Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus Jennifer C o o k , MB,ChB, FRACP, Denis D a n e m a n , MB,BCH, FRCP(C), M i c h a e l Spino, BSc, Phm, Pharmb, Etienne S o c h e t t , MB,BCh, FRCP(C), Kusiel Perlman, MD, FRCP(C), a n d J. Williamson Balfe, MD, FRCP(C) From the Divisionsof Endocrinology and Diabetes, Nephrology, and Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada It has been p r o p o s e d that lowering glomerular pressure in children with insulind e p e n d e n t d i a b e t e s mellitus will r e d u c e microalbuminuria and that this reduction may preserve renal function. We therefore c o n d u c t e d a double-blind, plac e b o - c o n t r o l l e d , crossover trial to c o m p a r e 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 m g / k g / d a y ) , and 3 months of p l a c e b o administration to 12 normotensive adolescents with insulin-dependent d i a b e t e s mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 /~g/min) and one with early overt nephropathy. Mean a g e (_SD) was 14.4 _+ 1.7 years, and disease duration was 5.1 _+ 2.5 years. Albumin excretion rate d e c r e a s e d significantly during captopril therapy ( b a s e l i n e 78 _+ 114 # g / min; mean of monthly measurements 38 __. 55 ~g/min vs p l a c e b o 78 + 140 t~g/ min; p < 0.001). During captopril therapy, albumin excretion was r e d u c e d by 41 _+ 44% a n d d e c r e a s e d in 10 of 12 subjects, but was u n c h a n g e d in two, one with a borderline albumin excretion rate (16.3 ug/min) and one with d i a b e t e s of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure d e c r e a s e d slightly ( p l a c e b o 81 + 7 mm Hg; captopril 76 + 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not c h a n g e significantly. Hemoglobin Ale values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We c o n c l u d e that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are i n d i c a t e d in an attempt to d e l a y or prevent overt nephropathy. (J PEDIATR1990;117:39-45)

Supported by Squibb Pharmaceuticals. Dr. Cook was suppOrted by a fellowship from the Hospital for Sick Children Foundation. Submitted for publication NOv. 2, 1989; accepted Feb. 8, 1990. Reprint requests: Denis Daneman, MB,BCh, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. 9/20/19994

Insulin-dependent diabetes mellitus is complicated by diabetic nephropathy in 30% to 45% of patients, 13 and this is the major cause of the increase in mortality rate associated with the disease. 3 The earliest sign of nephropathy is a persistent increase in the urinary albumin excretion rate at a level below detection by routine laboratory methods. This stage is termed incipient nephropathy, The presence of per-

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ACE AER BP ERPF GFR HbAlc IDDM MAP PRA

Angiotensin converting enzyme Albumin excretion rate Blood pressure Effective renal plasma flow Glomerular filtration rate Hemoglobin Ale Insulin-dependent diabetes mellitus Mean arterial pressure Plasma renin activity

smtent microalbuminuria has been shown to predict the progression to clinical diabetic nephropathy. 46 It is likely that a combination of structural changes in the glomerular basement membrane 7' 8 and a rise in intraglomerular blood pressure precedes the onset of systemic hypertension 9"11 and is responsible for initiating the increase in AER and for the progression to overt diabetic nephropathy. Hypertension almost invariably accompanies established diabetic nephropathy and accelerates the progression to renal failure. Antihypertensive therapy slows the rate of deCline in the glomerular filtration rate but does not prevent the advancing nephropathy. 12,i3 Angiotensin converting enzyme inhibitors may be the most effective antihypertensive agents in reducing albumin excretion in IDDM by lowering renal vascular resistance and thereby lowering glomerular capillary pressure. 14, 15 These agents reduce urinary A E R in mildly hypertensive diabetic patients with overt nephropathy 16 and in normotensive adults with IDDM and microalbuminuria. 1719 However, there have been no reports of the use of these agents in diabetic children with microalbuminuria. Captopril has been used widely in all age groups in the treatment of hypertension; its safety and efficacy have been well documented. 2~ We therefore aimed to evaluate the effectiveness of this ACE inhibitor in lowering AER in normotensive adolescents with IDDM and microalbuminuria. METHODS Patients. Two hundred ten patients, aged 12 to 18 years, with IDDM who were attending the Hospital for Sick Children's diabetes clinic were screened during a 3-month period for the presence of microalbuminuria with a 1-hour timed urine collection.23 All patients with microalbuminuria (defined by an A E R of 15 to 200 ~g/min) on the screening test (n = 32) collected two 24-hour urine specimens to confirm the presence of a raised AER. The patients avoided vigorous exercise on the day of the collection; urinary creatinine excretion was used to determined whether the collection was complete (normal range 15 to 20 mg/kg/day). Sixteen patients were identified as having AER >15 t~g/min; in one the A E R was >200 ug/min. Eleven agreed to enter the study and fulfilled the following criteria:

The Journal of Pediatrics July 1990

1. Microalbuminuria (AER 15 to 200 ~g/min) on a third 24-hour urine collection 2. Duration of IDDM equal to or greater than 2 years 3. Blood pressure equal to or below the 90th percentile for age 24 4. Stable metabolic control of diabetes 5. Absence of other major system or renal disease, or medication other than insulin and thyroxine One patient (No. 12) had a baseline A E R of 425 #g/min but otherwise fulfilled the selection criteria and was entered into the study. The study was approved by the Hospital for Sick Children Human Experimentation Review Committee, and informed consent was obtained from the subjects and their parents. Protocol, A double-blind, placebo-controlled, crossover study design was employed in which the patients were randomly assigned to receive either captopril or placebo for 3 months. They then received the alternate treatment for a further 3 months in the crossover phase of the 6-month study period. The initial dose of captopril, 0.3 mg/kg/dose given twice daily, was increased to 0.3 mg/kg/dose given three times daily after 1 week in the absence of symptoms. The patients all continued their conventional insulin regimen and diabetic diet. The baseline AER was calculated from the mean of the three 24-hour collections. The A E R was measured during the 6-month study on one 24-hour urine collection at 1, 2, 4, and 5 months and as the mean of two 24-hour urine collections at 3 and 6 months. Twenty-four-hour urinary urea, creatinine, and sodium excretion were also measured monthly. Urinary albumin concentration was measured by a double-antibody radioimmunoassay (Pharmacia AB, Uppsala, Sweden). Intraassay and interassay coefficients of variation were determined for three urinary albumin concentrations: 2.1% and 12.1% at low concentration (5 rag/L), 1.5% and 5.8% at medium concentration (25 rag/L), and 1.7% and 4%, respectively, at high concentration (55 rag/L). The A E R was calculated from the albumin concentration and the volume and duration of the respective collections. Urinary urea, creatinine, and sodium levels were measured by routine laboratory methods. Plasma renin activity (measured at 10 AM, after the subject had been supine for 1 hour), hemoglobin Alc level, complete blood cell count, and plasma urea, creatinine, and electrolyte levels were measured at day 1 and at 3 and 6 months. The HbAlc level was measured by high-pressure liquid chromatography after removal of the labile fraction. 25 The nondiabetic range is 4% to 6%. The PRA was measured at 37~ with an angiotensin I kit (Du Pont New England Nuclear Research Products, Boston, Mass.). Resting BP was measured monthly with a Dinamap Vi-

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A C E therapy in normotensive children with 1DDM

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Fig. 4. Mean AER (monthly measurements) in 11 normotensive,diabetic adolescentswith microalbuminuria. In patient 12, mean AER during placebo administration was 520 #g/rain, and during captopril use, 208 fzg/min. This patient has been excluded from Fig. 1 but was included in all statistical analyses.

tal Signs Monitor and an appropriate-size cuff (Critikon Inc., Tampa, Fla.). After the patients laid at rest for 30 minutes, BP measurements were taken every 2 minutes for 20 minutes; the mean of the final 10 minutes of measurement was then recorded. Mean arterial pressure was calculated as the sum of diastolic BP and one third of the pulse pressure. Glomerular filtration rate and effective renal plasma flow were measured on day 1 and after 3 months at 9 to 12 AM after a normal morning insulin dose and breakfast. Patients received Lugol iodine solution, 0.4 ml twice daily, on the preceding day. The simultaneous clearance of diethylenetriaminepentaacetic acid labeled with technetium 99m and o-iodohippurate-labeled with iodine 125 for 140 minutes after a sequential rapid injection was used to measure GFR and ERPF, respectively. Clearance was calculated by standard noncompartmental methods as previously reported. 26 An open two-compartment model was fit to the data with a computerized nonlinear regression fitting program, ADAPT. 27 Total renal resistance was calculated by dividing MAP by ERPF, and the filtration fraction by dividing GFR by ERPF. A 3-day food record was taken at 3 and 6 months to assess dietary sodium and protein intake. Statistical analysis. The AER values were not normally distributed and were analyzed after log transformation. The paired Student t test was used to compare both baseline with placebo and treatment values, and placebo with treatment

values for AER, HbAlc, systolic and diastolic BP and MAP, 24-hour sodium and urea excretion, creatinine clearance, GFR, and ERPF. The relationships among AER, GFR, and ERPF were analyzed by means of linear regression. Results are expressed as mean + SD unless otherwise stated. RESULTS The 12 study subjects included eight girls and four boys, with a mean _+ SD age of 14.4 + 1.7 years (range 12.8 to 17.9 years) and IDDM duration of 5.1 _+ 2.5 years (range 2.0 to 11.5 years). There was no significant difference between the group randomly assigned to begin with captopril therapy (n = 6) and the group starting placebo administration (n = 6) before crossover in terms of age, duration of disease, HbAlc level, and MAP. Albumin excretion. There was a significant decrease in AER during captopril therapy (Fig. 1), independent of the order of randomization. Baseline AER in the 12 patients (mean of three 24-hour collections for 2 months) was 78.4 _+ 114.4 Fzg/min (range 16.3 to 425 #g/min) with a variability of AER during the prestudy period of 25 _+ 19%. During 3 months of captopril therapy, AER fell to 35.8 _+ 55.2 lzg/min (mean of monthly measurements; range 8.5 to 208 izg/min; p