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Three Part Question

In [children with type 1 diabetes with persistent microalbuminuria], does [the use of ACEi]reduce [urinary albumin excretion rate]?

Clinical Scenario

A 14-year-old girl with type 1 diabetes mellitus (DM) attends clinic for her annual review appointment. An albumin creatinine ratio (ACR) on spot urine is 7.3 mg/mmol. Her blood pressure is 125/67 and HbA1c is 9.2%. Subsequently, three consecutive early morning urine samples have ACR of 6.8, 5.7 and 7.3 mg/mmol, respectively, and remain elevated when repeated 3 and 6 months later. You are aware that in adult women with diabetes persistent microalbuminuria (MA) is defined as an ACR greater than 3.5 mg/mmol on two out of three successive occasions, and that in such adults, treatment with angiotensin converting enzyme inhibitors (ACEi) confers renoprotection. You wonder whether your patient should be treated.

Search Strategy

Primary sources: Medline via PubMed.
Secondary sources: Cochrane database and BestBETs were searched using the term "Angiotensin" in the "Title, Abstract or Keywords" field: no review of ACEi use in children was found.

Pubmed:("Angiotensin-Converting Enzyme Inhibitors"[MeSH] OR "Angiotensin-Converting Enzyme Inhibitors"[Pharmacological Action]) AND "Diabetes Mellitus"[MeSH], limited to: All Child 0–18 years; 103 articles were found. To locate articles that had been published but were still waiting to be indexed, another search was carried out with the terms: ((angiotensin converting enzyme inhibitors) OR (ace inhibitors) OR (Captopril) OR (Cilazapril) OR (Enalapril) OR (Enalaprilat) OR (Fosinopril) OR (Lisinopril) OR (Perindopril) OR (Ramipril) OR (Saralasin) OR (Teprotide)) AND (diabet*) AND ((child*) OR (adolescent*)); 199 articles were found. Search results were combined in a reference managing software programme and duplications were deleted. A total of 203 articles were retrieved of which only four were included

