(Hypertension. 1997;29:744-750.)
© 1997 American Heart Association, Inc.
Articles |
Effect of Calcium Channel or ß-Blockade on the Progression of Diabetic Nephropathy in African Americans
the Department of Medicine, Division of Nephrology, Ochsner Clinic, New Orleans, La (G.L.B., J.B.C., N.V., R.S.), and Rush University Hypertension Center, Rush-Presbyterian/St Luke's Medical Center, Chicago, Ill (G.L.B., A.M.).
Correspondence to George L. Bakris, MD, FACP, Rush University Hypertension Center, Rush-Presbyterian/St Luke's Medical Center, 1725 W Harrison, Suite 117, Chicago, IL 60612. E-mail gbakris@rpslmc.edu
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Abstract |
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ß-Blockers are known to slow the progression of diabetic nephropathy by lowering arterial pressure. Moreover, in individuals with diabetic nephropathy, antihypertensive agents that provide sustained reductions in proteinuria slow the rate of decline in renal function compared with agents without this antiproteinuric effect. To examine whether differential effects on proteinuria affect the progression of diabetic nephropathy, we conducted a randomized study that compared the effects of a heart rate–lowering calcium channel blocker, sustained-release verapamil, with those of a ß-blocker, atenolol, on the progression of diabetic renal disease. The primary end point of the study was a change in creatinine clearance slope. Thirty-four African Americans with the following inclusion criteria were randomized to one of the two groups: serum creatinine greater than 1.4 mg/dL, proteinuria greater than 1500 mg/d, longer than a 5-year history of both non–insulin-dependent diabetes mellitus and hypertension, and exclusion of other renal diseases. Goal blood pressure was less than 140/90 mm Hg. All subjects received loop diuretics as second line agents to help achieve the blood pressure goal. Twenty-four-hour urinary protein and sodium excretions as well as creatinine clearance were measured at 6-month intervals. Blood pressure was measured every 3 months. After a mean follow-up of 54±6 months, the calcium channel blocker group demonstrated both a slower rate of decline in creatinine clearance (-1.7±0.9 versus -3.7±1.4 mL/min per year per 1.73 m2, P<.01) and a greater reduction in proteinuria compared with the atenolol group. Additionally, a greater proportion of the atenolol group had a 50% or more increase in serum creatinine compared with the verapamil group (32±9% versus 16±7%, P<.05). These between-group differences could not be explained by differences in blood pressure control. These data support the concept that antihypertensive agents that persistently maintain reductions in both arterial pressure and proteinuria slow the progression of diabetic renal disease in African Americans to a greater extent than those agents without these effects.
Key Words: blacks • diabetic nephropathies • calcium channel blockers • verapamil • atenolol • adrenergic beta-antagonists
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Introduction |
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African Americans account for the highest percentage of new patients starting dialysis in the United States.1 2 The primary causes of renal failure in this group are hypertension and diabetes.1 2 Mean blood pressure (BP) reduction to levels less than 94 mm Hg is known to slow the progression of both diabetic and nondiabetic renal disease.3 4 5 Moreover, data from two separate studies in African Americans with renal insufficiency secondary to hypertension demonstrate that BP reduction to such levels slows the progression of renal disease.4 5 However, at mean arterial pressure levels between 95 and 106 mm Hg, African Americans lose renal function at a faster rate than age-matched whites.4 Moreover, at these higher BP levels, it is unclear whether a particular class of antihypertensive drug offers an advantage with regard to slowing the progression of renal disease in this population.
