Treatment of Proteinuria with Lercanidipine Associated with Renin-Angiotensin Axis-Blocking Drugs

Abstract

Objective. Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. Design and Methods. The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 ± 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. Results. BP significantly decreases from 152 ± 15/86 ± 11 mmHg to 135 ± 12/77 ± 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 ± 48 to 192 ± 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 ± 77 to 134 ± 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 ± 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. Conclusions. Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.

Keywords:

• lercanidipine
• proteinuria
• hypertension

INTRODUCTION

It is well known that high blood pressure is a powerful determinant of progression of renal disease, irrespective of its cause. Even more, the relative risk of developing end-stage renal disease in hypertensive patients increases three-fold when diastolic blood pressure (DBP) rises to 90 mmHg.^[1] Thus, a straight blood pressure control is the main mechanism for preventing from the progression of chronic renal failure in most of patients.^[2,3] The presence of proteinuria in hypertensive patients is also a major predictor of higher cardiovascular morbidity and mortality.^[4] Additionally, several placebo controlled studies have shown that angiotensin receptor antagonists or ACE inhibitors can delay end stage renal disease or a significant increase in serum creatinine, and reduce or prevent microalbuminuria or proteinuria, in patients with both diabetic and nondiabetic nephropathy. Thus, current clinical guidelines recommend the use of renin-angiotensin blocking drugs as first-line antihypertensive drug in renal patients.^[5]

The use of calcium antagonists in hypertensive patients with renal disease is safe and has no deleterious effects on renal function. This kind of drugs also seems to be better than diuretics and beta blockers to protect renal function against hypertension. Renin-angiotensin axis-blocking drugs are more effective than classic calcium channel blockers to reduce proteinuria and prevent renal disease progression; however, new generation calcium antagonists, with the property of vasodilator action on afferent and efferent glomerular arterioles, might have special renoprotective effects.^[6]

Lercanidipine is one of these new dihydropyridine calcium antagonists with high lipophilicity and high vascular selectivity, which confers upon it a gradual and prolonged antihypertensive effect and a good tolerability as compared with other dihydropyridine calcium channel blockers.^[7,8] It can induce vasodilatation of glomerular efferent arterioles^[9] and reduce microalbuminuria in type II diabetic patients.^[10] A previous trial showed that lercanidipine (10 mg/day), associated in previous treatment with renin-angiotensin axis blockers, decreases heavy proteinuria in a group of patients with reduced renal function. The aim of this study has been to confirm these results and evaluate the effects of higher doses of lercanidipine on proteinuria in a group of proteinuric subjects with or without renal failure.

MATERIAL AND METHODS

Eighty hypertensive renal disease patients with proteinuria higher than 500 mg/day were recruited, but twelve patients were excluded from evaluation: five due to protocol violations, one after starting immunosuppressive therapy, three who were lost for follow-up, one subject who decided motu proprio to interrupt the treatment, and two more because of untoward side effects. Sixty-eight patients ended the study, 48 men and 20 women, with a mean age of 63.1 ± 12.9 years. Mean weight was 77.2 ± 13.7 kg and averaged body mass index was 28.3 ± 5.9 kg/m². Thirty patients (41.1%) were diabetics. The causes of renal failure of the final sample are shown in Table 1. According to K/DOQI (Kidney Disease Outcome Quality Index^[11]) guidelines, 10 patients (14.7%) were in stage 1 of chronic renal disease, 15 subjects (23.5%) were in stage 2; 32 of them (47.1%) were in stage 3, and 10 (14,7%) showed advanced renal failure (stage 4).

