Blood pressure response to conventional and low-dose enalapril in chronic renal failure

Abstract

Aims

In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat.

Methods

As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml⁻¹ (high) (n = 17) or below 10 ng ml⁻¹ (low) (n = 18), and the daily dose of enalapril titrated accordingly.

Results

Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min⁻¹ 1.73 m² in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5–10) and low (2.5–20) concentration group. At 3 months' follow-up, the dose was 10 (2.5–30) and 1.9 (1.25–5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22–244) ng ml⁻¹ and 9.1 (2.5–74.8) ng ml⁻¹ (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110–200) and 133 (110–165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105–170) and 130 (105–170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65–100) and at follow-up (60–95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR.

Conclusions

In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.

Introduction

Hypertension is common in renal disease and angiotensin-I-converting enzyme (ACE) inhibition is recommended to control blood pressure with the intention of limiting progression of renal failure as well as reducing cardiovascular morbidity and mortality [1–3]. However, the optimal dosage of the ACE inhibitors in this setting has not been established. Most ACE inhibitors or their active metabolites are excreted renally and doses should hence be reduced for cases of renal failure.

Enalapril is a widely used ACE inhibitor. It is a prodrug that is rapidly hydrolysed in the liver to the active metabolite enalaprilat, which is excreted by the kidneys [4]. Unadjusted dosage of enalapril in patients with chronic renal failure can hence lead to accumulation of enalaprilat. We have previously found elevated trough concentrations of enalaprilat in patients with renal impairment who were conventionally dosed with enalapril. Thus, in a cross-sectional study of 59 enalapril-treated patients with chronic renal failure of various aetiology, 90% had higher serum concentrations of enalaprilat than reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with a glomerular filtration rate (GFR) below 30 ml min⁻¹. There was considerable interpatient variation in plasma concentrations of enalaprilat when patients with comparable renal function were equally dosed [5]. The clinical significance of such an accumulation is not known. It might be speculated that a high level of enalaprilat in plasma leads to a better degree of blood pressure control and end-organ protection. On the other hand, it is most rational to prescribe the lowest dose that achieves the desired effect.

Blood pressure control per se is highly important in the management of progressive renal disease [1, 2]. The aim of the present paper is to present the blood pressure response during the first 3 months of an open, randomized, controlled trial of the effect of high and low plasma concentrations of enalaprilat on the progression of renal failure. The influence on GFR, proteinuria, anaemia and plasma potassium was also evaluated.

Methods

Patients

Thirty-five consecutive patients completing 90 days of follow-up were enrolled in this study, which was part of an open, randomized, controlled trial of the dosing of enalapril in chronic renal failure. All patients had progressive chronic renal disease with a plasma creatinine value between 175 and 700 µmol l⁻¹. The patients were randomly allocated to an enalaprilat trough plasma concentration either above 50 ng ml⁻¹ (n = 17) (high group) or below 10 ng ml⁻¹ (n = 18) (low group). The aim in the low-level treatment group was to achieve concentrations seen in patients with normal renal function, i.e. < 10 ng ml⁻¹[6–8]. The choice of the high concentration level> 50 ng ml⁻¹ was based upon observations in our previous cross-sectional study [5]. Randomization was done by the drawing of sealed envelopes after stratification by GFR above or below 15 ml min⁻¹.

Ethics

All patients gave their written informed consent and the trial was approved by the Medical Ethics Committee of Copenhagen County.

Study design

Titration of the enalapril dose was done after measurement of plasma enalaprilat at baseline in patients with ongoing enalapril treatment at randomization. Patients not on this treatment at baseline were given an initial dose of 2.5 mg enalapril daily. Adjustments of dose depended on renal function and were based on findings in our previous cross-sectional study of enalaprilat concentrations in patients with chronic renal failure [5]. No patients were to be given more than 40 mg enalapril daily. As enalapril is not commercially available in doses less than 2.5 mg, dosing every other day was allowed as needed. None of the patients was treated with steroids or nonsteroidal anti-inflammatory drugs during the study period, and treatment with other ACE inhibitors or angiotensin-II-receptor antagonists was not allowed after randomization. Concomitant antihypertensive therapy with diuretics, β-blockers, calcium antagonists and vasodilators was prescribed as needed to reach a blood pressure goal of 120/80 mmHg.

All patients were given dietary instruction when included in the study and were asked to adhere to a daily protein intake of around 0.8 g kg⁻¹ and to limit potassium intake during the study period. No restriction on salt intake was enforced.

