AJH
1992;
5:423-430
ORIGINAL CONTRIBUTIONS
Effect of Enalapril on the Progression of Chronic Renal Failure
A Randomized Controlled Trial
In order to study the influence of angiotensin con verting enzyme (ACE) inhibition on the progres-. sion of chronic nephropathy, 70 patients with a me dian glomerular filtration rate (GFR) of 15 (range, 6 to 54) mL/min/1.73 m were randomized in an open study to basic treatment with enalapril or conventional antihypertensive treatment. The pa tients were followed for at least 2 years or until they needed dialysis. The groups were comparable with respect to age and sex distribution, etiology of renal diseases, initial levels of renal function and arterial blood pressure (BP), and protein intake. The therapeutic goal was a BP of 120 to 140/80 to 90 mm Hg. The GFR, estimated by the plasma clearance of Cr-EDTA, was measured every third month, and the individual rate of progression was 2
51
C
hronic nephropathy in most instances pro gresses relentlessly to end-stage renal failure, amenable to treatment only with dialysis or renal transplantation. This deterioration of renal function tends to occur at a constant rate more characteristic of the individual patient than of the un derlying pathological disorder, suggesting that renal diseases, once established, progress through a common 1
Received July 29, 1991. Accepted March 18, 1992. From the Departments of Nephrology and Clinical Physiology, Herlev Hospital, and the Institute of Experimental Medicine, The Panum Institute, Copenhagen, Denmark. Dr. A.-L. Kamper was supported by a research grant from The University of Copenhagen. Statistical assistance was supported by a grant from the Danish Medical Research Council. Address correspondence and reprint requests to Anne-Lise Kamper, Department of Nephrology B, Herlev Hospital, DK-2730 Herlev, Denmark.
© 1992 by the American Journal of Hypertension, Inc.
calculated as the slope of the GFR ν time plot. In the enalapril group, the median decline in GFR was - 0 . 2 0 (range, + 0 . 1 8 to - 7 . 1 1 ) mL/min/1.73 m / month and in the control group it was —0.31 (+0.01 to - 1 . 9 7 ) mL/min/1.73 m /month (P < .05). There was no significant difference in blood pressure or plasma lipid levels between the groups. Thus, the progression of moderate to severe chronic nephrop athy was slower on a basic treatment with enalapril as compared to conventional antihypertensive ther apy. Am J Hypertens 1992;5:423-430 2
2
KEY WORDS: Angiotensin converting enzyme inhi bition, chronic renal failure, enalapril, glomerular filtration rate, progression of uremia.
final pathway. The pathogenesis of this progression of renal disease has not been clarified. It has been pro posed that a critical reduction in renal mass may be compensated by a hemodynamically mediated eleva tion of the glomerular capillary hydrostatic pressure, leading to glomerular sclerosis and further deterioration of renal function. " It has further been suggested that inhibition of the renin-angiotensin system, by way of efferent arteriolar dilatation, might lower glomerular capillary pressure and hence protect renal function in chronic nephropathy. This concept has gained some support from experimental studies " and uncontrolled clinical trials. " Recent controlled studies in diabetic patients have shown that angiotensin converting en zyme (ACE) inhibition postpones the development of diabetic nephropathy in normotensive diabetic patients with persistent microalbuminuria and reduces protein uria in diabetic nephropathy. ' 2
3
6
6
13
12
15
16
17
0895-7061/'92/'$5.00
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
Anne-Lise Kamper, Svend Strandgaard, and Paul P. Leyssac
424
AJH-JULY
KAMPER ET AL
The present study is a controlled clinical trial of the influence of ACE inhibition with enalapril on the pro gression of chronic renal insufficiency. PATIENTS AND METHODS Inclusion Criteria Patients between the ages of 15 and 75 years with progressive chronic nephropathy, regu larly controlled for at least 1 year, with plasma creati nine values between 150 and 900 μιηοΙ/L, were consid ered for inclusion in the study.
Classification of Nephropathy The diagnostic sub groups of chronic nephropathy were classified as previously described. 18
Ethics All patients gave their informed consent and the study was approved by the Ethical Committee of Co penhagen county. Design The study was a controlled randomized unblinded trial with patients followed for at least 2 years or until they needed dialysis. Simple randomization was done by the use of numbered sealed opaque envelopes and a random numbers table. The patients were allo cated to enalapril treatment of control. In both treatment groups the therapeutic goal was a systolic blood pres sure (BP) of 120 to 140 mm Hg and a diastolic BP of 80 to 90 mm Hg.
