Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus

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-

39

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Cook et al.

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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100

80

t.m

E

60

-I

r~ LU

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20

1

2

3

4

5

6

7

8

9

i0

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Patient Number

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 <0.001) but was unaltered during placebo use (mean of monthly measurements 78.2 _+ 140.4 #g/min; range 12.0 to 520 ~zg/min). The fall in AER during captopril therapy occurred within 1 to 2 months of treatment, and the rise of AER to baseline levels

42

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The Journal of Pediatrics July 1990

95-

o placebo 9 captopril

90-

85mmHg

~T 80-

75-

70

I

0

2

3

I

I

5

6

Time (months) Fig. 2. ProgressiveMAPs (bars represent SD). Solid line denotes group randomly assigned to placebo and then captopril (n = 6); broken line denotes group randomly assigned to receive captopril and then placebo (n = 6). Captopril caused significant fall in MAP (mean of monthly measurements) (p = 0.004).

during placebo use also occurred within 2 months. During treatment with captopril, mean AER during the 3 months was 41 __+44% lower than baseline values; 10 of 12 patients responded. Of the two patients who did not respond, one (patient 4, Fig. 1) had a borderline elevation of AER at baseline (16.3 ~g/min.) and the other (patient 5) had had diabetes for only 2.9 years. Blood pressure and metabolic control. Baseline systolic and diastolic BP and MAP for the 12 patients were t08/64 + 8/7 and 79 _+ 6 mm Hg, respectively. These did not change with placebo (mean of three measurements, taken monthly, of 113/65 + 15/7 and 81 _+ 7 mm Hg). Captopril caused a small but significant fall in diastolic BP and MAP (systolic pressure remained unchanged), with a mean of three measurements, taken monthly, of 110/59 + 10/5 (p <0.03) and76 + 5 m m H g ( p = 0.004). During captopril therapy, MAP fell in 11 of 12 patients; in one it remained unchanged (Fig. 2). No one became hypotensive, with or without symptoms. The HbAlc value did not change throughout the study (baseline mean of 8.6 _+ 1.3%); each patient had stable metabolic control, with the HbA1c value varying by no more than 0.5% and the insulin dose not changing significantly in any individual patient. The PRA was significantly higher after 3 months of captopril therapy compared with placebo (2.08 + 0.60 and 0.44 + 0.27 ng/L/sec, respectively; p = 0.001). This represented a response in 11 patients; one subject (patient 2),

who had a significant fall in AER during treatment with captopril, did not show a rise in PRA. There was no difference in mean 24-hour sodium and urea excretion after 3 months of captopril or placebo administration in the 12 patients. Plasma electrolyte, urea, and creatinine values were normal in all patients throughout the study period. The 3-day food record showed a mean daily sodium intake of 2.0 + 0.6 mmol/kg and a mean daily protein intake of 1.5 + 0.3 gm/kg in the 12 patients. Renal function studies. Eight patients (66%) had hyperfiltration at baseline, defined as a GFR greater than 150 ml/min/1.73 m2.28 The baseline range of GFR was 121 to 195 ml/min/1.73 m 2 (n = 11). The GFR did not change significantly after 3 months of captopril therapy (baseline 161 + 28; at 3 months 176 _+ 85 ml/min/1.73 m2; n = 6) or after 3 months of placebo administration (baseline 154 + 23; at 3 months 132 + 11 ml/min/1.73 m2; n = 4). The mean increase of 26% in ERPF after 3 months of captopril therapy was not statistically significant (baseline 671 _+ 285; at 3 months 845 _+ 415 ml/min/1.73 m2; n = 6), and there was no change with placebo (baseline 792 + 182; at 3 months 834 + 268.0 ml/min/1.73 m2; n = 4). Total renal resistance and filtration fraction did not change significantly during administration of either captopril or placebo. No relationship was observed between the fall in AER and changes in GFR or ERPF during captopril therapy.

