Verapamil Reverts Acute Renal Functional Impairment Induced by Angiotensin II Converting Enzyme Inhibitors

Abstract

Angiotensin converting enzyme inhibitors (ACEI) reduce blood pressure (BP) and provide end-organ protection, but may induce renal function deterioration. In these cases, serum creatinine (SCr) can be normalized by ACEI withdrawn. In some patients, it could be desirable to maintain the ACEI for the protection of the kidney and heart. The objective of the study was to evaluate the effect of Verapamil (V) on renal function added to patients with elevated SCr due to ACEI treatment. In 46 hypertensive patients without previous renal failure, in which ACEI treatment induced an acute increase in SCr (≥20% or 0.5 mg/dL), ACEI treatment was maintained and 180 mg/day of V was added for 12 weeks. Those patients showing further SCr increase or no BP control at four weeks were withdrawn. Patients under BP control were moved on the combination V 180 + Trandolapril 2 mg/day for eight weeks more. SCr decreased from 136 ± 49 µmol/L at baseline to 126 ± 49 at 12 weeks after adding V (p<0.001) and to 111 ± 31 µmol/L at 20 weeks (p<0.01). Creatinine clearance increased from 62 ± 22 mL/min at baseline to 68 ± 28 after 12 weeks of V (p<0.001). This article demonstrates than in patients with acute renal function impairment secondary to ACEI treatment, the addition of 180 mg/day of verapamil to ACEI reverses SCr towards previous values.

• ACE-Inhibitors
• Hypertension
• Renal failure
• Serum creatinine
• Verapamil

Introduction

Antihypertensive agents have been found effective in arresting glomerulosclerosis.[[1]], [[2]] Initially, it was thought that the healthy effect of these drugs was exclusively due to their hemodynamic effects. However, it has become clear that nonhemodynamic actions of these agents are an important component of their beneficial effects.[[1]], [[2]] Among the pharmacological agents that may have a favorable influence in the course of renal failure, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers (CCB) have generated the most interest. Angiotensin-converting enzyme inhibitors (ACEI) have proven to be effective drugs for the treatment of hypertension and represent a major therapeutic breakthrough in the management of hypertension and renal function preservation in diabetic and nondiabetic nephropathies.[[3]], [[4]], [[5]]

In some patients, ACEI may induce a rapid deterioration of renal function, assessed as an increase in serum creatinine (SCr), which can be reversed by withdrawing the drug.[[6]], [[7]], [[8]], [[9]] In these cases, maintaining the renal protection due to ACEI, instead of withdrawing these drugs could be desirable.[[9]]

Calcium antagonists are a heterogeneous group of agents with diverse effects in terms of nephroprotection.[[10]], [[11]] Some of these differences relate to their effects on renal microcirculation. Dihydropyridine agents appear to act only on the afferent arteriole, increasing intraglomerular pressure, and albumin excretion rate.[[12]] In contrast, nondihydropyridine agents like verapamil, may dilate efferent arterioles in addition to afferent arterioles[[12]] and with normalization of the systemic blood pressure, verapamil may reduce intraglomerular pressure, and proteinuria. However, some other nonhemodynamic protective effects of CCB could be explained by its capacity to inhibit the extracellular calcium influx, an important signal for the proliferative effect of mesangial cells mitogens,[[13]] its influence in the decrease in mesangial entrapment of macromolecules and, possibly, its effect as free radical scavenger[[14]], [[15]]

Münter et al.[[16]] describe that nephroprotective effects of ACEI/CCB combination can occur at doses, which do not significantly alter systemic blood pressure in the stroke-prone SHR. We have described that the combined therapy with these agents provide in the remnant kidney model a synergistic effect in preventing renal injury, independently of their effects on blood pressure.[[17]]

In a preliminary study, we have demonstrated in a small group of patients that nondihydropiridin (nonDHP) CCB are able to revert renal function reduction associated to ACEI treatment.[[18]]

The main purpose of this study was to assess the efficacy and safety of low doses of verapamil (180 mg/day) added to the previous ACEI treatment for reverting decreased glomerular filtration rate observed in patients treated with ACEI. A secondary purpose was to test the ability of the fixed combination Verapamil-SR 180 mg plus Trandolapril 2 mg in attaining BP control and maintaining the renal function throughout the study.

Subjects and Methods

This was a multicenter, nonrandomized, prospective, open study developed in five Spanish Hospitals. All patients were referred from the outpatients Departments of Internal Medicine and Nephrology. The Institutional Review Boards approved the study protocol and each patient entering the study signed a written informed consent.