5, NO. 7
Diuretic Treatment In both groups, diuretics were used as a treatment for hypertension, edema, and hyperkalemia. Diet All nondiabetic patients with a glomerular filtra tion rate (GFR) of < 3 0 mL/min/1.73 m adhered to a dietary regimen of fixed protein. A protein intake of 0.5 g/kg body weight/day was advised for patients with a GFR < 16 mL/min/1.73 m , and 1.0 g/kg body weight/day for patients with a GFR of 16 to 29 mL/ min/1.73 m . These diets were followed for at least 3 months prior to randomization. Diabetic patients re mained on their usual diet without protein restriction. The protein content of the diet was not changed during the study period. Dietary instruction and follow-up of the diet prescription was done by the renal nutritionist and adherence to the instructed diet was controlled by determination of the 24-h urinary excretion of urea. So dium intake was free. 2
2
2
Follow-Up All patients were followed in the outpa tient nephrology unit. The patients were seen weekly during the first month of the study, and thereafter monthly. The GFR was measured at the start of the study, after 1 and 3 months, and thereafter approxi mately every third month. In the enalapril group, GFR was also measured 24 h after the start of enalapril. Methods Auscultatory BP was measured with a mer cury sphygmomanometer in the morning after at least 10 min rest in the sitting position and using a standard cuff of 12 cm width. Korotkoff sound phase 5 was used for diastolic pressure recording. The GFR was estimated by the plasma clearance of Cr-EDTA. Between 08:00 and 09:00, an intravenous bolus injection of 4 MBq Cr-EDTA was given. An ex pected GFR was estimated on the basis of sex, age, body weight, and the plasma concentration of creatinine. In the case of an expected GFR above 15 mL/min, C r EDTA plasma clearance was calculated on the basis of plasma activity in four blood samples drawn at 20-min intervals in the fourth hour after injection. In the case of an expected GFR below 16 mL/min, blood samples were drawn at 5 and 24 h after injection and clearance calculated according to Brochner-Mortensen. The re liability of this method in predicting the GFR of the individual patient is ± 0 . 5 mL/min. Laboratory tests of blood and urine were done by routine clinical chemistry methods. 51
51
20
51
Enalapril Group Treatment with enalapril was started in the hospital with an oral test dose of 2.5 mg. Subse quently, the dose of enalapril was increased gradually to a level deemed appropriate for the individual patient's level of renal function and BP response. In patients on conventional antihypertensive treatment at start of the study, it was simultaneously attempted to reduce the dosage or completely discontinue the use of other anti hypertensive drugs. 19
Control Group Conventional antihypertensive ther apy included ^-blockers, diuretics, and vasodilators. Control patients receiving conventional antihyperten sive treatment at the start of the study, whose BP was at the goal level remained on their antihypertensive treat ment. Control patients without antihypertensive treat ment at start of the study, whose BP was at the goal level remained without antihypertensive treatment.
21
21,22
22
Statistical Analysis Progression of uremia in the indi vidual patient was judged from the slope of the GFR ν time plot as estimated by linear regression analysis. A sample size of 60 patients was estimated according to the following criteria: 2a = β = 0.05 and a minimally relevant difference in slope between the groups of 0.08 mL/min/1.73 m /month. The calculation of the mini2
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
Exclusion Criteria Patients with known renal artery stenosis, dilatation of the upper urinary tract as judged by ultrasonography, treatment with immunosuppres sive or nonsteroidal antiinflammatory drugs, cancer or other serious nonrenal diseases, and past or present treatment with an ACE inhibitor, were excluded from the study.
1992-VOL.
AJH-JULY
5, NO. 7
1992-VOL.