Previous studies have compared the efficacy of different classes of antihypertensive agents on BP reduction in African Americans.6 7 8 9 These studies demonstrate that antihypertensive agents such as calcium channel blockers and diuretics are more efficacious than others for reducing arterial pressure in African Americans. This increased efficacy may relate to a higher prevalence of salt sensitivity in this population.10 11 It may also help explain why two separate studies in African Americans with nephropathy report that antihypertensive agents with natriuretic properties slow the progression of renal disease to a greater extent than other agents.7 9
A blunted rise in proteinuria as well as a reduction in elevated levels of proteinuria strongly correlates with a slowed progression in diabetic nephropathy.12 13 Additionally, the Modification of Diet in Renal Disease (MDRD) trial, a study of renal disease in a nondiabetic population, also noted that the baseline level of proteinuria correlated with the degree of BP reduction needed to slow the progression of renal disease in African Americans.4
Antihypertensive agents clearly shown to reduce proteinuria beyond that predicted by BP reduction alone include the angiotensin-converting enzyme (ACE) inhibitors.14 Thus, one might have postulated that these agents would slow the rate of decline in renal function over other classes of antihypertensive agents, as has now been shown.15 16 At the inception of the present study, however, it was unclear whether this class of drugs would provide either greater efficacy to reduce BP or greater protection against the progression of diabetic nephropathy in African Americans compared with other agents. Thus, we excluded this class of drugs from the study.
Likewise, at the inception of the present study in 1988, there were no long-term data on the effect of calcium channel blockers on the progression of diabetic nephropathy. Moreover, the currently appreciated differential effects of calcium channel blockers on urinary protein excretion were not known.17 18 However, it was accepted that ß-blockers reduced the risk of cardiovascular events in part through a reduction in heart rate. It was also known that verapamil was the calcium channel blocker with the most potent heart rate–lowering effects. Thus, we designed the present study to examine the effects of two different classes of antihypertensive medications that lower heart rate on the progression of diabetic renal disease in African Americans with established nephropathy from non–insulin-dependent diabetes mellitus.
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Methods |
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Study Population
A total of 83 subjects were screened from the Nephrology Clinic of the Alton Ochsner Medical Clinic. Thirty-four met the inclusion and exclusion criteria (Table 1
) and were entered into the study. Table 2 summarizes the reasons why the remaining 49 subjects were excluded from the study. The majority of the subjects who qualified and participated in the study were men, primarily because of two factors: a greater reluctance on the part of women to enter the study and a relatively greater preponderance of men in the database used to screen subjects. All subjects gave informed consent to participate in this study. The consent form was approved by the Institutional Review Board of the Alton Ochsner Medical Foundation before participant entry. Demographic characteristics of all subjects who qualified for study participation are summarized in Table 3.
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Study Design
All antihypertensive medications were discontinued in each subject 2 weeks before baseline measurements. Subjects were monitored during this 2-week period with daily BP checks with a BP-monitoring device (Dinamap, Critikon, Inc).
After this 2-week period, a physical examination and the following laboratory screening tests were performed in all subjects: 24-hour urine collection for protein, albumin, creatinine clearance, and sodium; urinalysis; complete blood cell count; renal electrolyte profile (serum urea nitrogen, creatinine, sodium, potassium, chloride, and bicarbonate); and fasting blood glucose and hemoglobin A1c. In addition, a complete ophthalmologic examination, which included fluorescence angiography for confirmation of diabetic retinopathy, was performed at baseline. After titration to goal BP of less than 140/90 mm Hg, renal function studies were performed every 6 months throughout the study. An electrocardiogram was performed annually unless otherwise indicated. In addition to these studies, subjects were instructed by a renal dietitian to ingest a 1500-calorie American Diabetes Association diet. This diet restricted them to 90 mEq/d sodium and 0.8 g/kg per day protein. Dietary compliance was not assessed other than by urinary sodium excretion.
After these baseline laboratory measurements were obtained and instructions given, subjects were randomized to receive either atenolol (n=16) or sustained-release verapamil (n=18). We used a table of random numbers to assign each subject to a drug group. The dosage of each randomized drug was titrated during the first month of the study to ensure similar arterial pressure control in each group. Sustained-release verapamil and atenolol were titrated to maximum dosages of 480 and 100 mg/d, respectively. If the arterial pressure goal was still not achieved, furosemide was added. If additional BP control was needed, other antihypertensive agents, other than ACE inhibitors, were added. ACE inhibitors were not used because of the lack of evidence at the time of the study design of added efficacy on the progression of renal disease independent of arterial pressure reduction.
