Background Renal function declines progressively in patientswho have diabetic nephropathy, and the decline may be slowedby antihypertensive drugs. The purpose of this study was todetermine whether captopril has kidney-protecting propertiesindependent of its effect on blood pressure in diabetic nephropathy.
Methods We performed a randomized, controlled trial comparingcaptopril with placebo in patients with insulin-dependent diabetesmellitus in whom urinary protein excretion was 500 mg per dayand the serum creatinine concentration was 2.5 mg per deciliter(221 µmol per liter). Blood-pressure goals were definedto achieve control during a median follow-up of three years.The primary end point was a doubling of the base-line serumcreatinine concentration.
Results Two hundred seven patients received captopril, and 202placebo. Serum creatinine concentrations doubled in 25 patientsin the captopril group, as compared with 43 patients in theplacebo group (P =0.007). The associated reductions in riskof a doubling of the serum creatinine concentration were 48percent in the captopril group as a whole, 76 percent in thesubgroup with a base-line serum creatinine concentration of2.0 mg per deciliter (177 µmol per liter), 55 percentin the subgroup with a concentration of 1.5 mg per deciliter(133 µmol per liter), and 17 percent in the subgroup witha concentration of 1.0 mg per deciliter (88.4 µmol perliter). The mean (±SD) rate of decline in creatinineclearance was 11 ±21 percent per year in the captoprilgroup and 17 ±20 percent per year in the placebo group(P = 0.03). Among the patients whose base-line serum creatinineconcentration was 1.5 mg per deciliter, creatinine clearancedeclined at a rate of 23 ±25 percent per year in thecaptopril group and at a rate of 37 ±25 percent per yearin the placebo group (P = 0.01). Captopril treatment was associatedwith a 50 percent reduction in the risk of the combined endpoints of death, dialysis, and transplantation that was independentof the small disparity in blood pressure between the groups.
Conclusions Captopril protects against deterioration in renalfunction in insulin-dependent diabetic nephropathy and is significantlymore effective than blood-pressure control alone.
Patients with diabetic nephropathy have a progressive declinein glomerular function, and the treatment of hypertension inthese patients slows the rate of loss of renal function1,2,3,4,5.Angiotensin-converting-enzyme inhibitors have been used in severaltrials6,7,8. Findings in studies of animals with diabetes mellitussuggested that angiotensin-converting-enzyme inhibitors couldreduce glomerular damage by one or more mechanisms independentof their antihypertensive effects9,10,11. We report the resultsof a trial designed to determine whether the angiotensin-converting-enzymeinhibitor captopril is more effective in slowing the progressionof diabetic nephropathy than agents that act primarily by reducingblood pressure.
Methods
The study was a prospective, double-blind, randomized clinicaltrial performed in 30 clinical centers. The study protocol wasapproved by the institutional review board at each center, andall patients gave written informed consent.
Entry and Exclusion Criteria
Patients 18 to 49 years of age were eligible if they had hadinsulin-dependent diabetes mellitus for at least 7 years, withan onset before the age of 30 years, and had diabetic retinopathy,urinary protein excretion of 500 mg per 24 hours, and a serumcreatinine concentration of 2.5 mg per deciliter (221 µmolper liter). All patients satisfying these criteria during asingle examination were eligible for the study, regardless ofprevious blood-pressure status or a previous need for antihypertensivemedication. Patients who were receiving angiotensin-converting-enzymeinhibitors or calcium antagonists were eligible provided theirblood pressure could be maintained within the blood-pressuregoals required by the trial (see below) without these drugs.Therapy with an angiotensin-converting-enzyme inhibitor, otherthan the coded medication, and calcium antagonists was not allowedduring the trial. Patients were excluded for the following reasons:pregnancy, a dietary evaluation that indicated marked departurefrom standard dietary recommendations, white-cell count below2500 per cubic millimeter, congestive heart failure (New YorkHeart Association class III or worse), and a serum potassiumconcentration of 6 mmol per liter12.
