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Design of clinical trials in proteinuria and progressive renal disease
1 Diab Comp 1992; 6:4
microalbuminuria more often have left ventricular hypertrophy and elevated levels of serum triglycerides and insulin than do hypertensives without microalbuminuria. In mixed groups of normotensive and hypertensive nondiabetic subjects, microalbuminuria has been associated with increased prevalence of coronary heart disease and peripheral vascular disease and may predict early mortality. In a prospective population-based study in Gothenburg of 49-year-old men (n = 120; hypertension, 69; borderline hypertension, 30; normotension, 21) the urinary albumin excretion, serum cholesterol, and smoking habits were studied at baseline. The hypertensive patients were treated with a S-blocker alone or in combination with a diuretic or hydralazine. After 10 years, 19 of the men had developed cardiovascular disease. They had significantly higher albumin excretion at baseline (median value, 16.4; range, 4-731 mgl 24 h) than those who did not develop cardiovascular disease (9.7; O-308 mg/24 h). The former group had higher systolic blood pressure levels and were more often smokers than the latter group. The albumin excretion was significantly correlated to the baseline systolic, diastolic, and mean arterial blood pressure but not to smoking or serum cholesterol. The baseline urinary albumin excretion was also significantly correlated to the development of cardiovascular disease. This relationship was independent of the blood pressure level. The albumin excretion was a strong predictor of cardiovascular disease and a predictor superior to cholesterol and blood pressure. Conclusion: Microalbuminuria may be considered an early marker of the severity of hypertension and seems to be a strong predictor of the development of cardiovascular disease.
LONG-TERM PROGNOSIS FOR NORMO- AND MICROALBUMINURIC TYPE I (INSULINDEPENDENT) DIABETIC PATIENTS M. Mau Pedersen, C. K. Christensen, and C. E. Mogensen Medical Department M (Diabetes 6 Endocrinology), Aarhus Kommunehospifal, DK-8000 Aarhus C, Denmark Objective: To study the prognostic significance of microalbuminuria in type I diabetes. Design: A long-term [X3 ? 2 (SD) years], second, followup study was performed; 44 male patients with previous measurement of urinary albumin excretion rate (UAE) (radioimmunoassay, >3 timed collections) were identified for reinvestigation. Retrospectively, 30 patients were considered initially normoalbuminuric (UAE < 15 Fg/min) and 14 initially microalbuminuric (15 < UAE < 150 &min) (diabetes duration,
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12 ? 3 versus 13 ? 3 years, NS; age at diagnosis, 12 + 5 versus 13 + 4 years, NS). At followup UAE (3 overnight collections)/proteinuria, blood pressure, s-creatinine, kidney function (n = 16), and HbAi, were measured. Setting: Outpatient clinic, University Hospitals (referring center). Patients: Followup data were obtained in 27 of the initially normoalbuminuric patients and in all initially microalbuminuric patients. Of the remaining three patients, two did not want to participate in reinvestigation and one has not been investigated yet (all three normoalbuminuric at 10 years followup). Main Outcome Measures: UAE or proteinuria, need for dialysis, and death were considered main outcome measures. In addition glomerular filtration rate (GFR) was compared to initial GFR values when possible. Results: The normo- and microalbuminuric cohorts differed with respect to all-cause mortality (2 versus 5 death, p = 0.03, Fisher‘s exact test), development of renal failure (0 versus 4, p = 0.007) and of overt diabetic nephropathy (2 versus 10, p = 0.00005). Among initially normoalbuminuric patients, four showed microalbuminuria at followup, whereas 20 remained normoalbuminuric after 31 -+ 5 years of diabetes. Two initially microalbuminuric patients stayed such during antihypertensive therapy, and one spontaneously became normoalbuminuric. Remeasuring of glomerular filtration rate in nine persistently normoalbuminuric patients suggested a modest (age-dependent?) decline (132 2 5 versus 125 ? 12 ml/mm/l.73 m2 owup period 20 + 2 years, age 45 & 5 (p = O.lO), f o11 years). Within the initially normoaibuminuric group HbA1, at followup was 9.2% ? 1.5% in persistently normoalbuminuric patients and 7.0% ? 1.1% in patients showing progression (p = 0.006). Conclusion: The occurrence of microalbuminuria in type I diabetes is a strong risk marker for overt diabetic nephropathy, renal failure, and death. Conversely normoalbuminuria indicates a good long-term prognosis with well-preserved kidney function.
DESIGN OF CLINICAL TRIALS IN PROTEINURIA AND PROGRESSIVE RENAL DISEASE H.-H. Pawing Steno Diabetes Center, Copenhagen, Niels Sfeensensvej 2, DK-2820 Genfoffe, Denmark Objective: Critical analysis of clinical trials of medical treatments in chronic progressive nephropathy, e.g., diabetes.