Patients and Definitions

Eligible patients presented a previous diagnosis of hypertension and an increase in SCr of ≥20% or 45 µmol/L from last values, in the course of ACEI treatment for more than four weeks. Exclusion criteria were renal insufficiency, defined as SCr >354 µmol/L (4 mg/dL), stroke, AMI in the last three months, unstable angina, cardiac failure, other causes of renal hypo-perfusion, or low volume syndrome such as dehydration, vomiting, diarrhea, laxative, and known hypersensitivity to verapamil.

Study Design

In the selected group, a clinical evaluation was carried out, including clinical history, physical examination, BP measurement, ECG, and biochemistry (Visit 1). Patients fulfilling the inclusion/exclusion criteria were enrolled in the study. Three to ten days later a new BP measurement, serum, and urine creatinine and 24 h proteinuria were also measured (Visit 0 or Baseline) and creatinine clearance (CrCl) calculated. If the SCr was not higher than 10% respect to Visit 1, the patients were included in the study and Verapamil (180 mg/day) was added. Patients returned to the hospital after four weeks for new measurement of SCr and BP (Visit 1). If an increase on SCr superior to 10% respect to Visit 0 or BP was ≥140/90 mm Hg was detected, ACEI was discontinued, and the patient withdrawn from the study. If not, treatment was continued for eight weeks. At this moment (Visit 2) patients were evaluated again. If SCr had increased more than 20% with respect to baseline, or BP was ≥140/90 mm Hg, the patients were withdrawn. If not, the patients were placed on the Trandolapril (2 mg)-Verapamil (180 mg) association for eight more weeks. Patients were followed until 20 weeks of follow-up were completed. All the patients were recommended to limit sodium intake. The study flow chart is given in Fig. 1.

Figure 1. Scheme of the study.

Outcome Measurements

At each study visit, blood pressure was measured three times at 2 min intervals after 10 min rest in the sitting position, using calibrated mercury sphygmomanometers. Blood pressure values were estimated as the mean of the three readings. The mean value obtained in Visit 0 was accepted as BP basal level.

Biochemistry and SCr (Jaffé reaction) were determined in an automatic analyzer (Hitachi 747).[[19]] Creatinine clearance was calculated as: urinary creatinine (mg/L) × urine volume (mL)/serum creatinine (mg/L)/1.73 m².

Statistical Analysis

All the basal variables were analyzed descriptively. Data are given as Mean ±1 standard deviation. Adverse events are codified according to the WHO Adverse Reaction Terminology List (WHO-ARTL).

Repeated measurements ANOVA was used with an exploratory approach in order to test the following null hypotheses: changes of creatinine, systolic, and diastolic blood pressure, uric acid and potassium over time. The Wilcoxon test (two tailed) for paired samples was used to test the following hypotheses: changes of creatinine clearance and albuminuria between inclusion and week 12. Changes in creatinine between Visit 1 and inclusion, inclusion and week 12, inclusion and week 20, week 12, and week 20, historic control, and week 20. All the p-values are exploratory as type I error has not been adjusted for multiplicity.

Results

Forty-six patients, 23 female and 23 male, with a mean age of 54.9 ± 7.3 years and BMI of 27.3 ± 2.2 kg/m², were included. Five of them (10.9%) had suffered from cerebrovascular disease, eight (17.4%) coronary heart disease, 24 (52%) had left ventricular hypertrophy on ECG or echocardiography, seven (15%) lower limbs peripheral vascular disease, and 35 (76%) some degree of retinopathy. Fourteen patients had been diagnosed from diabetes 4.5 ± 8.0 years earlier (a median of 2.6 years): one was treated with diet, 12 with oral anti-diabetics drugs, and one with insulin. They were known hypertensive for a median of 4.5 years and all of them had been treated with ACEI for at least four weeks previous to SCr deterioration. Previously used ACEI were: enalapril in 12 patients, Lisinopril in nine, Cilazapril in seven, Perindopril in five, Quinapril in five, Ramipril in four, Trandolapril in two, and Captopril in two.

Nine patients were withdrawn from the study, three at week four and six at week 12. Eight were withdrawn due to no BP control and no treatment compliance in one patient. In one patient, the reason was no BP control plus SCr increase >20%. A total number of 37 patients finalized the study.

The evolution of the main clinical and biochemical parameters is shown in Table 1.