Search Outcome

Papers were excluded for the following reasons: subjects did not have type 1 DM (n = 86), no nephropathy (n = 8), normalbuminuric (n = 6), no ACEi intervention (n = 26), adult subjects (n = 45), review articles or letters (n = 24) or papers not published in English (n = 4).
Searches were performed on the 11 November 2006.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Cook et al, 1990, Canada	12 adolescents (mean age 14.4 (SD 1.7) years) with type 1 DM, 11 with MA (AER 15–200 µg/min) and one with early overt nephropathy (AER 425 µg/min), with normal BP (108/64 (SD 8/7) mm Hg), were randomly treated with either captopril (0.9 mg/kg/day) or placebo for 3 months and then received the alternate treatment for a further 3 months in the crossover phase of the 6-month study period.	RCT (level 1b)Randomised double-blind placebo controlled crossover trial of captopril 0.9 mg/kg/day vs placebo	AER, side effects, BP, plasma renin activity, kidney function and metabolic control	After 3 months, AER decreased in the captopril group from 78.4 (SD 114.4) to 35.8 (SD 55.2) µg/min but was unchanged during placebo use at 78.2 (SD 140.4) µg/min. Mean difference between the two groups was 42.4 µg/min (95% CI: –162.91 to 78.21). During captopril therapy, AER was reduced by 41% (SD 44%) and decreased in 10/12 subjects, but was unchanged in two: one had a borderline AER (16.3 µg/min) and one had diabetes of short duration (2.9 years). One subject reported diarrhoea following 2.5 months’ treatment with captopril.	There were a small number of participants (n = 12). Other diabetic therapy continued as previously. The reduction in AER during captopril therapy occurred within 1–2 months of starting treatment.
Rudberg et al, 1999, Sweden	13 adolescents (boys/girls: 5/8, mean age 18.8 years) with type 1 DM and MA (AER >15 µg/min) with BP of 127/80 (SD 13/8) mm Hg were randomised into two groups. Group 1 was treated with enalapril 20 mg/day (n = 7). Group 2 was treated with metoprolol 100 mg/day (n = 6). Renal biopsies were taken before and after 38 (36–48) months. A reference group (group 3; n = 9) without antihypertensive treatment of similar age, diabetes duration and degree of MA as groups 1 and 2 had baseline and follow-up renal biopsies taken previously at an interval of 26–34 months.	RCT (level 1b) RCT of enalapril 20 mg/day vs metoprolol 100 mg/day with a control group with no intervention	AER, kidney structure (BMT), mesangial volume fraction, matrix volume fraction, matrix star volume and overall diabetic glomerulopathy index (ie, index DGP), BP, HbA1c and GFR	There was a decrease in AER in group 1 (p = 0.01) from a median (range) of 31 (23–160) to 12 (8–16) µg/min but no change in the reference group from 33 (18–194) to 35 (6–187) µg/min. AER returned to normal in all patients in the enalapril group. The change in BMT adjusted for 24 months of follow-up (BMT/24 months) was lower in groups 1 and 2 (p = 0.01) than in group 3 (overall p = 0.008). Similarly, (index DGP/24 months) was lower in group 1 (p = 0.03) and group 2 (p = 0.04) than group 3 (overall p = 0.03).	There was no placebo arm and a small number of participants (n = 13). Participants were young adults rather than children (mean age 18.8 years). 18 participants were randomised at the beginning of whom 5 dropped out due to pregnancy (n = 2), social reasons (n = 2) and severe hypertension that required multiple antihypertensive drugs (n = 1). When taking all patients from the three groups into account, a decrease in AER tended to be inversely correlated with an increase in BMT (r = –0.38, p = 0.08) and index DGP (r = –0.41, p = 0.05).
Rudberg et al, 1990, Sweden	12 adolescents (boys/girls: 10/2, aged 15–20 years) with type 1 DM and persistent MA (AER >20 µg/min). Group 1 contained six patients with systolic BP 75th percentile for age and sex (135/85 (SD 5/5) mm Hg). Group 2 contained six normotensive patients (113/72 (SD 10/7) mm Hg). All participants received enalapril (10–20 mg/day) for 6 months.	Within participants comparison trial (level 2b) Prospective within participants comparison trial, hypertensive vs normotensive subjects with MA. Treated with enalapril 10–20 mg/day	AER, GFR, BP, renal plasma flow, kidney function tests, ACE activity, serum aldosterone, metabolic control and physical exercise test	After 3 weeks, AER decreased in both groups when compared with initial values (group 1: 55% decrease, from a median (range) of 25 (20–51) to 10 (5–37) µg/min, p = 0.02; group 2: 65% decrease, from 35 (20–236) to 9 (2–17) µg/min, p = 0.001). After 6 months, AER decreased in both groups when compared with initial values (group 1: 35% decrease, from a median (range) of 25 (20–51) to 17 (5–43) µg/min, p = 0.04; group 2: 61% decrease, from 35 (20–236) to 10 (7–17) µg/min, p = 0.003).	This was an uncontrolled trial with a small number of participants (n = 12). Participants were adolescents (aged 15–20 years). During the study the only drug used apart from enalapril was insulin.
Yuksel et al, 1998, Turkey	16 adolescents (boys/girls: 7/9, mean age 16.2 (SD 0.6) years) with type 1 DM and persistent MA (153 (SD 53) µg/min) and BP of 120/79 (SD 2.2/1.4) mm Hg took part. Participants were treated with enalapril (0.2 mg/kg/day) for 12 weeks.	Within participants comparison trial (level 2b) Prospective within participants comparison non-controlled trial, normotensive subjects with MA. Enalapril 0.2 mg/kg	AER, serum calcium, urine calcium excretion, serum phosphorus level and tubular reabsorption of phosphate	In the first 4 weeks, there was no change in AER. However, after 8 and 12 weeks, a reduction was reported to 38 (SD 22) µg/min, (p = 0.005) and 20 (SD 8) µg/min (p<0.01), respectively.	There was no placebo control and a small number of participants (n = 16).

Comment(s)