270
ABSTRACTS
Design: Self-controlled studies, crossover studies, and parallel studies; trials can be blinded versus open, randomized versus nonrandomized, parallel versus nonparallel, unicenter versus multicenter. Patients: Sufficient information on patients sources should always be presented, e.g., insulin-dependent diabetes mellitus versus non-insulin-dependent diabetes mellitus, hypertension versus normotension, cause of albuminuria. Apply homogenous well-characterized groups of subjects. Methods: Glomerular filtration rate (GFR), proteinuria, systemic blood pressure, and morphologic lesions, etc., can be used to assess progression of nephropathy. Main Outcome Measures: Surrogate end points: e.g., reduction in proteinuria, development of hypertension, and morphological lesions. Principal end points: e.g., rate of decline in GFR, dialysis/renal transplant, and death due to end-stage renal failure. Conclusion: The ideal study: double-blind randomized parallel trial of two treated groups, or a treated group with a separate but concurrent control group, conducted with accurate and precise methods.
FINAL RESULTS OF THE PROSPECTIVE MULTICENTER STUDY ON ANTIHYPERTENSIVE THERAPY IN CHRONIC RENAL FAILURE A. Fournier, P. Lundais, T. Hannedouche, F. Mignon, 1. Chanard, D. Durand, M. Godin, B. Goldfarb, and J. P. Griinfeld Department de Nephrologie, Hdpital Necker, Paris, France In a 3-year controlled prospective trial, 100 hypertensive (H) patients (pts) with chronic renal failure (CRF) were included to compare the effects of enalapril (E) to conventional (C) therapy on progression to endstage renal failure (ESRF). The protocol, preliminary results, and side effects were presented at the EDTAERA Congress in Vienna, 1990. At inclusion both groups were similar with regard to blood pressure, age, sex, glomerular filtration rate (GFR; assessed by C inulin). Blood pressure control and protein intake were identical along the study in the two groups. In the 3-year period, renal replacement therapy (RRT) was required for 27 H pts, 10 E pts, and 17 C pts. Survival analysis (Kaplan-Meier) showed that RRT was significantly delayed in the E compared to the C group (log-rank test, p < 0.05). The risk of presenting ESRF estimated by a Cox model, was 3.5-fold higher in the C than in the E group. Reciprocals of serum
J Diab Comp 1992; 6:4
creatinine and GFR (log Cin) plotted along time were not significantly different (BE: 42.3 f 8.5; BC: 62.4 ? 9.4 mmol-’ * month * 106; PE -43 5 13, BC .68 ? 15.106, respectively). The rate of progression to ESRF was prospectively-compared with a group of 38 normotensives (N), who received either E or placebo (P). Only one pt (of the P group) progressed to ESRF within the 3-year period. The hazard of progressing to ESRF is 65-fold lower in N versus H pts at entry. In the P group, 6 pts required antihypertensive therapy. The slope of log Cin was significantly lower in E (p -23 k-11) than in P (l3 -68 ? 12))(p. < 0.02). In conclusion: Enalapril, compared to conventional therapy, delays the progression to ESRF in hypertensive pts with CRF.
DETERMINANTS OF PROGRESSION IN DIABETIC NEPHROPATHY WITH AND WITHOUT ANTIHYPERTENSIVE TREATMENT P. Rossing, E. Hommel, U. M. Smidt, and H.-H. Pa&ng Steno Diabetes Center, Copenhagen, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark Objective: To evaluate putative predictors of the efficacy of long-term antihypertensive treatment on the rate of decline in glomerular filtration rate (GFR) in diabetic nephropathy. Design: Self-controlled before-after trial in hypertensive insulin-dependent diabetes meIlitus (IDDM) patients with nephropathy treated with metoprolol,furosemide, and hydralazine for 3 years. Patients were followed for 3 (range 2-5) years before start of antihypertensive treatment. Setting: center.