Table 1. Evolution of the clinical and biochemical parameters

	Last control	Visit 1	Baseline	Visit 1 4th week	Visit 2 12th week	Visit 3 20th week (n = 37)	P
SBP (mmHg)	—	151.1±13.2	148.5±10.4	137.6±3.4	137.0±7.0	136.2±5.7	0.0001a
DBP (mmHg)	—	95.5±6.2	93.7±6.4	86.2±4.2	85.7±6.1	84.4±5.8	0.0001a
Ser. Creat. (µmol/L)	97 ± 32	137±46	136±49	132±47	126±49	111±31	0.0001a
Ser. K^+ (mE/L)	—	—	4.53±0.42	—	4.43±0.33	4.33±0.25	0.0039a

^aRepeated measurements ANOVA. SBP: Systolic blood pressure, DBP: Diastolic blood pressure, N = 46 except in Visit 3.

Serum creatinine (SCr) in the regular follow-up was 97 ± 32 µmol/L, increasing to 137 ± 46 µmol/L in Visit 1. SCr decreased from this value to 126 ± 49 in Visit 2, (P<0.003). In Visit 3, SCr further decreased to 111 ± 31 µmol/L (P<0.0001 vs. V2). Changes in serum creatinine are graphically expressed in Fig. 2.

Figure 2. Evolution of serum creatinine from baseline values.

Creatinine clearance (CrCl) increased from 62.7 ± 22.0 mL/min in Basal Visit to 68.3 ± 28.6 mL/min in Visit 2 (Wilcoxon test for paired samples, P = 0.0194).

SBP decreased from 148.5 ± 10.4 mmHg in Baseline Visit to 137.6 ± 3.4 mmHg in Visit 1, to 137 ± 7 in Visit 2, and to 136.2 ± 5.66 at the end of the treatment period in Visit 3, (P = 0.0001). DBP decreased from 93.7 ± 6.4 in Baseline to 86.2 ± 4.2 mmHg in Visit 1, 85.7 ± 6.1 in Visit 2 and 84.4 ± 5.7 in Visit 3 (P = 0.0001).

Uric acid was 0.78 ± 0.13 m mol/L in Basal Visit and 0.74 ± 0.11 in Visit 3 (P = 0.004). Blood potassium changed from 4.53 ± 0.42 in Basal to 4.33 ± 0.25 mmol/L in Visit 3 (P<0.005).

Twenty-five patients had initial albuminuria >30 mg/24 h, decreasing from 317 ± 835 mg/24 h in Visit 0, to 198 ± 484 mg/24 h in Visit 2 (Wilcoxon test for paired samples, P = 0.0194). In four of the sixteen patients with initial micro-albuminuria (30–300 mg/24 h), the excretion of urinary albuminuria (EUA) had disappeared at the end of the study. In five of the nine patients with initial overt-albuminuria (>3000 mg/24 h) the EUA was reduced to the microalbuminuria levels.

All the 46 patients were considered for the safety analysis. Throughout the study, 13 patients reported 19 adverse events. Symptoms were mild/moderate in intensity in all cases. Any patient interrupted the study because of adverse events (Table 2).

Table 2. Adverse events (A.E.)

	A. E. (n)	Patients (n and %)
Dizziness	4	4 (8.7)
Headache	2	2 (4.3)
Urinary infection	2	2 (4.3)
Upper respiratory tract infection	2	2 (4.3)
Palpitations	3	2 (4.3)
Constipation	2	2 (4.3)
Abdominal discomfort	3	3 (6.5)
Anxiety	1	1 (2.2)
Total	19	18 (39)

Discussion

The major finding of this study is the possibility of reverting renal functional impairment induced by ACEI treatment in hypertensive patients by adding verapamil without further modification in ACEI therapeutical regime. These patients had normal serum creatinine levels before ACEI treatment.

ACEI have been demonstrated to reduce morbidity and mortality in patients with heart failure.[[20]] Renal impairment is the most important factor associated with prescription of lower-than-recommended doses.[[21]] A recent review of 12 randomized clinical trials[[9]] evaluating renal disease progression and ACEI-based therapy, shows that an acute increase of serum creatinine in the first two months usually follows the ACEI therapy in patients with preexisting renal failure. This is not our case, as the patients in our study had normal values of plasma creatinine before ACEI treatment. The review also shows that a limited elevation, of up to 30%, is strongly associated with long-term preservation of renal function when ACEI therapy is continued.[[9]] In our study, we have observed increases in plasma creatinine up to 50% respect to pretreatment levels. These increases were completely reverted by adding verapamil to the ACEI treatment.

