efferent channel block; untreated congestive heart failure; myocardial infarction or unstable angina over the prior 6 months; estimated glomerular filtration rate (eGFR) 530 ml/min/1.73 m2 (eGFR ¼ 186 [SCr]1.154 [Age]0.203 [0.742 if female]); active liver disease or AST/ALT levels greater than three times the upper limit of normality; any known malignancy; past or current evidence of Alzheimer’s disease or mental illness history; alcohol or drug abuse. The study was approved by the local ethics committee; all patients were enrolled in the study after participation acceptance and after specific written informed consent.
Intervention and drug treatment A renal artery balloon dilation and stenting approach was applied to all patients; the method has been previously described by us6. After stent placement, residual stenosis was 530% and no serious complications associated with surgery occurred, which is an index of surgery success. In the preoperative period (7 to 0 day [baseline]), according to the BP of each patient, patients received lercanidipine 10–20 mg, once a day (QD), possibly combined with a beta-blocker (metoprolol 25–50 mg twice a day, BID) and hydrochlorothiazide 12.5–25 mg QD. The BP target was set at 140/90 mmHg. After successful stent implantation, the assigned therapy could be modified on the basis of BP changes: in case of BP 5100/60 mmHg, patients were required to stop or reduce hydrochlorothiazide and metoprolol; if blood pressure increased, study medication doses could have been increased or additional drugs administered.
Patients and methods Subjects
Follow-up
Patients with atherosclerotic renal artery stenosis and successful PRAS, within the age range 30–75 years, were consecutively enrolled in this study, between September 2011 and October 2012 at Fu Wai Hospital (Beijing, China); patients had no contraindications for using lercanidipine after intervention. The inclusion criteria on the basis of renal artery stenting were as follows: (1) renal artery or main branch diameter stenosis 60%, if diameter was 60% to 75% it was required that the proximal to distal arterial pressure was 30 mmHg or positive captopril renography; (2) uncontrolled hypertension by three-drug therapy (including one diuretic), or in patients not taking antihypertensive drugs systolic blood pressure 180 mmHg and/or diastolic blood pressure 110 mmHg; (3) longitudinal renal length of the kidney with a stenosed artery.
All patients were invited to our institute for follow up visits at 3 and 6 months after the intervention. Serum creatinine, clinical BP, 24 hour ambulatory BP, pulse wave velocity (measured as carotid–femoral with a single measurement/patient), and 24 hour urine protein were assessed. Adverse events were recorded.
178
Lercanidipine and renal function in renal artery stenosis Peng et al.
Statistical analysis SPSS17.0 software was used to analyze the data derived from the subjects who completed the treatment. Data were analyzed by descriptive statistics; paired t test (normal distribution) or Wilcoxon (non-normal distribution) were used for intra-patient comparisons. A two-tailed p-value 50.05 was considered statistically significant. www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
110
eGFR (m1 × m in−1 × 1.73m−2)
∗ 100 90 80 70 60 50 baseline
3 months
6 months
Figure 1. eGFR. *p50.05 vs baseline. eGFR: estimated glomerular filtration rate. 4
24-hour urine protein
A total of 55 subjects were enrolled; 3 patients were withdrawn as lercanidipine treatment was interrupted for BP normalization; therefore, 52 patients completed the study. The demographic and clinical features of study subjects are shown in Table 1. Twenty-one subjects had bilateral renal artery stenosis (40.4%), 70 proximal or ostial lesions, 3 lesions in the middle; renal artery stenosis rate was 84.1 8.3%, and stent implantation was performed in 71 renal arteries. As for renal function, eGFR (75 27 ml/min/1.73 m2 vs 71 21 ml/min/1.73 m2, p ¼ 0.266) or 24 hour urine protein (0.055 [0.01–0.225] g vs 0.03 [0.01–0.28] g, p ¼ 0.742) at 3 months after the intervention were not different compared with baseline values (Figures 1 and 2). At 6 