Diabetic nephropathy, characterised by an increasing rate of urinary albumin excretion, hypertension and ultimately renal failure, affects approximately 35% to 40% of patients with either type 1 or type 2 diabetes (Knowler). MA is one of the main risk factors for nephropathy and is also an independent risk factor for cardiovascular disease. However, within the paediatric population, the albumin excretion rate (AER) is extremely variable. Children with type 1 DM rarely develop MA prior to puberty and although MA is positively correlated with both duration of diabetes and HbA1c, it is likely that there are additional genetic factors which may confer additional risk with this complication (Schultz). The benefits of adequate control of blood pressure on the progression of renal disease in DM are well described. ACEi may have specific renal effects that are distinct from the reduction in arterial pressure and since the landmark multi-centre trial in adults with type 1 DM by Lewis et al in 1993, the use of ACEi to limit the progression of diabetic nephropathy has become a widely accepted intervention within the adult population. Robust evidence (level 1a) suggests that intervention with ACEi leads to a reduction in overall AER as well as regression from MA to normalbuminuria (Strippoli). Currently in the UK, the National Institute for Health and Clinical Excellence (NICE) recommends commencing therapy with an ACEi in all adults with type 1 DM and MA with titration to full dose. Other than recommending annual screening from the age of 12 for MA, there is no guidance for the use of ACEi within the paediatric population. ACEi are not without adverse effects, with up to 10% of patients reporting cough and, importantly, ACEi are contraindicated in pregnancy as they have significant teratogenic effects on the fetus. We found little strong evidence for the use of ACEi within the paediatric population, with only one small randomised controlled trial (n = 12) and three small longitudinal within-individual comparison trials of ACEi treatment in microalbuminuric subjects with type 1 DM (Cook, Rudberg, 1990, 1999, Yuksel). However, overall the evidence does suggest that intervention with ACEi leads to a reduction in AER. Although the numbers were small, treatment with ACEi was well tolerated with only one case of moderate diarrhoea after 2.5 months of treatment with captopril being reported (Cook). Cook et al studied 12 normotensive adolescents (mean age 14.4 (SD 1.7) years) with MA (AER 15–200 µg/min). They report a 41% (SD 44%) decrease in AER after 3 months in the group given captopril. Rudberg et al describe seven normotensive adolescents (five boys and eight girls with mean age of 18.8 years) with MA (AER >15 µg/min) who were treated with enalapril and report a reduction in AER to the normalbuminaric range in all enalapril-treated patients. Rudberg also studied 12 adolescents (10 boys and two girls aged 15–20 years) with MA (AER >20 µg/min) receiving enalapril and showed a significant decrease in AER after 3 weeks and 6 months in both normotensive and hypertensive participants. Yuksel, however, reported that 16 adolescents (seven boys and nine girls aged approximately 16 years) with MA of 153 (SD 53) µg/min treated with enalapril showed no change in AER after 4 weeks but reductions in AER after 8 and 12 weeks. While these studies are encouraging and indicate that individuals respond to ACEi therapy, the results cannot be extrapolated directly to our patient. Three out of the four papers used enalapril and the fourth captopril and the subjects recruited varied in age between the studies but were predominantly older than our patient. A large randomised, placebo controlled trial in adolescents with MA is required to confirm the efficacy and examine possible adverse effects of this class of drugs in the adolescent population. Within the paediatric population, AER is extremely variable and may be transient, regressing in up to 50% of adolescents without intervention (Schultz). However, individuals with transient MA may be at increased risk of MA as young adults. Given the intrinsic variability of AER within in the paediatric population, it is important that a large scale randomised control trial be conducted in adolescents with type 1 DM to ascertain safety and confirm efficacy of ACE inhibition.

Editor Comment

ACE, angiotensin converting enzyme; AER, albumin excretion rate; BMT, basement membrane thickness; BP, blood pressure; DM, diabetes mellitus; GFR, glomerular filtration rate; MA, microalbuminuria; RCT, randomised controlled trial.

Clinical Bottom Line

There is limited evidence that the use of ACEi in adolescents and children decreases albumin excretion rate and reverses structural changes within the kidney. (Grade A) Sample sizes in the studies were small, but ACEi seemed to be well tolerated with few reported adverse events. (Grade A) A large placebo controlled trial is required to provide more robust evidence for the efficacy and adverse effects associated with the use of ACEi in children. (Grade A)

References

1. Knowler WC, Kuntzelman CL. Population comparisons of the frequency of diabetic nephropathy. In: Morgensen C E, ed. The kidney and hypertension in diabetes mellitus . Boston: Martinus Nijhoff, 1988: 25–32.
2. Schultz CJ, Konopelska-Bahu T, Dalton RN, et al. Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group. Diabetes Care 1999; 22 (3): 495–502.
3. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329 (20): 1456–62.
4. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004; 329 (7470): 828.
5. Cook J, Daneman D, Spino M, et al. Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus. J Pediatr 1990; 117(1 Pt 1): 39–45.
6. Rudberg S, Osterby R, Bangstad HJ, et al. Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with type I (insulin-dependent) diabetes mellitus. Diabetologia 1999; 42 (5): 589–95.
7. Rudberg S, Aperia A, Freyschuss U, et al. Enalapril reduces microalbuminuria in young normotensive type 1 (insulin-dependent) diabetic patients irrespective of its hypotensive effect. Diabetologia 1990; 33 (8): 470–6.
8. Yuksel H, Darcan S, Kabasakal C, et al. Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes. Pediatr Nephrol 1998; 12 (8): 648–50.