Randomization and Treatment Plan
Eligible patients were stratified according to center and randomlyassigned to a group according to a standard urn design13. Thoseassigned to the captopril group received a dose of 25 mg threetimes daily, and those assigned to the control group receivedidentical-appearing placebo tablets three times daily. The specificblood-pressure goals were a diastolic blood pressure below 90mm Hg and a systolic blood pressure below 140 mm Hg or, if thebase-line systolic blood pressure exceeded 150 mm Hg, a subsequentdecrease of at least 10 mm Hg and a maximal reading of 160 mmHg. Blood pressures were measured in seated patients at restby the nurse coordinator at each center according to a standardtechnique. The average of two consecutive readings taken 30seconds apart was recorded as the blood pressure for that visit.
Each patient underwent a dietary evaluation, and recommendationswere made according to American Diabetes Association guidelines.The recommended dietary protein intake was 1 g per kilogramof body weight per day. The patient's diabetes was managed inaccord with the patient's historical treatment schedule. Theextent to which diabetes was controlled was monitored by measurementsof glycosylated hemoglobin. After randomization, the patientswere seen at two weeks, at one month, and every three monthsthereafter until they died, required dialysis, or underwentrenal transplantation. Compliance in taking the coded medicationswas determined by the nurse coordinators with the pill-countmethod. The patients' vital status, need for dialysis, and needfor transplantation were monitored until September 30, 1992.Glycosylated hemoglobin, serum creatinine, and 24-hour urinaryexcretion of creatinine, protein, and urea were measured bythe central laboratory at each visit according to standard methods.
End Points
The primary study end point was a doubling of the base-lineserum creatinine concentration to at least 2.0 mg per deciliter(177 µmol per liter), confirmed by the central laboratory.Secondary analyses included the length of time to the combinedend points of death, dialysis, and transplantation and changesin renal function, assessed in terms of the serum creatinineconcentration, 24-hour creatinine clearance, and urinary proteinexcretion. Other stopping points were defined for patients whoseblood pressure could not be maintained within the limits dictatedby the study and those with persistent hyperkalemia (potassiumlevel exceeding 6 mmol per liter), adverse drug effects, pregnancy,or intercurrent illness that precluded their continued enrollmentin the study12.
Statistical Analysis
The results were analyzed with the Statistical Analysis System14and StatXact15 software. Dichotomous and polychotomous base-linecharacteristics of the groups were compared with Fisher's exacttest16; continuous base-line characteristics were compared withWilcoxon rank-sum tests17. The mean values of measurements atall follow-up visits were compared with t-tests18. For the analysisof the length of time to event end points, product-limit life-tabledistributions were compared with the log-rank test statistic19.Proportional-hazards regression analysis was used to determineinteractions between the treatment groups and the base-lineand time-dependent covariates, as well as to estimate the percentreduction in the number of events within subgroups and fromone subgroup to another19,20. Renal-function measurements overtime were compared with a two-stage, simple, linear random-effectmodel,21 with variables estimated by restricted maximum likelihoodand the multivariate Wilcoxon rank-sum test22. The analysesincluded all patients who underwent randomization, with allpatients retained in their assigned group regardless of theiradherence to the treatment regimen. To protect against increasingthe rate of a type I error due to interim analyses, the Lan-DeMetsgroup sequential procedure23 set the significance level forthe primary outcome in the final analysis at 0.044. For otheroutcomes, a P value of less than 0.05 was considered to indicatestatistical significance. All statistical tests were two-sided.
Quality Assurance and Study Monitoring
A clinical review committee, masked to patient assignment, classifiedall study outcomes. An external advisory board, appointed bythe National Institute of Diabetes and Digestive and KidneyDiseases, reviewed all medical, ethical, and statistical considerations.
Results
Four hundred nine patients entered the study at 30 centers betweenDecember 1987 and October 1990. Two hundred seven were assignedto the captopril group, and 202 to the placebo group. The demographic,clinical, and laboratory characteristics of the two groups weresimilar, except that urinary protein excretion was higher inthe placebo group than in the captopril group (P = 0.02) (Table 1).A total of 301 patients completed their final scheduledvisit (median follow-up, 3 years; range, 1.8 to 4.8). Of theremainder, 50 patients began dialysis, underwent renal transplantation,or died before their final scheduled visit (median follow-up,1.7 years; maximum, 4.5). The remaining 58 patients (31 in theplacebo group and 27 in the captopril group) discontinued theirquarterly scheduled visits (median follow-up, 0.7 year; maximum,3.3), but we were able to determine whether all but 4 of thesepatients (2 in each group) had died, begun dialysis treatment,or undergone transplantation as of September 30, 1992.