After the drug titration phase, BP and pulse rates were monitored weekly for the first month and every 3 months thereafter throughout the study. BP measurement in all subjects for the remainder of the study was performed with an appropriately sized BP arm cuff. All readings were obtained in the morning between 9 AM and noon and were taken at least 1 hour after subjects had eaten and 2 hours after medication ingestion. All readings were performed in triplicate with subjects in the sitting position; these values were then averaged.
Urinary protein was measured by means of a dye-binding colorimetric method (Biotrol USA), which required formation of a pyrogallol red–molybdate complex. The interassay and intra-assay variabilities were 3.2% and 2.3%, respectively. Fasting blood glucose levels were monitored daily by the subjects throughout the study by placing a drop of blood onto a plastic strip and inserting it into an AccuCheck II blood glucose–measuring device (Boehringer Mannheim). At the initiation of the study, all subjects were instructed on the proper use of the AccuCheck II device. Furthermore, all AccuCheck II blood glucose measurements were compared with standard laboratory glucose measurements.
End Points
The primary end point of the study was a change in the rate of renal function decline as assessed by the slope of creatinine clearance. Secondary end points included a greater than 50% increase in serum creatinine or proteinuria.
Statistical Analysis
Data were analyzed with SAS version 6.0719 and S-PLUS.20 Nominal characteristics are summarized by percentages; continuous variables are summarized by means and SD or by medians when the distributions were skewed. Dichotomous baseline characteristics were compared with Fisher's exact test; continuous baseline characteristics were compared primarily with Kruskal-Wallis nonparametric tests and secondarily with ANOVA. When the groups differed significantly, Wilcoxon rank sum tests were used for pairwise comparisons. A Wilcoxon matched-pair signed rank test was used to assess differences in side effect profiles among the groups. The time courses of BP and renal function were compared by reducing the data to slopes and intercepts of least-squares lines and then using Kruskal-Wallis tests and ANOVA as described above. A value of P<.05 was considered to indicate statistical significance of comparisons of the two groups. Bonferroni corrections were used for pairwise comparisons, so a nominal significance level of .05/6=.00833 was used for the pairwise comparisons. Such were performed for assessment of changes in the slope of creatinine clearance among the groups.
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Results |
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Thirty-four African Americans with nephropathy associated with non–insulin-dependent diabetes mellitus were randomized to either atenolol (n=16) or sustained-release verapamil (n=18) between January 1989 and February 1990. The baseline demographic, clinical, and laboratory characteristics of these two groups were similar (Table 3
). Twenty-nine of the 34 subjects completed the study (median follow-up, 54 months; range, 28 to 60). Five subjects either stopped the study for reasons other than drug side effects or did not return for follow-up visits.
BP Management
Goal BP was less than 140/90 mm Hg, and all subjects reached this goal by 8 weeks into the study. Mean systolic and diastolic pressures throughout the study are noted in Fig 1. The median baseline systolic pressure at baseline was 164 mm Hg in the verapamil group and 168 in the atenolol group. The median diastolic pressure was 106 mm Hg in the verapamil group and 102 in the atenolol group. During the study, median systolic pressure ranged from 128 to 136 mm Hg and median diastolic pressure from 80 to 88 mm Hg. Mean arterial pressure (±SD) averaged over all follow-up visits did not differ significantly between the two groups (99±4 versus 101±3 mm Hg, verapamil versus atenolol; P=.33). Moreover, during the study, the slopes of systolic (P=.41) and diastolic (P=.37) BPs between the groups did not differ significantly. Likewise, the decrease from baseline mean arterial pressure in each group did not differ (average of 26±6 mm Hg in the verapamil group and 24±5 in the atenolol group, P=.64).
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By the end of the second year, 100% of the subjects were receiving furosemide for either BP control or management of peripheral edema. Moreover, by the end of the study, 26 of 34 (76%) subjects received other BP medications, including 
-blockers and/or vasodilators to maintain BP control (Table 4).