All patients were followed for 90 days at the outpatient nephrology clinic. Patients were seen at baseline and on days 7, 14, 21, 28, 60 and 90.

Blood pressure measurement technique

Blood pressure was measured in the morning at all visits in the sitting position after 10 min of rest using a sphygmomanometer with a standard cuff of 12 cm width. Korotkoff sound phase 5 was used for the recording of diastolic blood pressure. Blood pressure was measured 24 h after the last intake of enalapril.

Measurement of glomerular filtration rate

GFR was estimated at baseline and on day 90 by the plasma clearance of ⁵¹Cr-EDTA. Between 08:00 and 09:00 h an intravenous bolus injection of 4 MBq ⁵¹Cr-EDTA was given. GFR was estimated on the basis of sex, age, body weight and plasma creatinine [9]. In the case of an estimated GFR ≥ 16 ml min⁻¹, blood samples were drawn at 0, 180, 200, 220 and 240 min after injection of the tracer. Patients with an expected GFR < 16 ml min⁻¹ had samples drawn at 0, 300 and 1440 min. ⁵¹Cr-EDTA plasma clearance was calculated on the basis of the plasma activity as described by Brøchner-Mortensen [10].

Measurement of enalaprilat

Total plasma concentrations of enalaprilat were measured at baseline in patients on prestudy treatment with enalapril and after 90 days in all patients as trough concentrations 24 h after the last dose of enalapril. Blood samples were drawn from a cubital vein and plasma was separated by centrifugation for 10 min at 1250 g at 24°C after the blood had been allowed to clot. Plasma was stored at −20°C until assay. Enalaprilat was isolated from plasma by solid-phase extraction using BondElut™ C-18 cartridges (500 mg). Determination of enalaprilat was achieved by an RP-LC-MS-MS (liquid chromatography-mass spectrometry) method in which an HPLC system (Waters 2690 Separations module) and a triple quadropole tandem mass spectrometer (Quattro LC; Micromass) were employed for analysis of the plasma samples. Separation was carried out on a SymmetryShield™ RP8 column (100 × 2.1 i.d., 3.5 µm). The mobile phase consisted of acetonitrile, water and formic acid (40 : 60 : 0.1 v/v/v). Regression lines were based on nine and eight plasma standards in the range of 0.5–375 ng ml⁻¹ and 1–375 ng ml⁻¹ for enalapril and enalaprilat, respectively. The lower limit of quantification was 2.5 ng ml⁻¹. The assay accuracy and precision were determined by analysing pools of drug-free plasma spiked with enalaprilat at three known concentrations. The assay showed an intraday precision of < 3.5% and an intraday accuracy ranging from 99% to 113%. The interday precision ranged from 4.4% to 20.2% and the interday accuracy ranged from 91% to 107%.

Measurement of angiotensin converting enzyme activity

Serum activity of ACE was measured on days 28 and 90 by photometry [11]. Samples were drawn and stored until analysis as described above.

Other analyses

Protein intake was evaluated by urinary excretion of urea. Protein excretion was evaluated as 24-h urinary excretion of albumin. Laboratory tests of blood and urine were done by routine clinical chemistry methods.

Statistical analysis

Data are presented as median values with range in parentheses. Statistical analysis was performed applying the Mann–Whitney U-test. A nonparametric method was chosen due to the relatively small scale of the study. Comparison of concomitant antihypertensive therapy was done by Fisher's exact test and Student's t-test. P-values <0.05 were considered statistically significant.

Results

Patient characteristics

A total of 35 patients participated in the study. Baseline characteristics are presented in Table 1. There were no statistically significant differences between the groups at baseline.

Table 1.

Baseline characteristics of 35 patients with chronic renal failure.

	Trough plasma concentration of enalaprilat
	> 50 ng ml−1 (n = 17)	< 10 ng ml−1 (n = 18)
Sex	9 M, 8 F	13 M, 5 F
Age (years)	58 (34–79)	56 (23–72)
GFR (ml min−11.73 m2)	18 (8–35)	17 (8–34)
Systolic BP (mmHg)	140 (110–200)	130 (110–165)
Diastolic BP (mmHg)	80 (70–95)	80 (65–100)
Haemoglobin(mmol l−1)	6.9 (6.0–8.9)	7.1 (6.0–8.2)
Creatinine (µmol l−1)	299 (189–683)	325 (176–549)
Urea (mmol l−1)	17.5 (9.8–38.3)	23.0 (9.7–30.4)
Potassium (mmol l−1)	4.7 (4.0–6.0)	4.6 (4.2–6.1)
Bicarbonate (mmol l−1)	24 (17–33)	25 (16–29)
Urinary albumin (µmol day−1)	14.76 (1.19–197.4)	5.31 (0.17–52.94)

Median (range).