Table 1. Base-Line Characteristics of the Patients with Diabetic Nephropathy in the Captopril and Placebo Groups.
Clinical Management
Only four patients (three in the placebo group and one in thecaptopril group) were removed from the study because of an inabilityto meet the predefined blood-pressure goals. The median systolicblood pressure at base line was 135 mm Hg in the captopril groupand 138 mm Hg in the placebo group. The median values obtainedat quarterly intervals during the study ranged from 128 to 134mm Hg in the captopril group and from 129 to 136 mm Hg in theplacebo group; at most times the difference between groups wasno more than 2 mm Hg. The median diastolic blood pressure atbase line was 86 mm Hg in both groups. The median diastolicvalues during the study ranged from 77 to 82 mm Hg in the captoprilgroup and from 80 to 84 mm Hg in the placebo group; the differencebetween groups was consistently less than 4 mm Hg, with thecaptopril group having the lower value at most times. The mean(±SD) arterial pressure, averaged over all follow-upvisits, was 96 ±8 mm Hg in the captopril group and 100±8 mm Hg in the placebo group.
The decrease in base-line mean arterial pressure in the 155patients in the captopril group who had preexisting hypertensionaveraged 7 ±11 mm Hg, and it averaged 5 ±11 mmHg in the 153 patients with preexisting hypertension in theplacebo group. This difference in blood-pressure control wasnot significant (P = 0.16). Among patients who were not hypertensivebefore entry into the trial (52 in the captopril group and 49in the placebo group), the difference in the control of meanarterial pressure was more pronounced, averaging 5 mm Hg throughthe follow-up period (P<0.001).
At base line, 59 percent of the patients in the placebo groupand 60 percent of those in the captopril group were receivingantihypertensive medication (Table 1). Sixty-four percent ofthe hypertensive patients in the placebo group were receivingdiuretic agents at base line, and this value ranged from 79to 93 percent during the study. By comparison, 62 percent ofthe hypertensive patients in the captopril group were receivingdiuretic agents at base line, and this value ranged from 74to 87 percent during the study. At no quarterly interval wasthe difference between groups statistically significant exceptat month 24 (P = 0.033). Fifteen percent of the hypertensivepatients in the placebo group were receiving beta-adrenergicantagonists at base line, and 34 to 46 percent were receivingthem during the study, whereas 11 percent of the hypertensivepatients in the captopril group were receiving these drugs atbase line, and 15 to 53 percent were receiving them during thestudy. The difference between groups was significant only duringthe first 12 months of the study. There were no significantdifferences in the use of other agents, including labetalol,clonidine, methyldopa, prazosin, hydralazine, guanabenz, terazosin,and minoxidil.
The mean changes from base line in the glycosylated hemoglobinconcentration (an increase of 0.5 percent) and 24-hour urinaryurea nitrogen excretion (a decrease of 0.9 g [32 mmol] per day)were not different between the treatment groups.
Changes in Serum Creatinine Concentrations
Sixty-eight patients had a doubling of serum creatinine concentrations:25 in the captopril group and 43 in the placebo group (P = 0.007)(Table 2 and Figure 1A). They included four patients in thecaptopril group and five patients in the placebo group who haddiscontinued their visits (and the study drug). The associatedreduction in risk in the captopril group was 48 percent (95percent confidence interval, 16 to 69 percent) (Table 3). Theeffect of treatment on the primary end point was assessed insubgroups defined by the base-line covariates summarized inTable 1. The beneficial effect of captopril was not alteredby any of these covariates except for the base-line creatinineconcentration. A higher base-line serum creatinine value wassignificantly associated (P = 0.02) with a decreased risk ofa twofold increase in serum creatinine in the captopril group(Table 3). Figure 2A shows the cumulative incidence curves forthe primary end point in the subgroup of 102 patients with abase-line serum creatinine concentration of 1.5 mg per deciliter(133 µmol per liter) (P<0.001; risk reduction, 68 percent;95 percent confidence interval, 39 to 83 percent) and in thesubgroup of 307 patients with a base-line serum creatinine concentrationbelow 1.5 mg per deciliter (P = 0.31; risk reduction, 33 percent;95 percent confidence interval, -44 to 69 percent). The differencein the risk of a doubling of the serum creatinine concentrationremained after adjustments for differences in mean arterialpressure20 (Table 3).