Table 1  Blood pressure and analytical changes

	Baseline	One month	Three months	Six months
SBP	152 ± 15	139 ± 1	136 ± 13	135 ± 13
DBP	86 ± 11	81 ± 8	77 ± 8	77 ± 10
HR	74 ± 12	75 ± 12	72 ± 11	71 ± 11
Creatinine	1.69 ± 1.02	1.71 ± 0.94	1.71 ± 1.12	1.69 ± 1.14
Urea	55.2 ± 26.9	64.9 ± 31.0	57.1 ± 29.5	54.2 ± 27.5
Urate	6.4 ± 1.3	6.5 ± 1.2	6.1 ± 1.1	6.3 ± 1.1
Glucose	118 ± 38	112 ± 35	109 ± 37^†	111 ± 30
Cholesterol	210 ± 48	198 ± 47	192 ± 36	192 ± 34^†
Triglycerides	151 ± 77	132 ± 54	130 ± 73	134 ± 72
Total proteins	7.3 ± 0.6	7.4 ± 0.5^†	7.4 ± 0.5^†	7.3 ± 0.6
Serum albumin	4.5 ± 0.7	4.6 ± 0.6	4.5 ± 0.6	4.4 ± 0.6
Clearance	43.5 ± 10.6	44.1 ± 12.5	43.9 ± 11.2	44.0 ± 1.0
Proteinuria	1.63 ± 1.39	1.16 ± 1.16	1.00 ± 1.04	1.09 ± 1.26

Blood pressure in mmHg. HR as bpm. Creatinine, urea, urate, glucose, cholesterol, and triglycerides in mg/dL. Total proteins and serum albumin in g/dL. Creatinine clearance as mL/min. Proteinuria in expressed as g/24h.

*p < 0.001 vs. baseline; ^†p < 0.05 vs. baseline; ^‡p = 0.001.

All patients were receiving treatment with either ACE inhibitors or ARB previously to the recruitment. 51.4% of patients were treated with ACE inhibitors at a dose equal or higher to 20 mg/day of enalapril, and 48.6% of subjects were treated with ARB at a dose equal or higher to 100 mg/day of losartan. Equivalences were calculated as were indicated by the VII Report of the National Joint Committee.^[12] This treatment was maintained at the same dosage all along the follow-up time. To be included, the patients should have high blood pressure defined by the 2007 Clinical Guidelines for Management of Hypertension of the European Cardiology Society and European Hypertension Society WHO-IHS for renal disease patients (SBP ≥ 130 and/or DBP ≥ 80 mmHg) in spite of treatment with ACE inhibitors or ARB. Patients might receive other cardiovascular therapy, excluding other calcium channel blockers, simultaneously to angiotensin axis-blocking agents. Patients receiving immunosuppressants previously (less than six months prior) or after starting treatment with lercanidipine were excluded to avoid its influence on the results.

Antihypertensive therapy with the lercanidipine at an initial dose of 10 to 20 mg once a day was given to all patients. The dose was increased to 20 mg in all patients in the following visits. They were followed for six months, and four visits were scheduled (at inclusion and one, three, and six months after beginning). After the second visit, additional antihypertensive therapy could be prescribed whenever needed to reach the target BP. Blood pressure, heart rate, adverse effects, symptom checklist, and compliance to treatment were assessed at each visit. BP was measured by a standard mercury sphygmomanometer approximately 24 hours after the last drug intake. Two measurements, taken at 3-min intervals in the sitting position, were averaged and used as the clinical BP reference value. Heart rate was measured from the radial pulse during 30 sec. Mean BP was calculated as DBP + 1/3*(SBP-DBP).

According to the protocol, serum creatinine had to be measured by standard laboratory techniques in every visit. Creatinine clearance was estimated using 24 h urine collection, which was also used to estimate proteinuria. Blood samples were also analyzed for cholesterol, triglycerides, glucose, urate, and ionogram. Complete hemogram was also performed in every visit.

Statistical analysis was performed by the computer statistical package SPSS for Windows 13.0. Data are reported as mean with one standard deviation. Differences between continuous variables were compared by the use of Student's t test for paired samples. Proteinuria was compared using Wilcoxon ranks test, as Kolmogorov-Smirnov test showed that this parameter did not follow a normal distribution. A p value of < 0.05 was considered statistically significant; all p values are two-tailed.

RESULTS

After one month of treatment, SBP and DBP were significantly reduced by lercanidipine (from 152.0 ± 15.4/86.3 ± 10.8 to 139.2 ± 11.1/81.20 ± 8.3 mmHg, p < 0.001) (values for every visit are shown in Figure 1 and Table 1). Higher differences were observed for values of SBP and DBP entering in the analysis at three and six months. At six months, mean BP reduction from baseline had reached −16.8/−9.3 mmHg (relative reduction 11.1/10.8%). Heart rate showed no changes during follow-up. After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5% and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Eighteen patients (26.5%) needed to add a third antihypertensive agent (10, hydrochlorothiazide 12.5 to 25 mg/day; 4, torsemide 5 to 10 mg/day; 3, beta blockers; 1, alpha-blockers).