ENALAPRIL AND CHRONIC RENAL FAILURE
2
2
2
2
2
2
TABLE 1. BASELINE CLINICAL DATA
Mean age in years (range) Sex (M/F) Classification of nephropathy Chronic glomerulonephri tis Chronic tubulointerstitial nephropathy Diabetic nephropathy Adult polycystic kidney disease Medullary sponge disease Nephropathy of unknown etiology Blood pressure Hypertension Normotension Dietary protein restriction
Enalapril (n = 35)
Control (n = 35)
48 (29-71) 17/18
49 (25-75) 20/15
8
9
8
9
6 6
7 5
0 7
1 4
30 5 26
29 6 24
( + 0.18 to - 7.11) mL/min/1.73 m /month. In the con trol group it was - 0.31 ( + 0.01 to - 1 . 9 7 ) mL/min/1.73 m /month (P < .05) (Figure 1). There was no correla tion between baseline GFR and the progression rate. The median progression rates of three functional sub groups are shown in Figure 2. To assess the decline in renal function a median of 10 (3 to 13) clearance measurements were performed in each patient in the enalapril group and 9 (5 to 12) in the control group. The median correlation coefficient of the GFR ν time plot was - 0 . 7 0 ( - 0 . 9 9 to + 0 . 7 7 ) in the enalapril group and - 0.86 (— 0.99 to - 0.07) in the con trol group. In the enalapril group, the median baseline plasma creatinine was 422 (150 to 806) μηιοΙ/L and in the con trol group it was 349 (157 to 862) μπιοΙ/L. At the last follow-up the median increase in plasma creatinine was 68 ( - 1 1 3 to 699) μπνοΙ/L in the enalapril group and 175 (— 65 to 2174) //mol/L in the control group. This differ ence was not significant. In the enalapril group, 10 patients progressed to endstage renal failure requiring dialysis, the median time interval from start of the study to the onset of dialysis was 17 (1 to 27) months. In the control group, 13 pa tients progressed to end-stage renal failure with a time interval of 18 (8 to 32) months. These patients did not show any difference between the groups with respect to age, etiology of renal disease, or initial level of renal function. However, it may be mentioned that three of the six normotensive control patients started dialysis while none of the five normotensive patients from the enalapril group progressed to end-stage renal failure. 2
RESULTS Recruitment to the study began on March 1, 1986, and stopped on October 1,1987. Seventy patients were ran domized: 35 to enalapril and 35 to controls. Four pa tients fulfilling the criteria for inclusion in the study refused to participate and thus they were not random ized. Before the study 59 of the 70 patients were on antihypertensive treatment with a diuretic, ^β-blocker, or vasodilator, or a combination of these drugs. Eleven patients were untreated normotensives with a sitting BP less than or equal to 160/95 mm Hg; three of these patients had BP greater than 140/90 mm Hg. At base line the clinical data of the treatment groups were com parable (Table 1, 2) and the examined characteristics of blood and urine were similar. The present report is based on data collected on Oc tober 1, 1989. Thus, each patient had been followed for at least 2 years or until he or she required dialysis or had to be withdrawn for other nonrenal reasons (Table 3). The median follow-up time was 26 (1 to 42) months in the enalapril group and 26 (8 to 42) months in the con trol group. Progression of Renal Failure In the enalapril group, the baseline GFR was slightly lower, 13.0 (6 to 54) mL/ min/1.73 m , than in the control group, 18.8 (7 to 47) mL/min/1.73 m . This difference was not significant (P = .30). The geometric mean of the baseline GFR was 18.7 mL/min/1.73 m in the enalapril group and 20.6 mL/min/1.73 m in the control group. In the enalapril group, the decline in GFR was —0.20 2
2
2
2
2
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
mally relevant difference was based on the following conditions. Based on the literature the progression rate of chronic nephropathy was supposed to be 5 mL/min/ 1.73 m /year = 0.40 mL/min/1.73 m /rnonth. Base line GFR in our study population was around 15 mL/ min/1.73 m and the need for dialysis is usually around 5 mL/min/1.73 m . Thus, predialysis time would be 25 months. We decided that an extension of the predialysis period of 6 months by enalapril would be a relevant benefit for our study group. To achieve that, the progres sion rate should be reduced to 0.32 mL/min/1.73 m / month. Thus, the minimally relevant difference in slopes between the groups was 0.08 mL/min/1.73 m / month. All analyses were performed according to the inten tion-to-treat principle. Characteristics at baseline were compared by Mann-Whitney test and Fisher's exact test. The slopes were compared by the Mann-Whitney test. Other parameters were compared by a two-way nonparametric analysis of variance or by the Mann-Whit ney test based upon changes. All data are given as medi ans with the range in parenthesis. A Ρ < .05 was judged statistically significant (two-tailed).
425
426
AJH-JULY
KAMPER ET AL
1992-VOL.
5, NO. 7
TABLE 2. ANTIHYPERTENSIVE TREATMENT Enalapril (n = 35) 3 Month Follow-Up
Baseline
34 (7.9) 22 (159) 8 25 14 3
22 (180) 1 17 6 1
End
Baseline
3 Month Follow-Up
End
22 (146) 8 21 11 4
27 (240) 6 26 16 8
29 (296) 9 25 14 8
35 (6.9) 23 (296) 2 16 5 5
Number of patients with mean dose in parenthesis. End = last observation of the individual patient. One patient started dialysis after one month.