Figure 1. Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups.
Panel A shows the cumulative percentage of patients with the primary end point: a doubling of the base-line serum creatinine concentration to at least 2.0 mg per deciliter. Panel B shows the cumulative percentage of patients who died or required dialysis or renal transplantation. The numbers at the bottom of each panel are the numbers of patients in each group at risk for the event at base line and after each six-month period.
Table 3. Percent Reduction in the Overall Risk of Progression of Diabetic Nephropathy with Captopril Treatment and According to the Base-Line Serum Creatinine Concentration.
Figure 2. Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups, According to the Base-Line Serum Creatinine Concentration.
A total of 102 patients had a base-line serum creatinine concentration of 1.5 mg per deciliter, and 307 had a base-line serum creatinine concentration below 1.5 mg per deciliter. Panel A shows the cumulative percentage of patients in each subgroup who had a doubling of the serum creatinine concentration to at least 2.0 mg per deciliter. Panel B shows the cumulative percentage of patients in each subgroup who died or required dialysis or renal transplantation. The numbers at the bottom of the figure are the numbers of patients in each subgroup at risk for the event at base line and after each six-month period.
Death, Dialysis, and Transplantation
As of September 30, 1992, 65 patients had died or required dialysisor renal transplantation: 23 in the captopril group and 42 inthe placebo group (P = 0.006) (Table 2 and Figure 1B). Of these65 patients, 7 in the captopril group and 8 in the placebo groupreached one or more of these three end points after they discontinuedtheir scheduled visits. Treatment with captopril was associatedwith a 50 percent reduction in the risk of the combined endpoints of death, dialysis, and transplantation (95 percent confidenceinterval, 18 to 70 percent) (Table 3). The beneficial effectof captopril on the three end points was consistent over therange of measurements of each covariate (Table 1) except thebase-line serum creatinine concentration (P = 0.02). The reductionin the combined risk increased as the base-line serum creatinineconcentration increased (Table 3). Figure 2B shows the cumulativeincidence curves for the combined end points in the subgroupof 102 patients with a base-line serum creatinine concentrationof 1.5 mg per deciliter (P = 0.002; risk reduction, 61 percent;95 percent confidence interval, 26 to 80 percent) and in thesubgroup of 307 patients with a base-line serum creatinine concentrationbelow 1.5 mg per deciliter (P = 0.14; risk reduction, 46 percent;95 percent confidence interval, 22 to 76 percent).
Sequential Measurements of Renal Function
Among the 405 patients who had 2 or more determinations of serumcreatinine (median, 13 determinations; maximum, 27) during anaverage follow-up of 2.7 years per patient (maximum, 4.8), themean rate of increase in serum creatinine in the patients inthe captopril group was 0.2 ±0.8 mg per deciliter peryear (22 ±67 µmol per liter per year), which wassignificantly lower (P = 0.004) than that in the patients inthe placebo group, in whom the values increased at a rate of0.5 ±0.8 mg per deciliter per year (42 ±67 µmolper liter per year). Among the patients with base-line serumcreatinine concentrations of less than 1.5 mg per deciliter,the increase was 0.1 ±0.4 mg per deciliter per year (11±37 µmol per liter per year) in the captopril groupand 0.2 ±0.4 mg per deciliter per year (17 ±37µmol per liter per year) in the placebo group (P = 0.15).Among the patients with base-line serum creatinine concentrationsof 1.5 mg per deciliter, the increase in serum creatinine inthe captopril group was 0.6 ±1.2 mg per deciliter peryear (72 ±102 µmol per liter per year), as comparedwith 1.4 ±1.2 mg per deciliter per year (122 ±102µmol per liter per year) in the placebo group (P = 0.002).For the sequential measurements of creatinine clearance, a logarithmictransformation was used to improve the distributional assumptionsof the simple, linear random-effects model. The rate of declinein 24-hour creatinine clearance in the 402 patients with 2 ormore determinations (maximum, 21) was 11 ±21 percentper year in the captopril group and 17 ±20 percent peryear in the placebo group (P = 0.03). The rate of decline wasmore pronounced among patients who had a base-line serum creatinineconcentration of 1.5 mg per deciliter: 23 ±25 percentper year in the captopril group and 37 ±25 percent peryear in the placebo group (P = 0.01).
