Division of Nephrology, University of Roma La Sapienza, Rome and Department of Nephrology S. Orsola-Malpighi Hospital, Bologna, Italy
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Abstract |
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Methods. In an open, multicentre study all eligible patients entered a 3 months run-in phase during which antihypertensive therapy (with exclusion of ACEi) was adjusted in order to obtain a supine diastolic blood pressure 90 mmHg and urinary protein excretion and renal function stability were verified. One hundred and thirty-one patients with chronic renal insufficiency (Clcr between 2050 ml/min) because of primary renoparenchymal diseases and proteinuria
1.0 g/day, were randomized to Lisinopril (L=66) or alternative antihypertensive therapy (C=65). Changes in renal function were assessed by inulin (Clin) clearance.
Results. During the follow-up period of 22.5±5.6 months, Clin did not change significantly in group L (-1.31±0.6 ml/min/1.73 m2) differing significantly from group C in which it declined markedly (-6.71±3.6 ml/min/1.73 m2) (P<0.04). Seven patients experienced adverse events that prompted discontinuation of treatment: four in group L and three in group C; in addition seven patients showed severe deterioration in renal function requiring dialysis: two in group L and five in group C. The overall risk of the combined end-points: need for dialysis or halving of GFR was significantly higher in group C versus group L. During the study the mean value for systolic blood pressure was 137.8±14.6 SD mmHg in group L and 140.8±14.1 SD mmHg in group C; the mean difference between groups, during and at the end of the study, was 2 mmHg (NS). The mean diastolic blood pressure during the study was 83.8±8.6 SD mmHg in group L and 84.3±7.56 SD mmHg in group C; during and at the end of the study the mean diastolic difference between groups was 1 mmHg.
Conclusion. This study, employing a sensitive measurement of renal function and with similar blood pressure in both groups, provides support to the hypothesis that ACEi have a specific renoprotective effect, in addition to blood pressure control, also in patients with mild proteinuria.
Keywords: ACE-inhibitors; antihypertensive therapy; non-diabetic renal diseases; renal failure; reno-protection
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Introduction |
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The Modification of Diet in Renal Disease (MDRD) Study has clearly demonstrated that aggressive blood pressure control may produce long-term benefits in CRD patients, particularly when baseline proteinuria is >1 g/day [5,6].
A central role for the continuous decline in renal function has been attributed to Angiotensin II through a number of haemodynamic and biological processes in many ways related to proteinuria [7]. Available evidence suggests that ACE-inhibitors (ACEi) are more effective than other antihypertensive agents in retarding progession and in reducing the risk of terminal renal failure, at least in patients with diabetic and non-diabetic renal diseases when important proteinuria is present [810]. An important observation is that the benefit of the various antihypertensive therapies, in patients with low-moderate renal insufficiency, has been studied using as a primary end-point the serum creatinine (Scr) level or a similar parameter, that cannot be considered an accurate index of the glomerular filtration decline [11,12].
We herein report the results of a prospective, open, randomized trial designed to determine whether Lisinopril, an ACEi, administered at relatively low dosage, is more effective in slowing the progression of non-diabetic chronic renal diseases (CRD) than other antihypertensive agents. The major aim of the study was to select patients with moderate renal insufficiency and baseline proteinuria 1.0 g/day. This particular type of CRD is not infrequent, accounting on the whole for at least one third of end-stage renal disease (ESRD). In addition, progression of renal insufficiency was evaluated by renal clearance of inulin, which is considered the gold standard for the GFR measurement.
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Patients and methods |
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The protocol of the study was approved by the Ethic Committee and by the Institutional Board of each hospital, and all the patients gave their written informed consent.
The primary study goal was to assess the effect of treatment with Lisinopril, a long-acting ACEi, on the rate of changes in renal function as determined by inulin clearance (GFR). Secondary objectives were to assess the long-term effect of treatment on the time to halving of GFR or the need for dialysis and changes over time of blood pressure.