Blood Pressure In the enalapril group, the median baseline BP was 151 (120 to 220)/92 (70 to 110) mmHg and in the control group it was 140 (110 to 200)/90 (70 to 120) mm Hg. The blood pressure in the enalapril group during the study was 133 (107 to 177)/82 (72 to 96) mm Hg, as compared with 136 (110 to 168)/86 (71 to 92) mm Hg in the control group. This difference was not significant. Antihypertensive Treatment The antihypertensive treatment during the study is given in Table 2. At the last follow-up check of the individual patients, 33 control patients and 24 enalapril-treated patients were taking a diuretic.
TABLE 3. WITHDRAWAL FROM THE STUDY Number of Patients Reason Side effects Angioneurotic edema Death Acute myocardial infarction Aortic aneurysm Diabetic coma Eosophageal rupture Other medical reasons Crural amputation Acute myocardial infarction/ hypotension Nonmedical reasons Patient's decision/removal Poor compliance Total
Enalapril (n = 35)
Control (n = 35)
1(2) 2 (13,22) 1(13) 1(13) 1(25) 1(21) 1(18) 1(17) 5
1(14)
2 (18,26) 7
Number of patients with follow-up time (months) in parentheses.
Urinary Albumin Excretion In the enalapril group, the median baseline 24-h urinary excretion of albumin was 12.2 (1.2 to 168.6) μιηοΐ and in the control group it was 20.7 (0.1 to 75.0) μτηοΐ During the study the 24-h urinary excretion of albumin decreased in the enalapril group while it remained nearly unchanged in the con trol group. The reduction in albumin excretion became significantly greater in the enalapril group at the 6 month follow-up where the median decrease in 24-h urinary excretion of albumin was 4.7 (—16.5 to 83.9) μπιοί in the enalapril group and 0.9 (— 46.4 to 30.3)μπιοί in the control group (P < .05). Hemoglobin Blood hemoglobin (Hgb) fell from 7.6 (5.7 to 10.8) mmol/L at baseline to 6.9 (4.4 to 9.4) mmol/L after 3 months of enalapril treatment. In the control group Hgb fell from 7.6 (4.9 to 10.2) mmol/L to 7.4 (5.2 to 10.0) mmol/L. The median reductions, 0.8 and 0.1 mmol/L, respectively, were significantly differ ent (P < .01). The fall in Hgb was also significantly greater in the enalapril group at the 6 month follow-up, while it was not present at the 12 month or the last follow-up. Plasma Potassium and Plasma Bicarbonate Plasma potassium increased from 4.6 (3.5 to 5.6) mmol/L to 5.1 (3.8 to 6.4) mmol/L after 3 months treatment in the enalapril group and remained at that level, while plasma potassium was stable around 4.5 mmol/L in the control group. The increase in plasma potassium in enalapriltreated patients was significant (P < .01) throughout the study. None of the patients in the enalapril group received any potassium supplementation or potassiumsparing diuretic treatment, while in the control group nine patients took potassium supplementation and three patients were receiving potassium-sparing diuret ics at the last follow-up visit of the study.
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
Enalapril (mg) Diuretics Furosemide (mg) Other ^-Blockers Vasodilators Calcium antagonists
Control (n = 35)
AJH-pjLY 1992-VOL. 5, NO. 7
ENALAPRIL AND CHRONIC R E N A L FAILURE
427
the enalapril group and 174 (85 to 471) in the control group.
Slope of GFR vs. time plot ml/min χ 1.73 m2 per month (-7.11)
Plasma Lipids There was no significant difference be tween the groups in plasma lipids (Table 4). Three pa tients in the enalapril group and four patients in the control group adhered to a low lipid diet.
-2.0i -1.8-1.6-1.4-1.2-
Other Parameters None of the treatment groups showed any changes in blood leucocytes or thrombo cytes or in plasma protein, albumin, sodium, calcium, or phosphate. There was no difference between the groups
-1.0-0.8 -0.6
40ρ < 0.05
-0.4H -0.2
I
0
··· ·
·
•v.
· t
30Φ
+ 0.2
.2 Ε
Enalapril (n = 35)
Is
Control (n = 35)
FIGURE 1. Slopes for the linear regression of GFR 1.73 m ) on time (months).