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Side effects. The only side effect was moderate diarrhea in one patient after 289 months on captopril. The symptoms abated when the drug was discontinued for 48 hours but reappeared when tlae dose was reinstituted at 0.9 m g / k g / d a y for the remaining 10 days of the trial period. Complete blood cell counts during captopril therapy were normal. DISCUSSION We found a significant decrease in AER during 3 months of ACE inhibitor therapy in 12 normotensive adolescents with IDDM and persistent microalbuminuria. Captopril also produced a small but significant fall in diastolic BP and MAP. The fall in A E R could not be attributed either to improved metabolic control or to changes in protein intake. The concomitant rise in P R A during captopril therapy suggested good compliance, with effective ACE inhibition at the time of measurement. Captopril was effective at the lower limit of the therapeutic dose range (0.9 m g / k g / d a y ) in comparison with doses of 2 to 4 m g / k g / d a y required to control hypertension in patients of a similar age. 22 The effect of captopril was prompt in onset, the response occurring after 1 to 2 months of treatment. In those patients randomly assigned to receive captopril before placebo, the rise of A E R to baseline levels on placebo also occurred by two months. Our findings support previous suggestions that captopril's effect on albumin excretion is maximal within 6 weeks of the initiation of treatment and rapidly dissipates on withdrawal of the drug. z9 Although ACE inhibitors have been used previously in adults with diabetic nephropathy, 1619, 30 our patients were adolescents with relatively short duration of disease, BP within the normal range for age, and only a small to moderate elevation of AER. Of the 12 patients, 10 had baseline AERs less than 70 ~g/min, which may represent a critical stage before renal function begins to deteriorate and irreversible glomerular damage has occurred. 31 After 3 months of captopril therapy, A E R had fallen into the norreal range in four patients and was only modestly elevated (less than 40 tzg/min) in seven of the remaining eight patients. The two subjects who failed to respond to captopril therapy warrant comment. One had a borderline A E R (16.5 #g/min), and this fell into the normal range (11.3 #g/rain) during captopril therapy. The lower limit of 15 #g/min in defining microalbuminuria is the lowest value that has been used, 4 and a persistent level of >20 #g/rain 31 may be more reliable for the purposes of intervention studies. However, differences in lower discrimination values in different studies of microalbuminuria have not affected the reliability of predicting progression of the renal disease. 4, 31 The other patient who did not respond showed little variation in A E R throughout the 6 months (range 22.3 to 44.9 #g/min). She

ACE therapy in normotensive children with IDDM

43

had had diabetes for only 2.9 years, and her treatment failure may have been related to either another renal disease process or erratic drug compliance. Her P R A during captopril therapy was only 0.98 ng/L/sec. Two thirds of the patients had hyperfiltration (GFR > 150 ml/min/1.73 m2), consistent with an early stage of incipient nephropathy, and only a modest elevation of AER. In these patients, intervention may well have been at a critical stage before a fall in G F R had begun. We saw no change in GFR during captopril therapy, and the 26% increase in ERPF and fall in total renal resistance and filtration fraction, although in the direction expected from A C E inhibition, was not statistically significant. During enalapril therapy in normotensive diabetic adults with microalbuminuria, ERPF rose and renal resistance fell progressively, the greatest effect being seen at 12 months. 18 Altered glomerular hemodynamics with increased glomerular plasma flow and transcapillary pressures are considered key factors in the initiation and progression of diabetic nephropathy.9-xl, 28, 3t The ACE inhibitors have potential therapeutic advantages over other antihypertensive drugs because they may selectively reduce efferent arteriolar pressures, and thereby glomerular capillary pressures, by lowering angiotensin I1 levels.32, 33 Enalapril has prevented proteinuria by lowering glomerular capillary pressure in diabetic rats 14 and in nondiabetic rats, in which conventional antihypertensive agents were ineffective. 34 A comparison of the short-term effects of captopril and a calciumchannel blocker in normotensive diabetic patients also showed that only captopril caused a reduction in A E R despite an equivalent reduction in systemic BP effected by each agent. 29 The relative importance of the decrease in systemic BP and a specific fall in intraglomerular pressure cannot be analyzed separately in our study or that of Matte et al. 17' 18We are currently comparing the effect of an ACE inhibitor with another antibypertensive drug in our patients with microalbuminuria. Small elevations of BP occur soon after the appearance of microalbuminuria 3s' 36; although our patients had BPs within the normal range for age, these may have represented a small, early rise. By identifying those patients with microalbuminuria, it may be possible to begin antihypertensive therapy (specifically ACE inhibition) before overt hypertension and irreversible renal injury develop. Captopril was chosen for this study because there is wide experience with its use in the pediatric age group and because it has been associated with very few side effects at low doses in the presence of normal renal function. 2~ Although this study shows the drug's beneficial effect on A E R in the short term, long-term follow-up is now required to answer the critical question of whether intervention at an early stage can prevent progression to established diabetic