Patients
Subjects of both sexes, aged 1870 years, with chronic renal insufficiency because of primary renoparenchymal diseases and who had not received ACEi therapy for at least 3 months were eligible for the study if they met the following criteria: (i) renal insufficiency duration of at least 12 months before the study with creatinine clearance between 20 and 50 ml/min per 1.73 m2 of body surface area and with variation of <30% during 3 months (at least three determinations over 3 months); (ii) hypertension defined as non-treated supine diastolic blood pressure 95 mmHg or well documented by the treatment with antihypertensive drugs; (iii) proteinuria
1.0 g/day.
The exclusion criteria were: patients with nephropathy secondary to diabetes or other systemic diseases, malignant hypertension or previous antihypertensive treatment with more than two drugs, cerebrovascular events in the last 6 months or myocardial infarction in the last 3 months, heart failure, angina or other major cardiac diseases; significant liver, hemopoietic or endocrine pathology, concomitant therapy with steroids or immunosuppressive drugs and erythropoietin. Pregnancy and lactation were exclusion criteria, along with serum potassium <3 mEq/l or >5.8 mEq/l and hypersensitivity or any controindication to the use of ACEi.
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Study design |
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At the first visit a complete medical history and physical examination, biochemical and haematological test, EKG, radiologic or ultrasonographic studies were carried out. Scr, creatinine clearance (Clcr), and urinary protein excretion on the basis of 24-h urine collection were evaluated at the first visit. Heart rate and blood pressure (after 10 min in the supine position) were measured three times, just before the ingestion of any antihypertensive drug. Each patient was subsequently examined by the same physician every 15 days for the first month and monthly for 2 months thereafter. At each visit antihypertensive therapy was adjusted, as necessary, eventually adding a second antihypertensive drug, in order to obtain a supine diastolic blood pressure 90 mmHg. After 1 and 2 months, Scr and electrolyte concentrations and other biochemical values, and a complete blood count, were repeated, as well as urinary protein excretion on 1-h morning collection. On the same day of visit 2 or 3 (1 or 2 months after the first visit) the GFR was assessed by inulin clearance.
At the end of the run-in phase (visit 5) only compliant patients with stabilized diastolic blood pressure 90 mmHg (with one or two drugs) and stable renal function (difference <30% in Clcr), entered the study.
The patients were centrally randomized to receive Lisinopril 510 mg or Lisinopril 10 mg associated with another antihypertensive drug (L group). The other group (C group) continued conventional antihypertensive therapy (obviously without ACEi). The post-randomization phase lasted 24 months with controls every 2 months in the first year and every 3 months in the second year. Patients were instructed to continue their recommended diet. At each visit heart rate and supine blood pressure were recorded and Clcr was measured as well as haematological, biochemical and electrolyte parameters.
GFR and urinary protein excretion were evaluated every 6 months of the follow-up period.
As for concomitant treatments, non-steroidal antiinflammatory drugs were allowed for no more than seven days; aspirin was allowed at a dosage <500 mg/day. Adverse reactions were assessed at each visit by spontaneous reporting and on clinical and laboratory basis.
Analytic methods
Serum and urinary creatinine concentration were measured with an Auto-analyser at each centre. Clcr was also calculated according to the Cockroft and Gault formula [13].
GFR was determined in the supine position during a constant intravenous infusion of inulin, on the morning following an overnight fast, as a mean of two 60 min periods; urine samples were collected by spontaneous voiding. An oral water load (approximately 15 ml/kg body weight) was given prior to inulin administration in order to maintain a high urine flow.
Urinary protein excretion, except for the first visit, was measured on the 1-h urine collection (from 07.00 to 08.00).
Serum and urinary inulin and protein excretion were measured by the central laboratory (Laboratory of Division of Nephrology, University of Rome) at each visit according to standard methods.
All blood pressure recordings were made at the end of dosing interval, using a mercury sphygmomanometer after 10 min in supine position; DBP was recorded at Korotkoff phase V; the average of three consecutive readings, taken 30 s apart, was registered as the blood pressure.