Figure 1.  SBP and DBP were significantly reduced in all visits.

Evolution of biochemical values has been reported in Table 1. Cholesterol (p = 0.001) significantly decreased at six months. Serum triglycerides levels lowered at the second and third visit (p < 0.001). No increase in the number of patients with abnormal biochemical findings was seen during treatment as compared to pre-treatment values. No changes in urea or serum creatinine were detected. Creatinine clearance did not show any change in the time. Proteinuria diminished significantly at the first month of treatment. This reduction increased at three months and persisted to the end of the follow-up (1.09 ± 1.26 vs. baseline, 1.63 ± 1.39 g/day, p < 0.001). Changes are showed in Figure 2.

Figure 2.  A significant decrease of proteinuria (expressed as percentage from baseline) was seen at the second visit; it was deeper at three months and remains until the end of follow-up. Comparative reduction of blood pressure was very less deep.

Porcentual changes on proteinuria were −29% at one month, −37% at three months, and −33% at six months. Comparatively, the changes obtained in mean blood pressure were less intense (−7.4% at the first month, −10.4% at the third month, and −10.8% at the last visit).

Incidence of untoward effects was low, six cases (7.5% of the sample), and only two of them interrupted the treatment. Three patients commented legs swelling, one more erectile dysfunction, another one tachycardia (nocturnal, hardly related to morning pills intake), and a sixth one commented mild epigastralgia after lercanidipine administration.

DISCUSSION

The present study in proteinuric patients demonstrates that lercanidipine, a new-generation calcium antagonists, is an effective antihypertensive drug in this kind of patients and can reduce proteinuria when it is associated with an angiotensin axis-blocking drug. This is the second report on the antiproteinuric effect of lercanidipine associated to these classes of antihypertensives (ACE inhibitors and ARB).

It has been clearly shown that BP reduction, regardless of the antihypertensive agent used, decreases the progression of renal disease.^[13–15] Angiotensin axis-blocking drugs are reputed to minimize the hypertension-induced renal damage by preserving renal blood flow in the face of systemic blood pressure reduction.^[16–18] Moreover, renin-angiotensin axis-blocking drugs seem to provide a higher antiproteinuric effect and an added degree of protection to the kidney damage, independent of their arterial pressure–reducing effects.^[19–22] In fact, the current recommendations for the treatment of hypertension suggest that renin-angiotensin should be used as first-line antihypertensives in patients with chronic kidney disease. Thus, it was considered ethically necessary that all patients recruited in this trial were previously under treatment with one of those drugs.

The obvious question is whether the calcium antagonists alone would be able to reduce proteinuria and renal failure progression. There are three classes of calcium channel blockers in clinical use: diltiazem, verapamil, and nifedipine serve as the prototypic agents for the benzodiazepines, phenylalkylamine, and dihydropyridine classes, with important differences between them in pharmacology and therapeutic indication. Then, calcium channel blockers should not be considered as a homogeneous group.^[23] In this way, the available data about the effects of non-dihydropyridine calcium antagonists on proteinuria are controversial.^[8] It has been documented that classic dihydropyridine calcium antagonists (i.e., amlodipine) cause a preferential dilation of the glomerular afferent arteriole, with only modest action on the efferent arteriole.^[24–26] Thus, it is inferred that whereas the depressor action of the calcium antagonist favors an attenuation of glomerular hypertension and the subsequent renal protection,^[27–30] the predominant activity of this agent on preglomerular vessels might cause glomerular hypertension that could finally be associated with the progression of renal disease.^[31–34] In contrast with this effect of classic calcium antagonists, a growing body of evidence has been accumulated demonstrating that certain types of these agents (i.e., lercanidipine) may act on postglomerular as well as preglomerular vessels.^[6] Thus, new-generation dihydropyridine calcium channel blockers may have antiproteinuric effects, as suggested by its in vitro effects on postglomerular arterioles.

