Irbesartan reduces creatinine clearance in type 1 diabetic children with renal hyperfunction: a randomized, double-blind, placebo-controlled trial

Mario Salcedo-Alejos1, Felipe Banda-Espinoza2, Martha Rodríguez-Morán3,4 and Fernando Guerrero-Romero3,4

1 Nephrology Department and 2 Pediatric Endocrinology Department, General Hospital, Mexican Social Security Institute, Torreón, Coah., 3 Medical Research Unit in Clinical Epidemiology, Mexican Social Security Institute and 4 Research Group on Diabetes and Chronic Illnesses, Durango, Mexico

Correspondence and offprint requests to: Fernando Guerrero-Romero, Siqueiros 225 esq./Castañeda, 34000 Durango, Mexico. Email: guerrero_romero{at}hotmail.com



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Previous studies in type 2 diabetes have demonstrated the renoprotective effect of AT1-receptor antagonist drugs, but data on type 1 diabetic (T1DM) children are scarce. The aim of this study was to evaluate the effectiveness of the AT1-receptor antagonist irbesartan in reducing creatinine clearance rate (CCR) in non-hypertensive T1DM children with renal hyperfunction.

Methods. In this randomized, double-blind, placebo-controlled trial we enrolled 20 T1DM children aged 6–16 years and randomly allocated them to receive either irbesartan (1 mg/kg body weight) or placebo daily for 12 weeks. Children were eligible to participate if they had renal hyperfunction, defined as a CCR >20 ml/min/1.73 m2 body surface area. In addition, the participants could not have high blood pressure or renal failure and they could not be receiving diuretics or angiotensin-converting enzyme inhibitors. The primary endpoint of the trial was the change in CCR.

Results. There were no significant differences in age, duration of diabetes or body mass index between the two groups. No subject dropped out, withdrew consent or had side effects or adverse events attributable to irbesartan or the placebo. In the irbesartan group, CCR decreased from 155.0±6.6 to 86.2±7.4 ml/min (P<0.0001); CCR did not change significantly in the control group (154.1±13.1 to 172.0±15.5 ml/min; P = 0.86). Blood pressures at baseline and throughout the study were similar in both groups.

Conclusions. Irbesartan significantly reduces CCR in non-hypertensive, non-controlled T1DM children; the clinical significance of this finding, however, remains to be established.

Keywords: acute renal hypertrophy–hyperfunction; AT1-receptor antagonist; children; creatinine clearance; irbesartan; type 1 diabetes



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
End-stage renal disease in diabetic patients could be prevented or delayed by the optimum control of glycaemia [1,2], but to achieve a tight metabolic control is not easy in the clinical setting. Therefore, strategies to prevent nephropathy in type 1 diabetes (T1DM) should focus on its early detection and treatment. The earliest stage in the development of diabetic renal disease, renal hyperfunction, characterized by the absence of high blood pressure and the increase of glomerular filtration rate (GFR) [1], is usually present when T1DM is diagnosed and it could be detected clinically by measuring creatinine clearance.

Angiotensin-converting enzyme (ACE) inhibition, which involves haemodynamic factors that reduce intraglomerular pressure [3], is essential for the prevention of renal disease in diabetic patients [4]. The effects of angiotensin II on vessel resistance are mediated through type 1 (AT1) and type 2 (AT2) receptors [5], of which the AT1 receptor mediates all of the known renal clinical effects of angiotensin II [4,6]. Irbesartan is a high-affinity AT1-receptor antagonist that does not have blocking effects on AT2 receptors [4].

Early renal changes in type 1 diabetic patients are characterized by increased GFR in the absence of high blood pressure and this could be reversed by strict insulin treatment [1]. Yet, the efforts to prevent the development of nephropathy have been focused on the treatment of microalbuminuria, which represents a more advanced stage in the natural history of diabetic nephropathy. Since reaching a strict diabetic control is not easy, and because renal hyperfiltration is a risk factor for the development of microalbuminuria in type 1 diabetic children [7], it would be reasonable to look for early alternative therapeutic approaches in order to reduce the possible progression of renal damage. With that in mind, we undertook a randomized, double-blind, placebo-controlled trial to evaluate the effectiveness of the AT1-receptor antagonist irbesartan in reducing creatinine clearance rate in non-hypertensive type 1 diabetic children with renal hyperfunction.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
With the approval of our protocol by the Mexican Social Security Institute Research Committee and after obtaining the subjects' informed consent, we conducted a randomized, double-blind, placebo-controlled trial.

Based on the creatinine clearance value for healthy children from Torreón, Coah., Mexico—which is 70–120 ml/min/1.73 m2 body surface area for the purpose of this study – non-hypertensive type 1 diabetic children were eligible to participate if they had renal hyperfunction, defined by a creatinine clearance >120 ml/min/1.73 m2 body surface area. All the children were evaluated clinically and laboratory-tested in order to determine the presence of renal failure or high blood pressure, which were exclusion criteria. Children who received diuretics or ACE inhibitors prior to randomization were excluded.