Statistical analysis
Data management and statistical analyses were carried out with SAS software version 6.08.
The differences between groups L and C were analysed for effects because of treatments; the centre and centre-by-treatment effect was not carried out because many centres had very few patients; the baseline value (visit 5) of each variable was used as covariate (ANCOVA). In the ANCOVA model the following factors were additionally considered: diastolic blood pressure (85 mmHg, >85 mmHg), GFR (
40 ml/min, <40 ml/min) and underlying renal disease (glomerulonephritis, tubulo-interstitial nephropathy and polycystic kidney disease).
For all patients who did not complete the 2-year study, the last value was used in analyses; pairwise comparisons between period means were carried out using LSMEAMS and a 95% confidence interval for differences between means calculated with SAS GLM procedure.
The odds ratio and 95% confidence interval was used to analyse efficacy qualitative outcomes. Fisher's exact test was used to analyse non-parametric safety variables. Statistical significance was set at P<0.05.
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Results |
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At randomization, the demographic, clinical and laboratory characteristics of the two groups were similar (Table 1). It is of note that the mean urinary protein excretion at baseline was 506±374 mg and 518±259 mg/day (0.35 and 0.36 mg/min), respectively, in L and C groups, with a maximum urinary protein excretion of 1200 mg/day during the run-in period. The underlying renal diseases were also similarly present between the two groups (Table 2
). The distribution of the antihypertensive therapy in both groups of patients did not differ at randomization: beta blockers 27/66; calcium channel blockers 30/66; diuretics 13/66; clonidine or alpha adrenoreceptor blockers 4/66 in L group. Beta blockers 30/65; calcium channel blockers 30/65; diuretics 14/65; clonidine 3/65 in C group.
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Renal function
One hundred and nine patients had four or five measurements of GFR including baseline value. In only eight patients (four in group L and four in group C) three GFR determinations were available : clinical characteristics, degree of renal function and blood pressure in that eight patients were similar to the others.
The Clin did not change significantly in group L (-1.31±0.6 ml/min/1.73 m2) while it significantly differed in group C in which an important decrease was observed (-6.71±3.6 ml/min/1.73 m2, P<0.04) (Figure 1).
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Combined end-points
The overall risk of the combined end-points, halving of GFR or need for dialysis, was significantly higher in group C versus group L, as shown in Table 3; with no difference in time to reach the combined end points. Additional analysis demonstrated that patients with baseline GFR >40 ml/min had a slower decline in renal function, independently from the treatment in use, the DBP at baseline and the underlying renal disease.
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Blood pressure
The mean systolic blood pressure at baseline (visit 5) was 141.0 mmHg in group L and 142.2 mmHg in group C. The mean value during the study ranged from 134.8 to 142.8 mmHg in group L (mean value during the study 137.8±14.6 SD mmHg) and from 138.5 to 142.2 mmHg in group C (mean value 140.8±14.1 SD mmHg). The mean difference between groups, during and at the end of the study, was 2 mmHg (NS). The mean DBP at baseline was 83.8 mmHg in group L and 84.9 mmHg in group C. The mean diastolic blood pressure during the study ranged from 80.8 to 84.0 mmHg in group L (mean value during the study 83.8±8.6 SD mmHg) and from 83.1 to 85.1 mmHg in group C (mean value 84.3±7.56 SD mmHg). During and at the end of the study the mean diastolic difference between groups was 1 mmHg (Figure 2).
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Discussion |
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Lisinopril is a non-sulphydryl drug, with a serum half-life of approximately 12 h, which determines a significant reduction in serum ACE activity and angiotensin II concentration for at least 36 h after an acute oral dose [14]. Kakinuma et al. [15] have experimentally demonstrated the greatest benefit of Lisinopril, among other ACEi, in protecting renal and extrarenal structures.