The median urinary protein excretion of the patients in thecaptopril group had decreased 0.3 g per day by the first quarterlyvisit, and it remained lower in this group than in the placebogroup throughout most of the remainder of the trial. An aggregateanalysis over the four years of the study revealed significantlyless proteinuria in the captopril group (P = 0.001).
Compliance with Treatment and Adverse Events
The number of patients taking their study drug at the one-yearvisit was similar in the captopril (170 of 185 patients, 92percent) and placebo (160 of 169 patients, 95 percent) groups.At the last scheduled visit, 128 of the 153 patients remainingin the captopril group (84 percent) who had not reached theprimary end point were still taking the study drug, as comparedwith 110 of the 121 patients remaining in the placebo group(91 percent) (P = 0.10).
Captopril or placebo was discontinued before the serum creatinineconcentration doubled or death occurred in 68 patients for reasonssummarized in Table 2. The most frequent intercurrent illnessesor conditions that prompted discontinuation of treatment weremyocardial infarction (seven patients), congestive heart failure(three patients), and stroke (three patients). Eleven otherpatients were thought by their physicians to require therapywith an angiotensin-converting-enzyme inhibitor or a calciumantagonist. A physician discontinued the study medication forother reasons in 7 patients, and 12 patients stopped takingthe study medication on their own initiative.
Discussion
We found that captopril significantly retarded the rate of lossof renal function in this group of patients with diabetic nephropathy.In the captopril group, the risk of a doubling of the serumcreatinine concentration was reduced by almost one half, aswas the combined risk of death, dialysis, or transplantation.The study was designed to determine whether captopril was associatedwith an effect that was independent of its role as an antihypertensiveagent. The magnitude of the blood-pressure reduction in thetwo groups was comparable, the median systolic blood pressurebeing very similar in the groups and the disparity between groupsin median diastolic blood pressure tending to be no more than2 to 3 mm Hg throughout the study, although the patients treatedwith captopril did have a marginally lower average mean arterialpressure. This difference was not significant among the patientswith preexisting hypertension, and 85 percent of the patientswho had a twofold increase in serum creatinine were in thissubgroup. The inclusion of mean arterial pressure during thestudy as a time-dependent covariate did not alter the estimatedreduction in the risk of a doubling of the serum creatinineconcentration in the captopril group, nor did it affect thedecreased combined risk of death, dialysis, or transplantationin the captopril group. The beneficial effect of captopril wastherefore not explained by the small differences in the levelof blood-pressure control between the two groups.
Our results support the proposal that captopril slows the progressionof diabetic nephropathy by a mechanism that is independent ofits antihypertensive properties. It has been proposed that angiotensin-converting-enzymeinhibition can beneficially influence the altered glomerularhemodynamics in patients with diabetes. Glomerular efferentarteriolar tone is increased in diabetic animals, and as a resultthere is an increase in transcapillary hydraulic pressure9,10.These alterations may decrease the functional integrity of theglomerular capillary wall. Removal of the tonic constrictoreffect of angiotensin II on efferent arterioles would be expectedto lower glomerular intracapillary pressure while preservingrenal plasma flow. In rats with diabetes, the long-term administrationof an angiotensin-converting-enzyme inhibitor diminishes thefunctional and morphologic evidence of glomerular injury anddecreases glomerular transcapillary pressure11; other antihypertensiveagents do not have these effects11. There are other possibleexplanations for the beneficial intrarenal actions of angiotensin-converting-enzymeinhibitors. They may interfere with trophic properties of angiotensinII to promote cellular and glomerular hypertrophy24,25,26 ordiminish the accumulation of mesangial matrix27. Either of theseprocesses could be an important initial step leading to glomerularscarring.