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Glucose Management
There were no differences in the annual values of hemoglobin A1c (Fig 2). This corresponded to the absence of significant differences in fasting blood glucose between groups (P=.19).
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Drug Administration
The mean dosage of sustained-release verapamil over the course of the study was 192±28 mg twice daily; it was 83±8 mg once daily for atenolol. Furosemide, in a dosage ranging from 20 to 80 mg twice daily, was used in all subjects over 4 years of the 5-year study. Additionally, a significantly greater number of people in the atenolol group required a third medication (hydralazine, prazosin, or minoxidil) to achieve BP goal (94% versus 61%, atenolol versus verapamil; P<.05) (Table 4). This may relate to the higher salt intake in the atenolol group (Fig 3).
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Changes in Creatinine Clearance Slopes
A minimum of three creatinine clearance determinations were performed in each subject over the course of the study. Each collection was checked for accuracy by examination of total creatinine value; if inadequate, the collection was repeated. The mean rates of decline in 24-hour creatinine clearance in the 34 subjects were -1.72±0.92 mL/min per year per 1.73 m2 in the verapamil group and -3.68±1.4 in the atenolol group (Fig 4).
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Changes in Serum Creatinine
Among the 34 subjects who had three or more determinations of serum creatinine during an average follow-up of 54 months per subject, the overall annual mean rate of increase in serum creatinine was 0.097±0.23 mg/dL. The mean annual rate of increase in serum creatinine was significantly slower in the verapamil group (0.09±0.24 versus 0.17±0.23 mg/dL per year, verapamil versus atenolol; P<.03).
Eight of the 29 subjects (28%) who completed the study had a 50% or greater increase in serum creatinine. Five of the 8 subjects were in the atenolol group; 4 of these 5 had to start dialysis by the end of the study. Although the total number of subjects whose creatinine increase was not significant compared with the entire group (P=.17), there was a significant difference in creatinine increases between groups (37±7% versus 63±12%, verapamil versus atenolol; P<.05). Moreover, only 4 of these 8 subjects doubled their serum creatinine by the study end; 3 of the 4 were in the atenolol group (P<.05). The mean (±SD) baseline serum creatinine among this group of 8 subjects was 2.4±0.11 mg/dL; the value in the 5 subjects who received atenolol was 2.7±0.09 mg/dL. The mean (±SD) baseline serum creatinine among the 4 subjects who doubled their serum creatinine was 2.9±0.04 mg/dL.
Changes in Urinary Protein Excretion Rate
The mean change from baseline in urinary protein excretion between the two groups was not significantly different at the first month visit (-518±663 versus -116±291 mg/dL, verapamil versus atenolol; P=.06). At 1 year, however, the mean proteinuria reduction from baseline differed significantly between the two groups (-1.3±0.7 versus -0.278±0.382 g/d, verapamil versus atenolol; P<.04). This difference between groups was established with a Bonferroni correction. Moreover, this difference in proteinuria reduction corresponded to similar levels in mean BP reduction over the same time (-24±4 versus -22±5 mm Hg, verapamil versus atenolol). The mean change from baseline proteinuria in each group at study end is shown in Fig 5. This reduction from baseline proteinuria was significantly less in the atenolol group than the verapamil group (P=.03). Moreover, these changes in proteinuria were independent of a reduction in systolic (P=.36) or diastolic (P=.52) BP as well as changes in creatinine clearance (P=.22).
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Adverse Effects of Treatment
Table 5 summarizes all adverse events related to drug therapy. The most common side effect was constipation in the sustained-release verapamil group. However, dietary modifications (high-fiber diet) made this side effect tolerable, so no one had to discontinue treatment. The most common side effect in the atenolol group was fatigue. Overall, the highest side effect profile was noted in the atenolol group (Table 5). Although dosage adjustments were made, no medication discontinuance was required due to side effects.