To avoid the confounding effect of a lower blood pressure in the group treated with the ACEi, in our study Lisinopril was used at a relatively low dosage. In addition, to provide a more accurate estimate of GFR, renal function was assessed by repeated measurement of inulin clearance. It is well known that differences in methods of measuring renal function can lead to discrepancies in the interpretation of the results of clinical studies.
At the final evaluation, change from baseline of inulin clearance was significantly different between the group of patients receiving Lisinopril and the group assigned to alternative therapy: indeed, the patients in group L showed a better preservation of renal function.
Many clinical trials, over the past decade, have shown that ACEi are effective in slowing the progression of diabetic nephropathy [8,16]. In addition, some important randomized studies in hypertensive non-diabetic renal disease have demonstrated that ACEi are more efficacious in retarding progression, with a significantly lower risk for ESRD, than conventional antihypertensive therapy [9,10]. In all these studies and in the Modification of Diet in Renal Disease study [5], the largest clinical trial to date in non-diabetic renal disease, the beneficial effect of ACEi or of a lower than usual blood pressure, was obtained in patients with proteinuria >1 g/day [5,6] and the renoprotective effect of ACEi seemed to correlate with the extent of urinary protein excretion reduction. Therefore, it has been suggested that diabetic and non-diabetic renal diseases with important proteinuria benefited most from ACEi.
In our patients with proteinuria 1 g/24 h the therapeutic benefit was less clear compared to what is published in patients with important proteinuria, nevertheless the difference between the ACEi group and the group treated with alternative antihypertensive drugs was still significant and may suggest that other protective mechanisms, aside from the reduction of proteinuria, could explain the effects of ACEi.
Our study was also designed to determine whether the protective effect of ACEi on renal function is independent of the antihypertensive action, as there is evidence that lowering blood pressure per se is beneficial in retarding the progression of renal damage. Recently published clinical trials [9,10,17,18] showed that the progression of renal damage was slower in patients treated with ACEi, as compared with conventional antihypertensive treatment; however, a preferential effect of the ACEi remains controversial. In the largest clinical trial in which an overall 53% reduction in the risk of progressive renal insufficiency was observed in the group assigned to benazepril, both systolic and diastolic blood pressure values were lower in the ACEi treated patients [9]. In our study blood pressure control was substantially satisfactory (mean arterial pressure averaged 101 mmHg), and the systolic and diastolic blood pressures were remarkably similar in both groups, suggesting a specific protective effect of ACEi.
Another finding of our study was the slow progression of renal damage in both groups of patients with mild to moderate renal insufficiency at baseline, assigned to Lisinopril or alternative conventional antihypertensive therapy. The mild proteinuria and strict control of blood pressure may have contributed to the result; moreover, it should be noted that about 50% of patients received a calcium channel blocker as antihypertensive therapy. The wide use of these agents may have blunted the differences between the two groups, and contributed to the slow progression of renal damage also in group C, as there is some evidence that this class of drugs, via different mechanisms, may have the capacity to slow the progression of renal damage [19].
ACEis may have detrimental effects on renal function in patients with renal impairment; we have demonstrated in another study that Lisinopril in monotherapy or associated with a diuretic is well tolerated and significantly reduced diastolic and systolic blood pressure, which returned to normal values in the majority of patients with moderate to severe renal insufficiency [20]; the present study corroborates these previous results, demonstrating safety of the drug.
We conclude that our study, in which appropriate measurements of renal function were carried out and blood pressure was titrated to the same level in both groups, gives support to previous experimental studies and clinical trials. Indeed, our data show that ACEi have specific renoprotective effect, additional to blood pressure control and independent from urinary protein excretion, probably related to the glomerular hemodynamic changes and the biochemical consequences of angiotensin synthesis inhibition.
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Acknowledgments |
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Notes |
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Correspondence and offprint requests to: Giulio A. Cinotti, Division of Nephrology, Dipartimento di Scienze Cliniche, Policlinico Umberto I, R-00161 Roma, Italy.
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References |
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