months after the intervention, eGFR significantly increased (78 23 ml/min/1.73 m2 vs 71 21 ml/min/ 1.73 m2, p ¼ 0.021) and 24 hour urine protein significantly decreased (0.02 g [IQR 0.01–0.1] vs 0.03 g [IQR 0.01– 0.28], p ¼ 0.042). BP control was more effective at 3 and 6 months after intervention than during the preoperative period (baseline). At 3 months, the number of different antihypertensive drugs administered to patients had significantly decreased (1.8 0.8 vs 2.3 0.7; p ¼ 0.001; in most cases, diuretics were suspended), as well as clinical and 24 hour systolic and diastolic BP (clinical systolic BP: 143 15 mmHg vs 158 17 mmHg, p50.001; clinical diastolic BP 77 11 mmHg vs 86 12 mmHg, p50.001; 24 hour systolic BP 133 15 mmHg vs 143 20 mmHg, p ¼ 0.001; 24 hour diastolic BP 71 9 mmHg vs 80 11 mmHg, p50.001) (Figures 3 and 4). At 6 months, the number of antihypertensive drugs
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significantly decreased (1.6 0.9 vs 2.3 0.7, p50.001), clinical systolic BP 136 15 mmHg vs 158 17 mmHg (p50.001), diastolic BP 73 9 mmHg vs 86 12 mmHg (p50.001) and 24 hour average systolic BP
3
∗ 2
1
Table 1. Baseline characteristics of the study population (n ¼ 55). 0
Males Mean age Previous (smoking cessation more than 6 months before enrolment) or current smokers Duration of hypertension Prior antihypertensive therapies Diabetes Hyperlipidemia Coronary heart disease Heart rate Body mass index preoperative serum creatinine Blood urea nitrogen High sensitivity C-reactive protein Erythrocyte sedimentation rate Total cholesterol Triglycerides HDL LDL Hemoglobin Left ventricular ejection fraction
37 (71.1%) 63.5 8.9 years 30 (57.7%) 14.8 12.5 years 2.3 0.7 10 (19.2%) 32 (61.5%) 16 (30.8%) 69 9 pulse/min 25.3 2.8 kg/m2 1.1 0.4 mg/dl 7.5 2.5 umol/L 3.4 2.8 mg/L 14 14 mm/h 5 1 mmol/L 1.0 0.7 mmol/L 1.1 0.2 mmol/L 2.7 1.0 mmol/L 134.2 17.6 g/L 63 5%
HDL: high-density lipoprotein; LDL: low-density lipoprotein.
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baseline
3 months
6 months
Figure 2. 24 hour urine protein. *p50.05 vs baseline.
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150 BP (mmHg)
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130 110
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SBP DBP
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90
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70 50 baseline
3 months
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Figure 3. Clinical blood pressure. *p50.05 vs baseline. SBP: systolic blood pressure; DBP: diastolic blood pressure.
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170 150
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∗
∗
∗
3 months
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BP (mmHg)
130 SBP DBP
110 90
50 baseline
Figure 4. 24 hour blood pressure. *p50.05 vs baseline. SBP: systolic blood pressure; DBP: diastolic blood pressure. 26
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24 pulse wave velocity (m/s)
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70
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22 20 18 16 14 12 10 baseline
3 months
6 months
Figure 5. Pulse wave velocity. *p50.05 vs baseline.
122 23 mmHg vs 143 20 mmHg (p50.001), and diastolic BP 69 10 mmHg vs 80 11 mmHg (p50.001) significantly decreased (Figure 3 and 4). Pulse wave velocity was significantly decreased at both 3 and 6 months compared with baseline (from 19.8 5.1 to 18.6 4.2 and then to 16.9 4.3 m/s; p50.05 vs baseline for both comparisons; the fact that a single measurement was taken should be considered) (Figure 5). No differences at 6 months versus 3 months were disclosed in any parameter. At the end of follow-up, none of the following adverse events occurred to study patients: death, dialysis, myocardial infarction or stroke. Mild lower extremity edema occurred in only one patient. No other side effects occurred.
Discussion If not properly treated, renal excretion of large amounts of protein can damage the kidney, with a consequent progression to chronic kidney disease7. Research is indeed 180
Lercanidipine and renal function in renal artery stenosis Peng et al.