Seven patients had chronic glomerulonephritis (verified by renal biopsy), four had diabetic nephropathy (verified by renal biopsy or made probable by a history of diabetes mellitus above 15 years with concomitant retinopathy and/or neuropathy), eight had adult polycystic kidney disease (verified by ultrasonography) and four had chronic tubulo-interstitial nephropathy (made probable by history and radiological features according to Churg [12]). The remaining 12 patients were classified as having chronic nephropathy of unknown aetiology.

Enalapril dose

When included in the study, nine patients in each group were on treatment with enalapril. At baseline the median daily dose of enalapril was 5 mg in both the high (5–10) and low (2.5–20) concentration groups, and at 3 months follow-up the median daily doses were 10 (2.5–30) and 1.9 (1.25–5) mg (P < 0.0001), respectively. As enalapril is not commercially available in doses less than 2.5 mg, some patients in the low group were dosed every other day.

Trough plasma concentration of enalaprilat

When plasma concentrations of enalaprilat were measured after 3 months, the patients in the high-level treatment group had a median concentration of 82.5 (22–244) ng ml⁻¹ and patients in the low group had a median concentration of 9.1 (2.5–74.8) ng ml⁻¹ (P < 0.002).

Blood pressure

Blood pressure results are presented in Figure 1. There were no statistically significant differences between the groups or when comparing baseline values with values obtained at follow-up in either group.

Figure 1.

Systolic (Syst) and diastolic (Dia) blood pressure response in 35 patients with chronic renal failure randomized to either a high (H) or a low (L) trough concentration of enalaprilat in plasma. Median (range) blood pressures are listed in the figure for days 0, 28, 60 and 90. Numbers in black above the lines refer to the high-concentration group and numbers in grey below the lines refer to the low-concentration group. ▴, Syst H; ▪, Syst L; ▵, Dia H, □, Dia L

Concomitant antihypertensive therapy

Patients in both groups received additional antihypertensive therapy. At baseline four patients in the high enalaprilat concentration group were treated with drugs blocking the renin–angiotensin system other than enalapril (captopril (n = 1), lisinopril (n = 1), losartan (n = 2)) compared with five patients in the low concentration group (fosinopril (n = 1), losartan (n = 4)) (NS). The number of patients treated with enalapril as well agents of other antihypertensive classes and the mean daily doses of the most commonly used drugs are shown in Table 2. There were no significant differences with respect to number of patients treated or mean dose administered between the high and low enalaprilat concentration group at any visit for any other class of antihypertensive drug but enalapril, where a difference in mean dose was found from month 1 onwards.

Table 2.

Antihypertensive therapy in 35 patients with chronic renal failure randomized to either a high (> 50 ng ml⁻¹) or a low (< 10 ng ml⁻¹) trough plasma concentration of enalaprilat.

	High (n = 17)				Low (n = 18)
	Baseline	Day 28	Day 60	Day 90	Baseline	Day 28	Day 60	Day 90
Enalapril	9	17	17	17	9	18	18	18
(mg)	(7.2)	(12.5)	(12.4)	(12.9)	(8.8)	(2.4)	(2.2)	(2.2)
Furosemide	11	14	14	14	15	17	17	17
(mg)	(105)	(103)	(103)	(103)	(70)	(85)	(85)	(82)
β-blockers	8	7	7	7	3	4	5	5
Metoprolol	6	6	6	6	3	4	5	5
(mg)	(142)	(142)	(142)	(142)	(133)	(133)	(133)	(133)
Ca-antagonists	9	10	10	10	7	9	8	8
Amlodipin	8	9	9	8	7	9	8	8
(mg)	(8)	(8)	(8)	(9)	(9)	(9)	(9)	(8)
Vasodilators	2	2	2	2	1	1	1	1

Number of patients treated, mean dose in parentheses.

Renal function

In the high enalaprilat concentration group, the median GFR fell from 18 (8–35) at baseline to 13 (5–31) after 3 months and in the low concentration group it rose from 17 (8–34) to 18 (9–33) ml min⁻¹ 1.73 m². The median change in GFR was −1.33 (−4 to 1) ml min⁻¹ month⁻¹ in the high group and +0.33 (−4.33 to 4) ml min⁻¹ month⁻¹ in the low group. The difference between the groups was statistically significant (P = 0.003). In the high concentration group, the median change in plasma creatinine from baseline to day 90 was +18 (−35 to 267) µm and in the low concentration group the median change was +15 (−79 to 303) µm (NS). Changes in plasma urea from baseline to day 90 were +2.5 (−11.5 to 13.3) mm and +0.55 (−8.6 to 16.7) mm (NS) in the high and low enalaprilat concentration groups, respectively.