Outpatient diabetic clinic in tertiary referral
Patients: Twenty IDDM patients with diabetic nephropathy. Main Outcome Measures: Rate of decline in GFR arterial blood pressure, albuminuria, fractional albumin clearance. Results: Rate of decline in GFR was 9.5 + 3.8 mL/ min/year in the years before and 3.6 ? 3.6 mL/min/ year during the 3 years of antihypertensive treatment. Arterial blood pressure was 148/96 + 1118 mm Hg in the last year before and 135/89 ? 1317 mm Hg in the first year during treatment. In the same time intervals albuminuria was 1442 (150-7564) pg/min and 880 (96-3310) pg/min, respectively. Stepwise multiple regression analysis identified only one independent variable as predictor of progression in kidney function during the 3 years of antihypertensive treatment: rela-
microalbuminuria more often have left ventricular hypertrophy and elevated levels of serum triglycerides and insulin than do hypertensives without microalbuminuria. In mixed groups of normotensive and hypertensive nondiabetic subjects, microalbuminuria has been associated with increased prevalence of coronary heart disease and peripheral vascular disease and may predict early mortality. In a prospective population-based study in Gothenburg of 49-year-old men (n = 120; hypertension, 69; borderline hypertension, 30; normotension, 21) the urinary albumin excretion, serum cholesterol, and smoking habits were studied at baseline. The hypertensive patients were treated with a S-blocker alone or in combination with a diuretic or hydralazine. After 10 years, 19 of the men had developed cardiovascular disease. They had significantly higher albumin excretion at baseline (median value, 16.4; range, 4-731 mgl 24 h) than those who did not develop cardiovascular disease (9.7; O-308 mg/24 h). The former group had higher systolic blood pressure levels and were more often smokers than the latter group. The albumin excretion was significantly correlated to the baseline systolic, diastolic, and mean arterial blood pressure but not to smoking or serum cholesterol. The baseline urinary albumin excretion was also significantly correlated to the development of cardiovascular disease. This relationship was independent of the blood pressure level. The albumin excretion was a strong predictor of cardiovascular disease and a predictor superior to cholesterol and blood pressure. Conclusion: Microalbuminuria may be considered an early marker of the severity of hypertension and seems to be a strong predictor of the development of cardiovascular disease.
LONG-TERM PROGNOSIS FOR NORMO- AND MICROALBUMINURIC TYPE I (INSULINDEPENDENT) DIABETIC PATIENTS M. Mau Pedersen, C. K. Christensen, and C. E. Mogensen Medical Department M (Diabetes 6 Endocrinology), Aarhus Kommunehospifal, DK-8000 Aarhus C, Denmark Objective: To study the prognostic significance of microalbuminuria in type I diabetes. Design: A long-term [X3 ? 2 (SD) years], second, followup study was performed; 44 male patients with previous measurement of urinary albumin excretion rate (UAE) (radioimmunoassay, >3 timed collections) were identified for reinvestigation. Retrospectively, 30 patients were considered initially normoalbuminuric (UAE < 15 Fg/min) and 14 initially microalbuminuric (15 < UAE < 150 &min) (diabetes duration,
ABSTRACTS
269
12 ? 3 versus 13 ? 3 years, NS; age at diagnosis, 12 + 5 versus 13 + 4 years, NS). At followup UAE (3 overnight collections)/proteinuria, blood pressure, s-creatinine, kidney function (n = 16), and HbAi, were measured. Setting: Outpatient clinic, University Hospitals (referring center). Patients: Followup data were obtained in 27 of the initially normoalbuminuric patients and in all initially microalbuminuric patients. Of the remaining three patients, two did not want to participate in reinvestigation and one has not been investigated yet (all three normoalbuminuric at 10 years followup). Main Outcome Measures: UAE or proteinuria, need for dialysis, and death were considered main outcome measures. In addition glomerular filtration rate (GFR) was compared to initial GFR values when possible. Results: The normo- and microalbuminuric cohorts differed with respect to all-cause mortality (2 versus 5 death, p = 0.03, Fisher‘s exact test), development of renal failure (0 versus 4, p = 0.007) and of overt diabetic nephropathy (2 versus 10, p = 0.00005). Among initially normoalbuminuric patients, four showed microalbuminuria at followup, whereas 20 remained normoalbuminuric after 31 -+ 5 years of diabetes. Two initially microalbuminuric patients stayed such during antihypertensive therapy, and one spontaneously became normoalbuminuric. Remeasuring of glomerular filtration rate in nine persistently normoalbuminuric patients suggested a modest (age-dependent?) decline (132 2 5 versus 125 ? 12 ml/mm/l.73 m2 owup period 20 + 2 years, age 45 & 5 (p = O.lO), f o11 years). Within the initially normoaibuminuric group HbA1, at followup was 9.2% ? 1.5% in persistently normoalbuminuric patients and 7.0% ? 1.1% in patients showing progression (p = 0.006). Conclusion: The occurrence of microalbuminuria in type I diabetes is a strong risk marker for overt diabetic nephropathy, renal failure, and death. Conversely normoalbuminuria indicates a good long-term prognosis with well-preserved kidney function.
DESIGN OF CLINICAL TRIALS IN PROTEINURIA AND PROGRESSIVE RENAL DISEASE H.-H. Pawing Steno Diabetes Center, Copenhagen, Niels Sfeensensvej 2, DK-2820 Genfoffe, Denmark Objective: Critical analysis of clinical trials of medical treatments in chronic progressive nephropathy, e.g., diabetes.