The results achieved in the placebo group in this study serveas a measure of the expected clinical course of patients withdiabetic nephropathy who have their blood pressure maintainedat normal levels. We were unable to confirm previous reportssuggesting that the progressive loss of renal function couldbe markedly diminished by blood-pressure control with agentsother than angiotensin-converting-enzyme inhibitors1,3,4,6,8.The patients who received only antihypertensive treatment lostrenal function at a rate substantially higher than would bepredicted from the existing literature.
Other studies have supported the notion that therapy with anangiotensin-converting-enzyme inhibitor preserves renal function.Bjorck et al. reported a reduction in the pretreatment rateof decline of renal function with the use of captopril7. Insmall, short-term studies, patients with diabetic nephropathy,both those with hypertension8 and those without hypertension,28had a slower rate of decline of renal function when treatedwith captopril than untreated patients. Others have focusedattention on the short-term antiproteinuric effect of angiotensin-converting-enzymeinhibitors at various stages of diabetes29,30. Whether a specifickidney-protecting effect was operative in these trials is difficultto judge, since the mean arterial pressure in the untreatedpatients was higher than in the captopril-treated patients8,28.
Angiotensin-converting-enzyme inhibitors are known to decreaseurinary protein excretion in patients with diabetes and otherglomerulopathies31,32,33. In our study, the administration ofcaptopril led to decreased proteinuria. This decrease couldbe explained by a beneficial effect of the drug on glomerularhemodynamics and glomerular pathology. It has been suggestedthat the magnitude of proteinuria itself may be associated withthe rate of progression of kidney damage34. We cannot rule outthe possibility that the amelioration of the proteinuria mayhave been pathogenetically relevant in the captopril-treatedpatients in this study34.
Our results indicate that captopril therapy is kidney-protectingin patients with insulin-dependent diabetes who have establishednephropathy. The beneficial effects of this therapy were accompaniedby relatively few serious side effects specifically attributableto the drug. We propose that this therapy be used in normotensiveand hypertensive patients with diabetes and clinically evidentnephropathy.
Supported by grants from the Public Health Service (5 R01-DK39908, 5 R01-DK 39826, MO1-RR00030, MO1-RR00034, MO1-RR00036,MO1-RR00051, MO1-RR00058, MO1-RR00059, and MO1-RR00425) andby the Bristol-Myers Squibb Pharmaceutical Research Institute(Princeton, N.J.).
Source Information
From the Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago (E.J.L., R.D.R.); the Department of Medicine, University of Iowa, Iowa City (L.G.H.); and the Biostatistics Center, George Washington University, Washington, D.C. (R.P.B.). Members of the Collaborative Study Group are listed in the Appendix.
Address reprint requests to Dr. Lewis at the Section of Nephrology, 1653 W. Congress Pky., Chicago, IL 60612.