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Discussion |
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It is well established that BP reduction, regardless of the antihypertensive agent used, slows the progression of diabetic nephropathy.3 4 5 14 15 16 Moreover, ACE inhibitors seem to provide an added degree of protection to the diabetic kidney, independent of their arterial pressure–reducing effects.14 15 16 21 22 23 This observation, however, is derived largely from a white population. Recent data suggest that African Americans with nephropathy require arterial pressure reductions significantly below that of whites to produce a comparable preservation of renal function even with the use of ACE inhibitors.3 4 5 The present study in African Americans with diabetic nephropathy demonstrates that BP reduction with a nondihydropyridine calcium channel blocker retards the decline in renal function and lowers proteinuria to a greater extent than comparable BP reduction with a ß-blocker. In addition, it supports previous reports of a higher side effect profile associated with ß-blockers than with other antihypertensive agents.22 23 24
It is difficult to explain why differences in renal preservation between the two treatment groups were observed. However, one possible factor relates to differences in compliance with BP medications between visits.24 Although compliance was not formally measured, the fact that the ß-blocker group required a significantly greater number of medications to lower BP coupled with a relatively higher side effect profile increases the likelihood that the observed differences between groups may relate to overall medication compliance. If true, this difference in compliance would lead to large within-group BP fluctuations and possibly diminish the protective effect of a BP-lowering medication.
Other possible reasons for differences in renal preservation between these groups include differences in sodium intake as well as differences in antiproteinuric effects of the antihypertensive agents themselves. These and related issues are discussed in greater detail below.
Reduction in proteinuria in individuals with insulin-dependent or non–insulin-dependent diabetes mellitus is known to correlate with the preservation of renal function.12 14 15 16 A report by Hebert et al25 demonstrated that only those individuals who manifested reductions in proteinuria had a slowed progression of diabetic nephropathy. However, a confounding variable in this previous trial was that BP was slightly lower in the ACE inhibitor group. Two different meta-analyses, however, demonstrate that reductions in proteinuria observed with ACE inhibitors are out of proportion to the level of BP reduction.14 15 Thus, these and other studies suggest that ACE inhibitors and nondihydropyridine calcium channel blockers reduce proteinuria to a degree greater than predicted by simple BP reduction.14 15 16 26 Our data support this contention, since there was a greater reduction in proteinuria with sustained-release verapamil than with atenolol, a difference not explained by differences in BP reduction.
A higher salt intake may also have contributed to the faster decline in renal function in the atenolol group. This group consistently had higher values of urinary sodium for 3 of the 5 years of follow-up. Previous studies document that BP control in African Americans is more difficult when a high salt diet is ingested.10 11 The higher dietary salt intake could also account for the greater number of antihypertensive medications used to achieve goal BP in this group. Last, recent data suggest that salt intake affects the antiproteinuric effects of heart rate–lowering calcium channel blockers.11 17 Salt intake apparently blunts the changes in glomerular permeability to albumin induced by certain calcium channel blockers in diabetic individuals.11 17 27 The resultant lack of change in albuminuria could have dire consequences for the kidney because the albumin is glycated in diabetic individuals. Glycated albumin has been shown to cause direct injury to renal cells.12 28 Therefore, decreased exposure to glycated albumin should result in a slowed decline in renal function.
A recent study demonstrates that if BP is adequately lowered in African Americans with hypertensive renal disease, the decline in renal function is virtually normalized.5 Although our data do not support this contention, we did not achieve the level of BP reduction seen in that previous study. Therefore, at BP levels achieved in conventional practice, there may be a difference in renal disease progression depending on the agent used.
Extrapolation of results from this study to the general African American hypertensive population should be viewed with caution as this study has several potential limitations that do not warrant generalization to a larger cohort. These limitations include a small number of studied subjects; the use of creatinine clearance rather than a more precise marker of glomerular filtration rate; use of an open label rather than double-blind, double-dummy design; and last, the lack of biopsy evidence to support the diagnosis of diabetic nephropathy. Each of these issues is discussed below.