270
ABSTRACTS
Design: Self-controlled studies, crossover studies, and parallel studies; trials can be blinded versus open, randomized versus nonrandomized, parallel versus nonparallel, unicenter versus multicenter. Patients: Sufficient information on patients sources should always be presented, e.g., insulin-dependent diabetes mellitus versus non-insulin-dependent diabetes mellitus, hypertension versus normotension, cause of albuminuria. Apply homogenous well-characterized groups of subjects. Methods: Glomerular filtration rate (GFR), proteinuria, systemic blood pressure, and morphologic lesions, etc., can be used to assess progression of nephropathy. Main Outcome Measures: Surrogate end points: e.g., reduction in proteinuria, development of hypertension, and morphological lesions. Principal end points: e.g., rate of decline in GFR, dialysis/renal transplant, and death due to end-stage renal failure. Conclusion: The ideal study: double-blind randomized parallel trial of two treated groups, or a treated group with a separate but concurrent control group, conducted with accurate and precise methods.
FINAL RESULTS OF THE PROSPECTIVE MULTICENTER STUDY ON ANTIHYPERTENSIVE THERAPY IN CHRONIC RENAL FAILURE A. Fournier, P. Lundais, T. Hannedouche, F. Mignon, 1. Chanard, D. Durand, M. Godin, B. Goldfarb, and J. P. Griinfeld Department de Nephrologie, Hdpital Necker, Paris, France In a 3-year controlled prospective trial, 100 hypertensive (H) patients (pts) with chronic renal failure (CRF) were included to compare the effects of enalapril (E) to conventional (C) therapy on progression to endstage renal failure (ESRF). The protocol, preliminary results, and side effects were presented at the EDTAERA Congress in Vienna, 1990. At inclusion both groups were similar with regard to blood pressure, age, sex, glomerular filtration rate (GFR; assessed by C inulin). Blood pressure control and protein intake were identical along the study in the two groups. In the 3-year period, renal replacement therapy (RRT) was required for 27 H pts, 10 E pts, and 17 C pts. Survival analysis (Kaplan-Meier) showed that RRT was significantly delayed in the E compared to the C group (log-rank test, p < 0.05). The risk of presenting ESRF estimated by a Cox model, was 3.5-fold higher in the C than in the E group. Reciprocals of serum
J Diab Comp 1992; 6:4
creatinine and GFR (log Cin) plotted along time were not significantly different (BE: 42.3 f 8.5; BC: 62.4 ? 9.4 mmol-’ * month * 106; PE -43 5 13, BC .68 ? 15.106, respectively). The rate of progression to ESRF was prospectively-compared with a group of 38 normotensives (N), who received either E or placebo (P). Only one pt (of the P group) progressed to ESRF within the 3-year period. The hazard of progressing to ESRF is 65-fold lower in N versus H pts at entry. In the P group, 6 pts required antihypertensive therapy. The slope of log Cin was significantly lower in E (p -23 k-11) than in P (l3 -68 ? 12))(p. < 0.02). In conclusion: Enalapril, compared to conventional therapy, delays the progression to ESRF in hypertensive pts with CRF.
DETERMINANTS OF PROGRESSION IN DIABETIC NEPHROPATHY WITH AND WITHOUT ANTIHYPERTENSIVE TREATMENT P. Rossing, E. Hommel, U. M. Smidt, and H.-H. Pa&ng Steno Diabetes Center, Copenhagen, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark Objective: To evaluate putative predictors of the efficacy of long-term antihypertensive treatment on the rate of decline in glomerular filtration rate (GFR) in diabetic nephropathy. Design: Self-controlled before-after trial in hypertensive insulin-dependent diabetes meIlitus (IDDM) patients with nephropathy treated with metoprolol,furosemide, and hydralazine for 3 years. Patients were followed for 3 (range 2-5) years before start of antihypertensive treatment. Setting: center.
Outpatient diabetic clinic in tertiary referral
Patients: Twenty IDDM patients with diabetic nephropathy. Main Outcome Measures: Rate of decline in GFR arterial blood pressure, albuminuria, fractional albumin clearance. Results: Rate of decline in GFR was 9.5 + 3.8 mL/ min/year in the years before and 3.6 ? 3.6 mL/min/ year during the 3 years of antihypertensive treatment. Arterial blood pressure was 148/96 + 1118 mm Hg in the last year before and 135/89 ? 1317 mm Hg in the first year during treatment. In the same time intervals albuminuria was 1442 (150-7564) pg/min and 880 (96-3310) pg/min, respectively. Stepwise multiple regression analysis identified only one independent variable as predictor of progression in kidney function during the 3 years of antihypertensive treatment: rela-