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Appendix
The following institutions and persons participated in the CollaborativeStudy Group trial: Clinical Coordinating Center, Rush-Presbyterian-St.Luke's Medical Center, Chicago -- E.J. Lewis, R. Rohde, andM. Nemcek; University of Iowa, Iowa City -- L.G. Hunsicker;Biostatistical Coordinating Center, George Washington University,Washington, D.C. -- R.P. Bain, J. Lachin, S.W. Greenhouse, D.A.Verme, T.R. Turlington, and P.K. Burrows; Collaborating Clinicsand Investigators: Case Western Reserve University, Cleveland-- J. Wish and J. Sheehan; Cleveland Clinic, Cleveland -- M.Pohl; University of Colorado, Denver -- T. Berl; Henry FordHospital, Detroit -- G. Santiago; Medical College of Wisconsin,Milwaukee -- J. Lemann, Jr., S. Blumenthal, and B.A. Bresnahan;Ohio State University, Columbus -- L. Hebert and N.S. Nahman,Jr.; University of Pennsylvania, Philadelphia -- S. Goldfarband S. Kobrin; Rush-Presbyterian-St. Luke's Medical Center,Chicago -- R. Rodby; University of Illinois, Chicago -- S. Lietzand D. Valaitis; New England Medical Center, Boston -- A. Leveyand M. McLaughlin; Joslin Diabetes Center, Boston -- M. Williams;Washington University, St. Louis -- J. McGill; Affiliated Hospitalsof Canton, Canton, Ohio -- F. Whittier; University of Toronto,Toronto -- D. Cattran; Loyola Medical Center, Maywood, Ill.-- J. Hano; Indiana University, Indianapolis -- D. Maxwell;Brookdale Hospital Medical Center, Brooklyn, N.Y. -- J. Porushand S. Spitalewitz; Nyack Hospital, Nyack, N.Y. -- K. Shapiro;Harbor-UCLA Medical Center, Torrance, Calif. -- S. Adler; Syracuse,N.Y. -- N. Tolchin; Lovelace Institutes, Albuquerque, N.M. -- W. Hoy and R. Bernstein; Duke University, Durham, N.C. --L. Svetkey; Atlanta Nephrology Referral Center, Decatur, Ga.-- Z. Sharon and B. Rosenbaum; Endocrine Associates of SouthJersey, Moorestown, N.J. -- J.R. Anolik; St. Paul's Hospital,Vancouver, B.C. -- H. Tidesley; Memorial University, St. Johns,Newf. -- C. Joyce; and Vanderbilt University, Nashville -- J.Breyer.
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Hadjadj, S., Fumeron, F., Roussel, R., Saulnier, P.-J., Gallois, Y., Ankotche, A., Travert, F., Khalil, C. A., Miot, A., Alhenc-Gelas, F., Lievre, M., Marre, M., on behalf of the DIABHYCAR, DIAB2NEPHROGENE, and S,
(2008). Prognostic Value of the Insertion/Deletion Polymorphism of the ACE Gene in Type 2 Diabetic Subjects: Results from the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies . Diabetes Care
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(2008). Aldosterone, but not angiotensin II, increases profibrotic factors in kidney of adrenalectomized stroke-prone spontaneously hypertensive rats. Am. J. Physiol. Endocrinol. Metab.
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Chapman, A. B.
(2008). Approaches to Testing New Treatments in Autosomal Dominant Polycystic Kidney Disease: Insights from the CRISP and HALT-PKD Studies. CJASN
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Feldman, D. L., Jin, L., Xuan, H., Contrepas, A., Zhou, Y., Webb, R. L., Mueller, D. N., Feldt, S., Cumin, F., Maniara, W., Persohn, E., Schuetz, H., Jan Danser, A.H., Nguyen, G.
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Mima, A., Arai, H., Matsubara, T., Abe, H., Nagai, K., Tamura, Y., Torikoshi, K., Araki, M., Kanamori, H., Takahashi, T., Tominaga, T., Matsuura, M., Iehara, N., Fukatsu, A., Kita, T., Doi, T.
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Peng, F., Wu, D., Gao, B., Ingram, A. J., Zhang, B., Chorneyko, K., McKenzie, R., Krepinsky, J. C.
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Arfa, I., Abid, A., Nouira, S., Elloumi-Zghal, H., Malouche, D., Mannai, I., Zorgati, M. M., Ben Alaya, N., Rebai, A., Zouari, B., Ben Ammar, S., Ben Rayana, M. C., Hmida, S., Blousa-Chabchoub, S., Abdelhak, S.
(2008). Lack of association between the angiotensin-converting enzyme gene (I/D) polymorphism and diabetic nephropathy in Tunisian type 2 diabetic patients. Journal of Renin-Angiotensin-Aldosterone System
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Rosendorff, C., Black, H. R., Cannon, C. P., Gersh, B. J., Gore, J., Izzo, J. L. Jr, Kaplan, N. M., O'Connor, C. M., O'Gara, P. T., Oparil, S.