The use of creatinine clearance as a marker is a potential limitation of this study. Although we are aware that it is imprecise as a measure of glomerular filtration rate, especially in African Americans, recent studies found it to be a good predictor of renal function decline.29 30 Moreover, we found a good correlation with the reciprocal of serum creatinine and calculated creatinine clearance, measures that correlate better with the use of iothalamate for measurement of glomerular filtration rate in African Americans.31 This difference may also relate to the fact that all our creatinine clearances were checked for adequacy of collection as well as corrected for body surface area. Therefore, even with the limitations of this marker, we feel our data are reliable and meaningful.
Another limitation of the study is the use of an open label design. Although the study was randomized, the absence of a double-blind design allows for bias in the data interpretation. Hence, the data should not be generalized.
Finally, we are aware that up to 25% of individuals with diabetic nephropathy have declines in renal function secondary to another glomerular disease.32 33 However, we feel that our inclusion and exclusion criteria made causes other than diabetic nephropathy very unlikely as contributions to renal function decline. Thus, we are confident that the progressive loss of renal function in our subjects was secondary to diabetic nephropathy.
This study therefore supports the concept that at similar levels of arterial pressure reduction, the nondihydropyridine calcium channel blocker verapamil slows the progression of established diabetic renal disease in African Americans to a greater extent than atenolol. It should be remembered, however, that all subjects had lost at least 50% of their renal function before entry into the study. Therefore, in light of recent data that demonstrate a clear benefit of ACE inhibitors to markedly slow the progression of diabetic renal disease, especially in the early stages of renal disease, verapamil is not advocated as a substitute for early antihypertensive treatment. Additionally, data from other small clinical studies in individuals with progressive diabetic nephropathy demonstrate a relatively greater reduction in proteinuria at similar levels of arterial pressure reduction when verapamil is combined with an ACE inhibitor compared with either agent alone.13 34 35 Further large-scale clinical trials are needed to confirm the observations made in this study.
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Acknowledgments |
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This study was funded in part by the American Diabetes Association, Louisiana Affiliate; American Heart Association, Louisiana Affiliate; American Association of Kidney Disease Patients; and the Alton Ochsner Medical Foundation. We would also like to thank Yvette Jackson for her excellent secretarial assistance with this manuscript.
Received July 3, 1996;
first decision July 31, 1996;
first decision September 9, 1996;
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10. Luft FC, Miller JZ, Grim CE. Salt sensitivity and resistance of blood pressure, age and race as factors in physiological responses. Hypertension. 1991;17(suppl I):I-102-I-108.
11. Bakris GL, Weir MR. Salt intake and reductions in arterial pressure and proteinuria: is there a direct link? Am J Hypertens. 1996;9:200S-206S.[Medline] [Order article via Infotrieve]
12. Bakris GL. Microalbuminuria: prognostic implications. Curr Opin Nephrol Hypertens.. 1996;5:219-223.[Medline] [Order article via Infotrieve]
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Bakris GL, Smith AC. Effects of sodium intake on albumin excretion in patients with diabetic nephropathy treated with long-acting calcium antagonists. Ann Intern Med.. 1996;125:201-203.
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35. Bakris GL. Combination therapy for hypertension and renal disease in diabetes. In: Mogensen CE, ed. The Kidney and Hypertension in Diabetes Mellitus. 3rd ed. Boston, Mass: Kluwer Academic Press; 1997:561-568.
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G. L. Bakris A Practical Approach to Achieving Recommended Blood Pressure Goals in Diabetic Patients Arch Intern Med, December 10, 2001; 161(22): 2661 - 2667. [Abstract] [Full Text] [PDF]
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L. Y. Agodoa, L. Appel, G. L. Bakris, G. Beck, J. Bourgoignie, J. P. Briggs, J. Charleston, D. Cheek, W. Cleveland, J. G. Douglas, et al. Effect of Ramipril vs Amlodipine on Renal Outcomes in Hypertensive Nephrosclerosis: A Randomized Controlled Trial JAMA, June 6, 2001; 285(21): 2719 - 2728. [Abstract] [Full Text] [PDF]
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M. Hemmelder, D. de Zeeuw, and P. de Jong Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease Nephrol. Dial. Transplant., January 1, 1999; 14(1): 98 - 104. [Abstract] [PDF]
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