Proteinuria, potassium and haemoglobin

In the high concentration group, 24-h urinary excretion of albumin at baseline was 14.76 (1.19–197.4) µmol compared with 5.31 (0.17–52.94) µmol in the low concentration group (P = 0.23), and after 90 days it was 11.51 (0.22–89.38) µmol and 4.04 (0.26–61.25) µmol (P = 0.49), respectively. No significant differences were found either between or within the groups with respect to changes in proteinuria over time. Plasma potassium was 4.7 (4.0–6.0) mm in the high concentration group and 4.6 (4.2–6.1) mm in the low concentration group at baseline (NS). At day 90 it had risen in the high concentration group to 5.1 (4.1–5.9) mm, whereas it was unchanged in the low concentration group at 4.5 (3.6–5.7) mm (P < 0.01). In the high concentration group, blood haemoglobin at baseline was 6.9 (6.0–8.9) mm compared with 7.05 (6.0–8.2) mm in the low concentration group (NS). It remained stable during the study period and at day 90 it was 7.4 (6.3–8.7) and 7.0 (5.4–8.4) mm in the high and low concentration groups, respectively (NS).

Angiotensin converting enzyme

The serum activity of ACE was suppressed below the normal range in almost all patients, the reference range being from 30 to 115 U l⁻¹. A total of 14 and 17 patients had undetectable ACE activity after 28 and 90 days, respectively, no differences in frequency between the groups being detectable. At day 28, one patient allocated to the high enalaprilat concentration group had a value of 48 U l⁻¹ and two patients allocated to the low concentration group had a serum activity of ACE of 55 U l⁻¹. At day 90, ACE activity was not suppressed below the reference range in one patient in each treatment group. In these patients, the ACE activity was 34 U l⁻¹ and 84 U l⁻¹, respectively. No correlation between ACE activity and enalaprilat trough concentrations could be demonstrated. Likewise, no correlation was found between ACE activity and blood pressure control.

Protein intake

Protein intake as evaluated by 24-h urinary excretion of urea was unchanged in both groups during the study period. At baseline, daily urinary excretion of urea was 281 (164–508) and 297 (122–528) mmol in the high and low enalaprilat concentration group, respectively (NS). After 3 months of follow-up, urea excretion was 278 (152–475) in the high and 241 (196–470) mmol day⁻¹ in the low concentration group (NS).

Discussion

The present study shows that during treatment with enalapril in chronic, progressive nephropathy, the same degree of blood pressure control was achieved in patients on a low-dose regimen as in patients on a moderate/high-dose regimen. This was found to be independent of concomitant antihypertensive therapy, as judged by number of patients treated and mean daily doses. Thus, blood pressures were comparable during 3 months of low- and high-trough enalaprilat concentrations. Our findings in blood pressure response are in accordance with previously published smaller studies. In an abstract published by Riley et al., mean arterial pressure did not differ between four groups of patients with different degrees of renal insufficiency (one group required dialysis) after 12 days of treatment with 5 mg of enalapril daily, although accumulation of enalaprilat was demonstrated [13]. A similar finding was reported by Hersh et al., who compared enalapril pharmacokinetics and blood pressure response in hypertensive patients with no, mild or moderate renal impairment [14].

The aim in the low-level treatment group was to achieve concentrations seen in patients with normal renal function, i.e. < 10 ng ml⁻¹[6–8]. The choice of the high concentration level above 50 ng ml⁻¹ was based upon observations in our previous cross-sectional study [5]. A higher cut-off value in the high concentration group was not deemed feasible out of safety concerns, because patients with only moderately impaired renal function might have needed more than the recommended maximum dose of enalapril (40 mg daily) to achieve that. During the study, statistically significant differences between the groups were demonstrated in both the daily dose of enalapril as well as in trough plasma concentrations of enalaprilat. Even though not all patients reached the enalaprilat concentrations aimed for, there was an eight-fold difference in the median concentrations.