(ml/min/
2
At the 3, 6, and 12 month follow-up, the enalapril group had minor but significant reductions in plasma bicarbonate as compared with the control group. At the start of the study one patient in each group received sodium bicarbonate supplementation while at the last follow-up, 12 patients in the enalapril group and six patients in the control group were receiving this therapy. Urinary Urea Excretion In the enalapril group, the median baseline 24-h urinary excretion of urea was 182 (57 to 540) mmol and in the control group it was 220 (101 to 462) mmol. During the study it remained stable and at the last follow-up it was 180 (58 to 479) mmol in
II
1992;
5:423-430
ORIGINAL CONTRIBUTIONS
Effect of Enalapril on the Progression of Chronic Renal Failure
A Randomized Controlled Trial
In order to study the influence of angiotensin con verting enzyme (ACE) inhibition on the progres-. sion of chronic nephropathy, 70 patients with a me dian glomerular filtration rate (GFR) of 15 (range, 6 to 54) mL/min/1.73 m were randomized in an open study to basic treatment with enalapril or conventional antihypertensive treatment. The pa tients were followed for at least 2 years or until they needed dialysis. The groups were comparable with respect to age and sex distribution, etiology of renal diseases, initial levels of renal function and arterial blood pressure (BP), and protein intake. The therapeutic goal was a BP of 120 to 140/80 to 90 mm Hg. The GFR, estimated by the plasma clearance of Cr-EDTA, was measured every third month, and the individual rate of progression was 2
51
C
hronic nephropathy in most instances pro gresses relentlessly to end-stage renal failure, amenable to treatment only with dialysis or renal transplantation. This deterioration of renal function tends to occur at a constant rate more characteristic of the individual patient than of the un derlying pathological disorder, suggesting that renal diseases, once established, progress through a common 1
Received July 29, 1991. Accepted March 18, 1992. From the Departments of Nephrology and Clinical Physiology, Herlev Hospital, and the Institute of Experimental Medicine, The Panum Institute, Copenhagen, Denmark. Dr. A.-L. Kamper was supported by a research grant from The University of Copenhagen. Statistical assistance was supported by a grant from the Danish Medical Research Council. Address correspondence and reprint requests to Anne-Lise Kamper, Department of Nephrology B, Herlev Hospital, DK-2730 Herlev, Denmark.
© 1992 by the American Journal of Hypertension, Inc.
calculated as the slope of the GFR ν time plot. In the enalapril group, the median decline in GFR was - 0 . 2 0 (range, + 0 . 1 8 to - 7 . 1 1 ) mL/min/1.73 m / month and in the control group it was —0.31 (+0.01 to - 1 . 9 7 ) mL/min/1.73 m /month (P < .05). There was no significant difference in blood pressure or plasma lipid levels between the groups. Thus, the progression of moderate to severe chronic nephrop athy was slower on a basic treatment with enalapril as compared to conventional antihypertensive ther apy. Am J Hypertens 1992;5:423-430 2
2
KEY WORDS: Angiotensin converting enzyme inhi bition, chronic renal failure, enalapril, glomerular filtration rate, progression of uremia.
final pathway. The pathogenesis of this progression of renal disease has not been clarified. It has been pro posed that a critical reduction in renal mass may be compensated by a hemodynamically mediated eleva tion of the glomerular capillary hydrostatic pressure, leading to glomerular sclerosis and further deterioration of renal function. " It has further been suggested that inhibition of the renin-angiotensin system, by way of efferent arteriolar dilatation, might lower glomerular capillary pressure and hence protect renal function in chronic nephropathy. This concept has gained some support from experimental studies " and uncontrolled clinical trials. " Recent controlled studies in diabetic patients have shown that angiotensin converting en zyme (ACE) inhibition postpones the development of diabetic nephropathy in normotensive diabetic patients with persistent microalbuminuria and reduces protein uria in diabetic nephropathy. ' 2
3
6
6
13
12
15
16
17
0895-7061/'92/'$5.00
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
Anne-Lise Kamper, Svend Strandgaard, and Paul P. Leyssac
424
AJH-JULY
KAMPER ET AL
The present study is a controlled clinical trial of the influence of ACE inhibition with enalapril on the pro gression of chronic renal insufficiency. PATIENTS AND METHODS Inclusion Criteria Patients between the ages of 15 and 75 years with progressive chronic nephropathy, regu larly controlled for at least 1 year, with plasma creati nine values between 150 and 900 μιηοΙ/L, were consid ered for inclusion in the study.
Classification of Nephropathy The diagnostic sub groups of chronic nephropathy were classified as previously described. 18
Ethics All patients gave their informed consent and the study was approved by the Ethical Committee of Co penhagen county. Design The study was a controlled randomized unblinded trial with patients followed for at least 2 years or until they needed dialysis. Simple randomization was done by the use of numbered sealed opaque envelopes and a random numbers table. The patients were allo cated to enalapril treatment of control. In both treatment groups the therapeutic goal was a systolic blood pres sure (BP) of 120 to 140 mm Hg and a diastolic BP of 80 to 90 mm Hg.