The primary endpoint of the trial was the change in creatinine clearance. Sample size was estimated based on a statistical power of 80% and an {alpha}-value of 0.05 and allowing non-improvement in the creatinine clearance of 25% and 90% for the subjects receiving irbesartan or placebo, respectively. The sample size required to detect a treatment effect was 10 subjects in each group [8].

We enrolled 20 eligible children aged 6–16 years and randomly allocated them to receive either irbesartan 1 mg/kg body weight or placebo daily for 12 weeks. Since in Mexico irbesartan is available as pills of 150 mg, a solution containing 25 mg irbesartan/ml tri-distilled water, which preserves its bioavailability, was prepared under sterile and controlled conditions. Computer-generated random numbers were used to assign participants to irbesartan or placebo groups. The final distribution of participants in the study is showed in Figure 1.



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Fig. 1. Subjects' flow diagram.

 
In order to quantify variations in creatinine clearance, all the children had laboratory tests monthly, starting 3 months prior to their randomization and at 1 month after the end of the intervention phase of the study. All participants were prescribed a diet with >50% of its calories from carbohydrates, <10% from saturated fat (20% from mono- and polyunsaturated fats) and ~1 g protein per kg ideal body weight per day. Insulin dosage was calculated based on individual body weight and glucose levels. Rapid-acting insulin (crystalline or insulin lispro) and intermediate-acting insulin (insulin NPH) were used twice daily.

Anthropometric parameters and haemoglobin (HbA1c) were measured at baseline and after 3 months of treatment. Creatinine clearance and serum glucose levels were measured once a month throughout the study. The subjects and personnel assessing outcomes were blinded to group assignment.

Adherence to pharmacological treatment was assessed every month by personal interviews and by measuring the remnant of the solutions provided to the subjects.

Measurements
Height and weight were measured using standard protocols, with the children in light clothing and without shoes. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared.

Blood pressure measurements followed the technique recommended in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. High blood pressure was defined by a value of systolic and diastolic pressures equal or greater than the 90th percentile for age and gender. For the purpose of this study, hypertensive children were not included. In this regard, children reported by their parents as hypertensives or who were taking antihypertensive drugs were considered to be hypertensive irrespective of their systolic and diastolic blood pressure values. Blood pressure was measured with a calibrated electronic device (Omron HEM-431C) after ≥5 min of rest, with the children seated, their arms bared and supported at heart level and using an appropriate cuff size. The average of three readings separated by 2 min was used to define BP.

Serum glucose was measured by a glucose-oxidase method. Its intra- and interassay variations were 2.5% and 2%, respectively. Creatinine clearance was calculated in 24 h urine collections as:

Statistical analysis
The pre-planned intention-to-treat analysis of the primary endpoint of the study was done for all the randomly allocated participants who satisfactorily completed the follow-up (Figure 1).

Differences between the groups were established by a one-way analysis of variance (ANOVA) test. Skewed data were logn-transformed to normalize their distribution. The two-tailed paired t-test (Wilcoxon test) was performed for before and after treatment comparisons within each group.

A 95% confidence interval was taken into account and a P-value of <0.05 was defined the level of statistical significance. Data analysis was performed using the SPSS 10.0 statistical package (SPSS Inc., Chicago, IL, USA).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Initially, 68 children were screened. Of them, 20 who satisfactorily fulfilled the inclusion criteria were randomized to receive either irbesartan 1 mg/kg body weight or placebo (Figure 1).

For the children in the irbesartan and placebo groups, respectively, average age was 11.5±3.9 and 11.1±4.2 years (P = 0.83) and average duration of diabetes was 3.8±2.6 and 2.9±1.1 years (P = 0.35).

At baseline, the BMI was 21.5±5.0 and 20.6±4.0 kg/m2 (P = 0.08) for the children who received irbesartan and placebo, respectively. Throughout the study, there were no significant variations in the weights of the participants (53.3±23.9 vs 53.9±23.2 kg and 42.8±16.8 vs 43.6±16.5 kg, for the baseline and final weights in the irbesartan and placebo groups, respectively).

No subject dropped out or withdrew consent; thus, all the randomized children satisfactorily completed the intervention trial and were included in the analysis of data (Figure 1). Irbesartan was well tolerated and there were no adverse events or side effects attributable to irbesartan or the placebo. The adherence to treatment was 100% in all the subjects in both groups.

Table 1 shows the characteristics of the participants. At baseline, there were no statistically significant differences between the groups. At the end of the study, creatinine clearance significantly decreased in the children who received irbesartan, remaining without significant changes in the control group. Similarly, urinary albumin excretion decreased in the irbesartan group but not in the controls.


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Table 1. Laboratory characteristics of the randomized children

 
Although fasting serum glucose levels and HbA1c were elevated in both groups, insulin requirements remained without significant changes throughout the 3 months of intervention and without significant differences between the two groups (Table 2).