Almost all ACE inhibitors or their active metabolites are excreted by the kidneys, and thus according to common pharmacological principles, doses should be reduced in renal failure. Usually the dosage of renally excreted drugs is reduced, aiming at serum concentrations in the same range as in subjects with normal kidney function. Recommendations for dose reduction of ACE inhibitors in chronic renal failure are at present rather unspecific [1]. On the other hand, it has been suggested that ACE inhibitor dosage should be high in chronic renal disease in order to reduce proteinuria, to lower blood pressure effectively and to limit progression of renal failure [15].

In our study both a high and low concentration of enalaprilat kept proteinuria stable without any significant differences either between or within the groups. Similarly, in a recent study of 13 patients with mild chronic renal insufficiency (GFR 51 ± 5.5 ml min⁻¹), Keilani et al. found a low dose (1.25 mg) of ramipril to be just as effective in reducing proteinuria as a higher (10 mg) dose, even though the low dose did not reduce blood pressure significantly [16]. In contrast, a recent study in patients with chronic heart failure, a small but statistically significant difference in the combined endpoint of mortality and morbidity was reached, favouring a high dose (33.2 mg) of lisinopril over a low (4.5 mg) dose [17].

As to blood pressure control, there seems to be no indication for increasing the dose of enalapril in patients with renal failure. In the present study, no additional reduction in blood pressure was seen in the high-concentration group. The reason could be that the maximum effect is reached at enalaprilat concentrations <10 ng ml⁻¹. Dose-dependency has been demonstrated in pharmacodynamic studies on subjects with normal renal function for enalapril doses up to 10 mg, with higher doses prolonging the effect [17–21].

Serum activity of ACE was suppressed in almost all patients in the present study, indicating inhibition of circulating ACE even in the low-concentration group where some patients were dosed every other day. Previous studies have shown a close inverse correlation between plasma concentrations of enalaprilat and activity of circulating ACE [22]. As the concentration of enalaprilat required to exert a 50% inhibition (IC₅₀) on ACE activity has been reported to be from 1 to 6 ng ml⁻¹[23], our finding is not surprising.

The main aim of treatment with ACE inhibitors in chronic renal failure is to halt the continuing fall in GFR. In the present study there was a reduction in GFR in the group of patients treated with the high dose of enalapril compared with a small rise in the group of patients treated with the low doses. This might be haemodynamically mediated, due to greater dilation of the efferent arteriole in patients on the high-concentration regime. Ten patients randomized to the low-concentration group had increased their GFR after 3 months (median increase 3 ml min⁻¹, range 1–12 ml min⁻¹) compared with three patients in the high-concentration group (2 ml min⁻¹, 1–3 ml min⁻¹). In five of the patients in the low-concentration group who were treated with enalapril at baseline, the dose of enalapril was reduced during the observation period. In the high-concentration group all three patients had had their doses increased. It can be speculated that the five patients on the low-concentration regimen were prescribed an inappropriately high dose of ACE inhibitor before entering the trial and that dose reduction led to improvement of renal function. These short-term changes in GFR should not be uncritically interpreted as harbingers of the future course of renal function. Actually, an initial fall in GFR when ACE inhibitor treatment is started may be followed by stabilization and a slower decline in renal function than before drug intervention [24, 25].

Hyperkalaemia and worsening of anaemia are well-known unwanted side-effects of ACE inhibitors in renal failure. In the present study, patients on the high-dose enalapril regime experienced an increase in plasma potassium. None of the patients had hyperkalaemia that necessitated acute interventions to lower plasma potassium. All patients received the same instructions in dietary measures to keep potassium intake low upon entering the trial, and no patients received dietary potassium supplementation or were treated with potassium-sparing diuretics. Loop-diuretics were used to alleviate hyperkalaemia, but as treatment with furosemide did not differ between the groups, the observed difference in hyperkalaemia appears to be a dose-dependent side-effect of treatment with enalapril. In a recent case-control study of 1818 patients using ACE inhibitors, 11% developed hyperkalaemia. The risk was associated with impaired renal function, congestive heart failure and age above 70 years [26].

Treatment with an ACE inhibitor tends to worsen nephrogenic anaemia. In the present study, there was no statistically significant difference between the groups regarding changes in haemoglobin concentration. Erythropoietin was used in six patients in each group during the study period.

In conclusion, patients with chronic renal failure showed no difference in blood pressure control or proteinuria during 3 months' therapy with enalapril in low or high dosage. The results emphasize that patients with renal impairment can reach effective blood pressure control even at very low daily doses of enalapril. Patients in the high-concentration group had higher plasma potassium concentrations after 90 days of treatment, and patients in the low-concentration group experienced a slight rise in GFR. All patients could continue in a long-term study to clarify if better renal protection is achieved by high-dose treatment.