5, NO. 7
Diuretic Treatment In both groups, diuretics were used as a treatment for hypertension, edema, and hyperkalemia. Diet All nondiabetic patients with a glomerular filtra tion rate (GFR) of < 3 0 mL/min/1.73 m adhered to a dietary regimen of fixed protein. A protein intake of 0.5 g/kg body weight/day was advised for patients with a GFR < 16 mL/min/1.73 m , and 1.0 g/kg body weight/day for patients with a GFR of 16 to 29 mL/ min/1.73 m . These diets were followed for at least 3 months prior to randomization. Diabetic patients re mained on their usual diet without protein restriction. The protein content of the diet was not changed during the study period. Dietary instruction and follow-up of the diet prescription was done by the renal nutritionist and adherence to the instructed diet was controlled by determination of the 24-h urinary excretion of urea. So dium intake was free. 2
2
2
Follow-Up All patients were followed in the outpa tient nephrology unit. The patients were seen weekly during the first month of the study, and thereafter monthly. The GFR was measured at the start of the study, after 1 and 3 months, and thereafter approxi mately every third month. In the enalapril group, GFR was also measured 24 h after the start of enalapril. Methods Auscultatory BP was measured with a mer cury sphygmomanometer in the morning after at least 10 min rest in the sitting position and using a standard cuff of 12 cm width. Korotkoff sound phase 5 was used for diastolic pressure recording. The GFR was estimated by the plasma clearance of Cr-EDTA. Between 08:00 and 09:00, an intravenous bolus injection of 4 MBq Cr-EDTA was given. An ex pected GFR was estimated on the basis of sex, age, body weight, and the plasma concentration of creatinine. In the case of an expected GFR above 15 mL/min, C r EDTA plasma clearance was calculated on the basis of plasma activity in four blood samples drawn at 20-min intervals in the fourth hour after injection. In the case of an expected GFR below 16 mL/min, blood samples were drawn at 5 and 24 h after injection and clearance calculated according to Brochner-Mortensen. The re liability of this method in predicting the GFR of the individual patient is ± 0 . 5 mL/min. Laboratory tests of blood and urine were done by routine clinical chemistry methods. 51
51
20
51
Enalapril Group Treatment with enalapril was started in the hospital with an oral test dose of 2.5 mg. Subse quently, the dose of enalapril was increased gradually to a level deemed appropriate for the individual patient's level of renal function and BP response. In patients on conventional antihypertensive treatment at start of the study, it was simultaneously attempted to reduce the dosage or completely discontinue the use of other anti hypertensive drugs. 19
Control Group Conventional antihypertensive ther apy included ^-blockers, diuretics, and vasodilators. Control patients receiving conventional antihyperten sive treatment at the start of the study, whose BP was at the goal level remained on their antihypertensive treat ment. Control patients without antihypertensive treat ment at start of the study, whose BP was at the goal level remained without antihypertensive treatment.
21
21,22
22
Statistical Analysis Progression of uremia in the indi vidual patient was judged from the slope of the GFR ν time plot as estimated by linear regression analysis. A sample size of 60 patients was estimated according to the following criteria: 2a = β = 0.05 and a minimally relevant difference in slope between the groups of 0.08 mL/min/1.73 m /month. The calculation of the mini2
Downloaded from http://ajh.oxfordjournals.org/ at University of Arizona on October 3, 2015
Exclusion Criteria Patients with known renal artery stenosis, dilatation of the upper urinary tract as judged by ultrasonography, treatment with immunosuppres sive or nonsteroidal antiinflammatory drugs, cancer or other serious nonrenal diseases, and past or present treatment with an ACE inhibitor, were excluded from the study.
1992-VOL.
AJH-JULY
5, NO. 7
1992-VOL.