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n e p h r o p a t h y without significant drug-related adverse side effects. This approach, in conjunction with a t t e m p t s to achieve optimal metabolic control, 3v-39 provides the best outlook for the diabetic patient with microalbuminuria. We acknowledge Prof. David Andrews, of the Clinical Research Support Unit, University of Toronto, for his invaluable help with the data analysis. We thank Nila Soriano for technical assistance, Cheryl Ryans, RN, for assistance with procedures, and Dr. R. M. Ehrlich, whose patients were part of the study. REFERENCES 1. Oakley WG, Pyle DA, Tattersall RB, Watkins RJ. Long-term diabetes: a clinical study of 92 patients after 40 years. Q J Med 1974;43:145-56. 2. Deckert T, Parring H-H, Anderson AR, et al: Diabetic nephropathy: a clinical and morphometric study. In: Eschwege E, ed. Advances in diabetes epidemiology. Amsterdam: Excerpta Medica (INSERM Symposium No. 22), 1982:235-43. 3. Anderson AR, Christiansen JS, Anderson JK, Kreiner S, Deckert T. Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983;25:496501. 4. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 1984;311:8993. 5. Parring H-H, Oxenboll B, Sevendsen P, Christiansen JS, Anderson AR. Early detection of patients at risk of developing diabetic nephropathy: a longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh) 1982;100:550-5. 6. Viberti GL, Hill RD, Jarrett R J, Argyropaulos A, Mahmud Y, Keen H. Micro-albuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes. Lancet t 982; 1:1430-2. 7. Cohen MP. Glomerular metabolism in experimental diabetes. Diabetic Nephropathy 1986;5:4-6. 8. Sternberg M, Cohen-Forterre L, Peyroux J. Connective tissue in diabetes mellitus: biochemical alterations of the intercellular matrix with special reference to proteoglyeans, collagens and basement membranes. Diabetes Metab 1985;11:27-50. 9. Parving H-H, Viberti GC, Keen H, Christiansen JS, Lassen NA. Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 1982;32:943-9. 10. Hostetter TH, Rennke HG, Brenner BM. The case of intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 1982;72:375-380. 11. Zatz R, Brenner BM. Pathogenesis of diabetic microangiopathy. The hemodynamie view. Am J Med 1986;80:443-53. 12. Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J 1982;285:685-8. 13. Parving H-H, Anderson AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PAA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 1987;294:795-8. 14. Zatz R, Dunn R, Meyer T, Anderson S, Rennke H, Brenner B. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986;77:1925-30. 15. Ando K, Fujita T, Ito Y, Noda H, Yamashita K. The role of renal haemodynamics in the anti-hypertensive effect of captopril. Am Heart J 1986;111:347-52.

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16. Hommel E, Parving H-H, Mathiesen E, Edsberg B, Nielsen M, Giese J. Effect of captopril on kidney function in insulindependent diabetic patients with nephropathy. Br Med J 1986;293:467-70. 17. Marre M, Leblanc H, Suarez L, Guyenne T, Menard J, Pasa P. Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med J 1987;294:1448-52. 18. Marre M, Chatellier G, Leblanc H, Guyere T, Menard J, Passa P. Prevention of diabetic nephropathy with enalapril in normotensive diabetes with microalbuminuria. Br Med J 1988;297:1092-6. 19. Mimran A, Insua A, Ribstein J, Monnier L, Bringer J, Mirouze J. Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. J Hypertens 1988;6:919-23. 20. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med 1984;144:1441-4. 21. Vidt OG, Bravo EL, Fouad FM, Koch-Weser J. Captopril. N Engl J Med 1982;306:214-9. 22. Mirkin BE, Newman TJ. Efficacy and safety of captopril in the treatment of severe childhood hypertension: report of the International Collaborative Study Group. Pediatrics 1985; 75:1091-100. 23. Sochett E, Daneman D. Screening tests to detect microalhuminuria in children with diabetes. J PEOIATR 1988;122:744-8, 24. Report of the Second Task Force on Blood Pressure Control in Children. Pediatrics 1987;79:1-25. 25. Ellis G, Diamandis EP, Giesbrecht EE, Daneman D, Allen LC, An automated "high pressure" liquid-chromatographic assay for haemoglobin Ale. Clin Chem 1984;30:1746-52. 26. Spino M, Chai RP, Isles AF, et al. Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis. J PEt)lATR 1985;107:64-70. 27. D'Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comp Prog Biomed 1979;9:115-34. 28. Mogensen CE, Christensen CK, Christiansen JS, Boyle N, Pederson MM, Schmitz A. Early hyperfiltration and late renal damage in insulin-dependent diabetes. Pediatr Adolesc Endocrinol 1988;17:197-205. 29. Mimran A, Insua A, Ribstein J, Bringer J, Mornier L. Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care 1988;11:850-3. 30. Taguma Y, Kilamoto Y, Futaki G, et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J Med 1985;313:1617-20. 3 l. Mogensen CE. Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int 1987;31:673-89. 32. Zusman RM. Renin- and non-renin-mediated antihypertensire actions of converting enzyme inhibitors. Kidney lnt 1984;25:969-83. 33. Bohrer MP, Deen WM, Robertson CR, Grenner BM, Mechanism of angiotensin II proteinuria in the rat. Am J Physiol 1977;233:F13-21. 34. Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 1986;77:1993-2000. 35. Mogensen CE, Christensen CK. Blood pressure changes and

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renal function changes in incipient and overt diabetic nephropathy. Hypertension 1985;7(11):64-73. 36. Christensen CK, Mogensen CE. The course of incipient diabetic nephropathy: studies of albumin excretion and blood pressure. Diabetic 19led 1985;2:97-102. 37. Feldt-Rasmussen B, Mathiesen E, Deckert T. Effect of two years of strict metabolic control on the progressionof incipient nephropathy in insulin-dependent diabetics. Lancet 1986;2: 1300-4.

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38. The Kroc Collaborative S~udy Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial. N Engl J Med 1984;311:365-72. 39. Dahl-Jorgensen K, Hanssen KF, Kierulf P, Bjoro T, Sandvik L, Aagenaes O. Reduction of Urinaryalbumin excretion after 4 years of continuous subcutaneous insulin infusion in insulindependent diabetes mellitus. Acta Endocrinol (Copenh) 1988; 117:19-25.

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