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McWilliams, J. M., Meara, E., Zaslavsky, A. M., Ayanian, J. Z.
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Tuttle, K. R., McGill, J. B., Haney, D. J., Lin, T. E., Anderson, P. W., for the PKC-DRS, PKC-DMES, and PKC-DRS 2 Study Gro,
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(2007). 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J
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(2007). Survival among Patients with Kidney Failure in Jalisco, Mexico. J. Am. Soc. Nephrol.
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Rosendorff, C., Black, H. R., Cannon, C. P., Gersh, B. J., Gore, J., Izzo, J. L. Jr, Kaplan, N. M., O'Connor, C. M., O'Gara, P. T., Oparil, S.
(2007). Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation
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Fischer, M. A., Choudhry, N. K., Winkelmayer, W. C.
(2007). Impact Of Medicaid Prior Authorization On Angiotensin-Receptor Blockers: Can Policy Promote Rational Prescribing?. Health Aff (Millwood)
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Ficociello, L. H., Perkins, B. A., Silva, K. H., Finkelstein, D. M., Ignatowska-Switalska, H., Gaciong, Z., Cupples, L. A., Aschengrau, A., Warram, J. H., Krolewski, A. S.
(2007). Determinants of Progression from Microalbuminuria to Proteinuria in Patients Who Have Type 1 Diabetes and Are Treated with Angiotensin-Converting Enzyme Inhibitors. CJASN
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Hadjadj, S., Tarnow, L., Forsblom, C., Kazeem, G., Marre, M., Groop, P.-H., Parving, H.-H., Cambien, F., Tregouet, D. A., Gut, I. G., Theva, A., Gauguier, D., Farrall, M., Cox, R., Matsuda, F., Lathrop, M., FinnDiane Study Group, , Hager-Vionnet, N., for the EURAGEDIC (European Rational Approach for,
(2007). Association between Angiotensin-Converting Enzyme Gene Polymorphisms and Diabetic Nephropathy: Case-Control, Haplotype, and Family-Based Study in Three European Populations. J. Am. Soc. Nephrol.
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(2007). Effect of combination therapy with enalapril and the TGF-beta antagonist 1D11 in unilateral ureteral obstruction. Am. J. Physiol. Renal Physiol.
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(2007). Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?. Endocrinology
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(2007). Kidney Failure Stabilizes after a Two-Decade Increase: Impact on Global (Renal and Cardiovascular) Health. CJASN
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American Diabetes Association,
(2007). Standards of Medical Care in Diabetes--2007. Diabetes Care
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291: H2021-H2025
[Abstract][Full Text]
van de Wal, R. M.A., Gansevoort, R. T., van der Harst, P., Boomsma, F., Thijs Plokker, H.W., van Veldhuisen, D. J., de Jong, P. E., van Gilst, W. H., Voors, A. A.
(2006). Predictors of Angiotensin-Converting Enzyme Inhibitor-Induced Reduction of Urinary Albumin Excretion in Nondiabetic Patients. Hypertension
48: 870-876
[Abstract][Full Text]
Sarkar, P., Nicholson, G., Hall, G.
(2006). Brief review: Angiotensin converting enzyme inhibitors and angioedema: anesthetic implications: [Revue sommaire sur les implications anesthesiques de l'oedeme de Quincke et des inhibiteurs de l'enzyme de conversion de l'angiotensine].. Canadian J. Anesthesia
53: 994-1003
[Abstract][Full Text]
Soma, J., Sato, K., Saito, H., Tsuchiya, Y.
(2006). Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant
21: 2795-2799
[Abstract][Full Text]
Winkelmayer, W. C., Zhang, Z., Shahinfar, S., Cooper, M. E., Avorn, J., Brenner, B. M.
(2006). Efficacy and Safety of Angiotensin II Receptor Blockade in Elderly Patients With Diabetes. Diabetes Care
29: 2210-2217
[Abstract][Full Text]
A correction has been published: N Engl J Med 1994;330(2):152.
500 mg per day and the serum creatinine concentration was 
2.5 mg per deciliter (221 µmol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. 
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