ENALAPRIL AND CHRONIC RENAL FAILURE
2
2
2
2
2
2
TABLE 1. BASELINE CLINICAL DATA
Mean age in years (range) Sex (M/F) Classification of nephropathy Chronic glomerulonephri tis Chronic tubulointerstitial nephropathy Diabetic nephropathy Adult polycystic kidney disease Medullary sponge disease Nephropathy of unknown etiology Blood pressure Hypertension Normotension Dietary protein restriction
Enalapril (n = 35)
Control (n = 35)
48 (29-71) 17/18
49 (25-75) 20/15
8
9
8
9
6 6
7 5
0 7
1 4
30 5 26
29 6 24
( + 0.18 to - 7.11) mL/min/1.73 m /month. In the con trol group it was - 0.31 ( + 0.01 to - 1 . 9 7 ) mL/min/1.73 m /month (P < .05) (Figure 1). There was no correla tion between baseline GFR and the progression rate. The median progression rates of three functional sub groups are shown in Figure 2. To assess the decline in renal function a median of 10 (3 to 13) clearance measurements were performed in each patient in the enalapril group and 9 (5 to 12) in the control group. The median correlation coefficient of the GFR ν time plot was - 0 . 7 0 ( - 0 . 9 9 to + 0 . 7 7 ) in the enalapril group and - 0.86 (— 0.99 to - 0.07) in the con trol group. In the enalapril group, the median baseline plasma creatinine was 422 (150 to 806) μηιοΙ/L and in the con trol group it was 349 (157 to 862) μπιοΙ/L. At the last follow-up the median increase in plasma creatinine was 68 ( - 1 1 3 to 699) μπνοΙ/L in the enalapril group and 175 (— 65 to 2174) //mol/L in the control group. This differ ence was not significant. In the enalapril group, 10 patients progressed to endstage renal failure requiring dialysis, the median time interval from start of the study to the onset of dialysis was 17 (1 to 27) months. In the control group, 13 pa tients progressed to end-stage renal failure with a time interval of 18 (8 to 32) months. These patients did not show any difference between the groups with respect to age, etiology of renal disease, or initial level of renal function. However, it may be mentioned that three of the six normotensive control patients started dialysis while none of the five normotensive patients from the enalapril group progressed to end-stage renal failure. 2
RESULTS Recruitment to the study began on March 1, 1986, and stopped on October 1,1987. Seventy patients were ran domized: 35 to enalapril and 35 to controls. Four pa tients fulfilling the criteria for inclusion in the study refused to participate and thus they were not random ized. Before the study 59 of the 70 patients were on antihypertensive treatment with a diuretic, ^β-blocker, or vasodilator, or a combination of these drugs. Eleven patients were untreated normotensives with a sitting BP less than or equal to 160/95 mm Hg; three of these patients had BP greater than 140/90 mm Hg. At base line the clinical data of the treatment groups were com parable (Table 1, 2) and the examined characteristics of blood and urine were similar. The present report is based on data collected on Oc tober 1, 1989. Thus, each patient had been followed for at least 2 years or until he or she required dialysis or had to be withdrawn for other nonrenal reasons (Table 3). The median follow-up time was 26 (1 to 42) months in the enalapril group and 26 (8 to 42) months in the con trol group. Progression of Renal Failure In the enalapril group, the baseline GFR was slightly lower, 13.0 (6 to 54) mL/ min/1.73 m , than in the control group, 18.8 (7 to 47) mL/min/1.73 m . This difference was not significant (P = .30). The geometric mean of the baseline GFR was 18.7 mL/min/1.73 m in the enalapril group and 20.6 mL/min/1.73 m in the control group. In the enalapril group, the decline in GFR was —0.20 2
2
2
2
2
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mally relevant difference was based on the following conditions. Based on the literature the progression rate of chronic nephropathy was supposed to be 5 mL/min/ 1.73 m /year = 0.40 mL/min/1.73 m /rnonth. Base line GFR in our study population was around 15 mL/ min/1.73 m and the need for dialysis is usually around 5 mL/min/1.73 m . Thus, predialysis time would be 25 months. We decided that an extension of the predialysis period of 6 months by enalapril would be a relevant benefit for our study group. To achieve that, the progres sion rate should be reduced to 0.32 mL/min/1.73 m / month. Thus, the minimally relevant difference in slopes between the groups was 0.08 mL/min/1.73 m / month. All analyses were performed according to the inten tion-to-treat principle. Characteristics at baseline were compared by Mann-Whitney test and Fisher's exact test. The slopes were compared by the Mann-Whitney test. Other parameters were compared by a two-way nonparametric analysis of variance or by the Mann-Whit ney test based upon changes. All data are given as medi ans with the range in parenthesis. A Ρ < .05 was judged statistically significant (two-tailed).
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1992-VOL.
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TABLE 2. ANTIHYPERTENSIVE TREATMENT Enalapril (n = 35) 3 Month Follow-Up
Baseline
34 (7.9) 22 (159) 8 25 14 3
22 (180) 1 17 6 1
End
Baseline
3 Month Follow-Up
End
22 (146) 8 21 11 4
27 (240) 6 26 16 8
29 (296) 9 25 14 8
35 (6.9) 23 (296) 2 16 5 5
Number of patients with mean dose in parenthesis. End = last observation of the individual patient. One patient started dialysis after one month.