interested in the understanding of the mechanisms for reducing urine protein secretion and the related progress to glomerular sclerosis. At present, only few works report the impact of renal artery intervention on protein secretion in urine in patient with renal artery stenosis. Coen et al. reported that in 27 patients with unilateral renal artery stenosis, urinary protein significantly increased at 1 year after stenting compared with baseline values8. Our outcomes show that, already after 6 months since intervention, urine protein is significantly lower than values at baseline. Some studies evaluating eGFR reported that, in the 6 months after stenting, the eGFR did not change significantly compared with preoperative values9,10. On the contrary, in our study, 6 months after intervention, eGFR was significantly raised by 6 ml/min/1.73 m2. Considering our results regarding eGFR increase and urine protein decrease after the intervention, it can be speculated that both parameters may be related to the effect of lercanidipine. Animal experiments showed that, in rat models, lercanidipine can significantly improve renal function, reducing proteinuria11. In a randomized, double-blind clinical trial, 277 hypertensive patients with diabetes and microalbuminuria reported a decrease in the rate of urinary albumin secretion with lercanidipine, the same effect shown with ramipril3. Studies described that low doses of lercanidipine, even without exerting any antihypertensive effect, result in kidney protection12. The mechanisms of this improved renal function and reduced proteinuria with lercanidipine may be related to the following aspects: first, lercanidipine is the latest generation calcium antagonist and the expansion of renal afferent arterioles artery effect is similar to the expansion of renal efferent arterioles; secondly, lercanidipine may reduce the concentration of intracellular calcium, inhibit the angiotensin-induced protein kinase C (PKC)-a and d activation, reduce inflammation and fibrosis, and can increase the biological effects of nitric oxide11. A possible relationship has also been hypothesized between increased PKC-a activity and enhanced endothelial cell layer protein leakage, with important consequences in proteinuria, cardiac hypertrophy and fibrosis, and heart failure control13–16. Lercanidipine may improve blood vessel elasticity, inhibit proliferation of vascular smooth muscle, reducing oxidative stress5, inhibit cell proliferation, reduce expression of glomerular endothelial cell adhesion molecules, and reduce tissue inflammation and renal tubule interstitial fibrosis11. Last, another possible renoprotective mechanism of lercanidipine is by offsetting platelet-derived growth factors and platelet-activating factors17. Collectively, these changes in the kidneys will reduce proteinuria and improve renal function. These renoprotective effects were also noted when lercanidipine was administered in a fixeddose combination with enalapril18. In the present study, BP was effectively controlled at 3 and 6 month after intervention compared with baseline; www.cmrojournal.com ! 2015 Informa UK Ltd
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one of the reasons – in addition to the antihypertensive effect of lercanidipine – is that PRAS plays a positive role in BP control19. This study also showed a modest incidence of adverse events (only one patient experienced mild lower extremity edema) in patients under lercanidipine after intervention. This outcome is in line with the report by Barrios et al., who reported that lercanidipine has a good antihypertensive effect, and fewer adverse events occurred in comparison with other CCBs20. A significant decrease of pulse wave velocity (an important indicator of arterial elasticity response) was observed, although on the basis of a single measurement. This may be due to lercanidipine which can reduce oxidative stress, inhibit proliferation of vascular smooth muscle and improve blood vessel elasticity5. Moreover, renal artery stenosis activates the renin–angiotensin–aldosterone system, aldosterone increase determines arterial function and structural changes, accumulation collagen and growth factors in vascular smooth muscle cells, leading to an increase in pulse wave velocity21. Renal artery interventional surgery can reduce the renin–angiotensin–aldosterone activation level, thus improving the elasticity of blood vessels, and therefore reducing pulse wave velocity. The cohort study design could be considered as a limiting factor, while a randomized controlled study versus an active comparator should be considered as the best option to better investigate the renal-protective effect of lercanidipine in the same study population (for a comprehensive review of this topic, see Burnier22). Notably, other factors (e.g., conditions which induce renal damage such as diabetes or renal protection exerted by other therapies such as pioglitazione in diabetic patients) may be considered confounding factors. In addition, this is a single site study, and a multicenter trial could allow confirmation of our initial results and their reliability. Therefore, we are planning a multicenter randomized controlled trial to evaluate the renal protection role of lercanidipine and ACEIs in patients with atherosclerotic renal artery stenosis who will undergo stent implantation.
Conclusion This study showed that lercanidipine can improve renal function in patients undergoing renal artery intervention. Considering that lercanidipine has also showed great efficacy in hypertension control with good tolerability, it might be considered as an elective therapy for patients with hypertension and renal impairment.
Transparency Declaration of funding Editorial support for this manuscript was funded by Recordati.
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Declaration of financial/other relationships M.P., X.-j.J., H.D., Y.-b.Z., H.-m.Z., H.y.W., and Y.Y. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose. Acknowledgments Editorial assistance was provided by Chiara Mossali PhD and Luca Giacomelli PhD of Content Ed Net.
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metabolic syndrome: results from the TOLERANCE study. Int J Clin Pract 2008;62:723-8 21. Rosa J, Somloova Z, Petrak O, et al. Peripheral arterial stiffness in primary aldosteronism. Physiol Res 2012;61:461-8 22. Burnier M. Renal protection with calcium antagonists: the role of lercanidipine. Curr Med Res Opin 2013;29:1727-35
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19. Nordmann AJ, Woo K, Parkes R, et al. Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials. Am J Med 2003;114:44-50 20. Barrios V, Escobar C, de la Figuera M, et al. High doses of lercanidipine are better tolerated than other dihydropyridines in hypertensive patients with
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