Some calcium antagonists seem to offer additional benefit in hypertensive patients when renal function is impaired, and may reduce proteinuria in hypertensive diabetic patients.[[22]]

The deterioration of renal function in patients receiving ACE-inhibitors seems to be due to a decrease in intraglomerular pressure, and, subsequently in the filtration net pressure. Thus, as angiotensin II has a predominant vasoconstrictor effect in the efferent arteriole, the decrease in angiotensin II due to ACE inhibition leads to an efferent arteriolar vasodilatation, and subsequently to a decrease in glomerular capillary pressure. This is one of the major beneficial effects of ACE inhibitors, as increased capillary pressure is a major cause of the progression of renal failure,[[23]] but if the decrease on glomerular pressure is below normal values, glomerular filtration rate will be also decreased. However, it is difficult to accept this as the only cause of filtration rate decrease after ACEI treatment, because the autoregulation threshold is not always reached. If it is overpassed, an immediate deterioration in renal function must occurs at least in absence of decreased effective arterial volume, by far the commonest cause of acute rise in serum creatinine.[[7]], [[8]]

An excess of BK due to the blockade of BK metabolic pathway by ACEI may also be involved in renal function decrease associated to ACEI treatment. It is now clear that endogenous kinins regulate the glomerular ultrafiltration coefficient and papillary blood flow.[[24]] Bradykinin (BK) receptors have been classified into two types on a pharmacological basis[[25]]; the more prevalent is the B2 receptor showing a high affinity for the BK nonapeptide. The B1 type presents a selective affinity for the natural metabolite des-Arg⁹BK. Under physiological conditions, most of the biological effects of kinins are mediated through the B2 receptor, since B1 receptor is not expressed at significant levels under these conditions. Recently, the presence of B1 and B2 receptors have been demonstrated in rat glomerulus and mesangial cells.[[26]], [[27]]

In normal conditions, ACEI, via increasing BK levels, may stimulate nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin formation in the presence of normal functioning endothelium,[[28]] thus inducing increased renal blood flow and filtration rate. However, in vitro experiments BK induces mesangial cell contraction and proliferation,[[29]], [[30]] and increases cytosolic free calcium in cultured smooth muscle cells, a fact that is associated with cell contraction.[[31]] Thus, it can be suggested that in the presence of an altered endothelium, BK behaves as a vasoconstrictor due to the fact that the direct vasoconstrictor effect of BK on smooth muscle or mesangial cells is not counterbalanced by the vasodilator agents synthesized by endothelial cells in response to BK. In agreement with this hypothesis, it has been reported that perindopril induces contraction and proliferation in cultured mesangial cells, both actions being prevented by blocking B2 receptors.[[30]]

The additive effect of verapamil and ACEIs could be owing to that the two drug types protect the kidney by different mechanisms. Dworkin et al.[[32]] have reported that either enalapril or nifedipine reduce renal injury in the remnant kidney model by different mechanisms: nifedipine reduces glomerular hypertrophy whereas enalapril reduces glomerular hypertension. Verapamil is able to diminish renal vasoconstriction mediated by BK receptor activation,[[29]] prevent intrarenal vasoconstriction mediated by adenosine,[[33]] and prevent from mesangial cells contraction and proliferation induced by several agents.[[34]], [[35]], [[36]] Verapamil is also able to stimulate NO release.[[37]] The addition of verapamil to trandolapril treatment might promote other beneficial effects on renal structure and function. Thus, CCB are able to inhibit platelet aggregation,[[38]] and this inhibition has been reported to ameliorate glomerular injury in rats with reduced renal mass.[[39]] In addition, Harris et al.[[40]] have shown that verapamil lessened oxygen consumption in the isolated, perfused remnant kidney and, therefore, it might ameliorate glomerular injury by reducing damaging oxygen radicals production rate.

Results

The results of this study confirm our previous preliminary data[[18]] suggesting a therapeutical approach, which allows revert the renal failure induced by ACEI treatment in hypertensive patients with previous normal renal function, maintaining this therapy, and adding verapamil 180 mg/day to the ACEI treatment. These findings are clinically relevant and will be of paramount interest for the patients in which ACE illicit a doubtless protection of target organs, even in nonhypertensive patients. The trandolapril + verapamil combination allows maintain an excellent BP control decreasing further the levels of serum creatinine.

Acknowledgment

The authors wish to thank Dr. R. Gascueña, for his critical review and J. García Polavieja for her statistical support. This study has been supported in part by a grant of Laboratorios Knoll, Spain.