Blood Pressure In the enalapril group, the median baseline BP was 151 (120 to 220)/92 (70 to 110) mmHg and in the control group it was 140 (110 to 200)/90 (70 to 120) mm Hg. The blood pressure in the enalapril group during the study was 133 (107 to 177)/82 (72 to 96) mm Hg, as compared with 136 (110 to 168)/86 (71 to 92) mm Hg in the control group. This difference was not significant. Antihypertensive Treatment The antihypertensive treatment during the study is given in Table 2. At the last follow-up check of the individual patients, 33 control patients and 24 enalapril-treated patients were taking a diuretic.
TABLE 3. WITHDRAWAL FROM THE STUDY Number of Patients Reason Side effects Angioneurotic edema Death Acute myocardial infarction Aortic aneurysm Diabetic coma Eosophageal rupture Other medical reasons Crural amputation Acute myocardial infarction/ hypotension Nonmedical reasons Patient's decision/removal Poor compliance Total
Enalapril (n = 35)
Control (n = 35)
1(2) 2 (13,22) 1(13) 1(13) 1(25) 1(21) 1(18) 1(17) 5
1(14)
2 (18,26) 7
Number of patients with follow-up time (months) in parentheses.
Urinary Albumin Excretion In the enalapril group, the median baseline 24-h urinary excretion of albumin was 12.2 (1.2 to 168.6) μιηοΐ and in the control group it was 20.7 (0.1 to 75.0) μτηοΐ During the study the 24-h urinary excretion of albumin decreased in the enalapril group while it remained nearly unchanged in the con trol group. The reduction in albumin excretion became significantly greater in the enalapril group at the 6 month follow-up where the median decrease in 24-h urinary excretion of albumin was 4.7 (—16.5 to 83.9) μπιοί in the enalapril group and 0.9 (— 46.4 to 30.3)μπιοί in the control group (P < .05). Hemoglobin Blood hemoglobin (Hgb) fell from 7.6 (5.7 to 10.8) mmol/L at baseline to 6.9 (4.4 to 9.4) mmol/L after 3 months of enalapril treatment. In the control group Hgb fell from 7.6 (4.9 to 10.2) mmol/L to 7.4 (5.2 to 10.0) mmol/L. The median reductions, 0.8 and 0.1 mmol/L, respectively, were significantly differ ent (P < .01). The fall in Hgb was also significantly greater in the enalapril group at the 6 month follow-up, while it was not present at the 12 month or the last follow-up. Plasma Potassium and Plasma Bicarbonate Plasma potassium increased from 4.6 (3.5 to 5.6) mmol/L to 5.1 (3.8 to 6.4) mmol/L after 3 months treatment in the enalapril group and remained at that level, while plasma potassium was stable around 4.5 mmol/L in the control group. The increase in plasma potassium in enalapriltreated patients was significant (P < .01) throughout the study. None of the patients in the enalapril group received any potassium supplementation or potassiumsparing diuretic treatment, while in the control group nine patients took potassium supplementation and three patients were receiving potassium-sparing diuret ics at the last follow-up visit of the study.
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Enalapril (mg) Diuretics Furosemide (mg) Other ^-Blockers Vasodilators Calcium antagonists
Control (n = 35)
AJH-pjLY 1992-VOL. 5, NO. 7
ENALAPRIL AND CHRONIC R E N A L FAILURE
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the enalapril group and 174 (85 to 471) in the control group.
Slope of GFR vs. time plot ml/min χ 1.73 m2 per month (-7.11)
Plasma Lipids There was no significant difference be tween the groups in plasma lipids (Table 4). Three pa tients in the enalapril group and four patients in the control group adhered to a low lipid diet.
-2.0i -1.8-1.6-1.4-1.2-
Other Parameters None of the treatment groups showed any changes in blood leucocytes or thrombo cytes or in plasma protein, albumin, sodium, calcium, or phosphate. There was no difference between the groups
-1.0-0.8 -0.6
40ρ < 0.05
-0.4H -0.2
I
0
··· ·
·
•v.
· t
30Φ
+ 0.2
.2 Ε
Enalapril (n = 35)
Is
Control (n = 35)
FIGURE 1. Slopes for the linear regression of GFR 1.73 m ) on time (months).
(ml/min/
2
At the 3, 6, and 12 month follow-up, the enalapril group had minor but significant reductions in plasma bicarbonate as compared with the control group. At the start of the study one patient in each group received sodium bicarbonate supplementation while at the last follow-up, 12 patients in the enalapril group and six patients in the control group were receiving this therapy. Urinary Urea Excretion In the enalapril group, the median baseline 24-h urinary excretion of urea was 182 (57 to 540) mmol and in the control group it was 220 (101 to 462) mmol. During the study it remained stable and at the last follow-up it was 180 (58 to 479) mmol in
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