Although there are still few reports on the clinical renal effects of new calcium antagonists, they have rendered promising results on microalbuminuria when compared with classic calcium channel blockers^[35,36] and even when compared to ACE inhibitors.^[37] Regarding lercanidipine specifically, the Diabetes Ipertensione Albuminuria Lercanidipina (DIAL) study evaluated the effectiveness of lercanidipine (10–20 mg/day) in comparison with ramipril (5–10 mg) on the reduction in albuminuria. After 9–12 months of follow-up, albuminuria was reduced by both drugs, without differences between the groups.^[38] The ZAFRA study showed a positive effect on proteinuria of the combination of the new calcium channel blocker lercanidipine (10 mg once daily) and renin-angiotensin axis-blocking drugs.^[39] The comparison between our results and this latter trial gives interesting suggestions. The ZAFRA study used a small dose of lercanidipine and gets a small and non-significant reduction of proteinuria at first month, but it become significant at the last visit (six months). We have doubled the dosage, and the reduction is much higher at the end (20% vs. 37%, nearly double the effect). This was significant since the first visit of follow-up. In other words, higher doses of lercanidipine are more effective on reducing proteinuria and get a faster effect.

Because blood pressure reduction was shorter in this study than in the ZAFRA trial, in spite of using higher doses of lercanidipine, we argue that the antiproteinuric effect of lercanidipine might be beyond blood pressure control, as it has been suggested for renin-angiotensin axis blockers. In this way, there is only one more report on the antiproteinuric effect of a new generation calcium antagonist, efonidipine, compared to a “classic” one, amlodipine. The study subjects were chronic glomerulonephritis patients presenting with proteinuria and normal renal function. The averaged blood pressure reached was comparable between the efonidipine and the amlodipine periods, but urinary protein excretion was significantly less in the efonidipine period than in the amlodipine period. Thus, it seems that these effects occurred by a mechanism independent of blood pressure reduction; in other words, efonidipine, but not amlodipine, produces postglomerular arteriole vasodilatation.^[40] Our data also suggest a similar explanation, especially when compared with previous reports of lercanidipine use for treatment of proteinuria.

Caution about side effects is probably the most important factor limiting the use of higher doses of antihypertensive drugs in the initial treatment of hypertension. Treatment for hypertension has traditionally been commenced with low doses, with subsequent up-titration as needed. This pattern was primarily due to fear of side effects associated with older therapies, especially adrenergic blockers, which were associated with dose-related side effects such as postural hypotension, drowsiness, and dry mouth. In comparison with these other classes of drugs, side effects associated with angiotensin receptor blockers can hardly be differentiated from placebo. In fact supramaximal doses of antagonist receptor blockers are safe and well tolerated in patients with chronic kidney disease, while reducing both BP and proteinuria.^[41] In spite of their antihypertensive efficacy, dihydropyridine calcium antagonists are often reported to induce side effects responsible for treatment withdrawal or replacement with drugs of a different class. Lercanidipine is a new compound with high lipophilicity and high vascular selectivity, which ensure a gradual and prolonged antihypertensive effect; as a result, it shows a very good tolerability, especially when compared with other dihydropyridine calcium antagonists.^[7,8,42,43] In our study, the incidence of edema and vasodilatory-related side effects was really low in spite of the proteinuria of a high number of patients, a well-known edema prone status. Nevertheless, vasodilatory edema associated with dihydropyridine calcium antagonists responds well to agents that dilate the postcapillary vessel such as ACE inhibitors or ARB^[44]; thus, the simultaneous treatment with those drugs classes might have influenced our results.

This study has some limitations, as it is a single, open, and uncontrolled trial. It would not be ethical to introduce a placebo branch in the study, as cardiovascular risk is highly increased in renal patients. On the other hand, a comparison could be planned with a classic calcium antagonist, but cumulated evidence with classic non-dihydropyridine calcium antagonist is definitive, and they cannot reduce proteinuria in spite of intensive blood pressure reduction.^[8] Thus, this pitfall in design should not mist over the results offered by this trial.

Lercanidipine shows a good efficacy as antihypertensive agent in proteinuric patients. The incidence of untoward effects was very low along the follow-up. This study confirms that lercanidipine, a new-generation dihydropyridine calcium channel blocker, decreases proteinuria, at least when it is associated with an ACE inhibitor or ARB. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and higher than the antihypertensive effect. Further large-scale comparative clinical trials will be needed to confirm the observations made in this study.

ACKNOWLEDGMENTS

The authors declare no conflicts of interest.