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Table 2. Daily insulin requirements

 
At end of follow-up, only four children, two in each group, achieved serum glucose levels <140 mg/dl [132.0±4.2 vs 122.4±1.4 mg/dl (P = 0.49) in the groups with irbesartan and placebo, respectively]. In this subgroup of children, creatinine clearance was significantly lower in those patients who received irbesartan (85.5±8.4 vs 172.3±33.8 ml/min; P = 0.038). On the other hand, three children who received irbesartan and four in the placebo group remained with serum glucose levels >200 mg/dl (215.2±16.8 vs 230.2±31.5 mg/dl; P = 0.21). In these uncontrolled diabetic patients, also the creatinine clearance at the end of the study showed a significant decrease (87.5±9.0 vs 157.0±9.8 ml/min; P = 0.0003) in those who received irbesartan.

Figure 2 shows the variations of creatinine clearance starting 3 months before randomization, through 3 months of pharmacological intervention and ending 1 month after the intervention phase of the study. In the irbesartan group, creatinine clearance showed a significant reduction from the first month of treatment — a decrease that was sustained throughout the intervention period. Creatinine clearance did not vary significantly in the control subjects. Following the stoppage of irbesartan, there was a significant increase of creatinine clearance in the subjects who received it and 1 month later its levels were similar to the baseline values.



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Fig. 2. Creatinine clearance variations in the children receiving irbesartan (filled circles) and placebo (open squares). The x-axis shows months (0 corresponds to randomization and month +1 to the first month after the end of the pharmacological intervention phase of the study) and the y-axis shows creatinine clearance values. Before randomization there were no variations in creatinine clearance. From the first month of treatment, children in the irbesartan group showed a significant fall in creatinine clearance, whereas children in the placebo group showed no changes. At month +1, creatinine clearance in the children who received irbesartan returned to levels similar to baseline values. *P<0.05.

 
Systolic and diastolic blood pressures before the administration of irbesartan or placebo and through the intervention phase of the study were nearly identical in both groups (Figure 3).



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Fig. 3. Systolic/diastolic blood pressure in the children receiving irbesartan (filled circles) and placebo (open squares). The x-axis shows months (0 corresponds to randomization) and the y-axis shows blood pressure. At the beginning of the study, 3 months prior to randomization, systolic blood pressures in the irbesartan group were significantly higher than in the placebo group, but from month 1, blood pressures were similar in both groups. *P < 0.05.

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our study demonstrates that treatment with irbesartan significantly reduces creatinine clearance in non-hypertensive type 1 diabetic children with renal hyperfunction.

Diabetic patients go through several stages of renal disease, moving from normo- to micro- to macroalbuminuria to renal failure [1]. Although the Diabetes Control and Complications Trial [2] showed that optimized glucose control could reduce the incidence of microalbuminuria and nephropathy, 20% of diabetics developed microalbuminuria even with optimal care. Thus, what is required is the early recognition and treatment of subjects at high risk for developing diabetic nephropathy. In this regard, the presence of glomerular hyperfiltration, frequently detectable in type 1 diabetic subjects without any other evidence of incipient diabetic nephropathy [7], has been identified as an independent predictor of the development of albuminuria [7,9,10]. Therefore, the early recognition and treatment of glomerular hyperfiltration in uncontrolled type 1 diabetic patients may prevent or delay the development of microalbuminuria [11,12].

The renin–angiotensin system, a paracrine regulator of renal function, plays an important role in the progression of renal disease. Since angiotensin II constricts the efferent arteriole, increasing glomerular pressure and altering permeability, ACE inhibitors are usually indicated in diabetic subjects with microalbuminuria [1] to improve renal haemodynamics and delay progression to end-stage renal disease [13]. On the other hand, the selective blockade of the receptors of AT1 — which inhibits angiotensin more directly than ACE inhibitors, blocking the angiotensin generated by non-ACE pathways without significant alteration in bradykinin metabolism [14] — also could be successfully used in microalbuminuric diabetic patients.

The mechanism of renoprotection by an AT1-receptor antagonist is complex, involving haemodynamic, biochemical and hormonal effects that decrease intraglomerular pressure and collagen formation and invoking also the lowering of the rate of protein excretion [15,16]. In addition, a transient increase in urinary sodium excretion has been described; however, this natriuretic response to AT1-receptor antagonist has not been investigated exhaustively in humans [15]. Since we did not evaluate the role of these factors possibly involved in the renoprotection induced by irbesartan, it was not possible in this study to determine the mechanism implicated in the observed reduction of creatinine clearance. It will be necessary to conduct specific long-term follow-up studies to increase knowledge in this area.

Experiments with AT1-receptor antagonists suggest that these agents can decrease the filtration fraction and, thus, could exert a favourable influence on renal function [17]. None the less, there are no previous studies to show the effect of irbesartan on renal hyperfunction in non-hypertensive, uncontrolled diabetic children. So, although glomerular hyperfiltration increases the risk of developing microalbuminuria in type 1 diabetic patients [7,9], whether or not reducing the GFR has clinical significance in the renoprotection of non-hypertensive, uncontrolled diabetic patients remains to be established. Since this study for the first time provides evidence about the effect of irbesartan on the earliest phase of renal disease in type 1 diabetic children, its clinical relevance is not supported by any other evidence in the paediatric literature.

A previous controlled 8 year follow-up study in type 1 diabetic patients showed that ACE inhibitors exert their nephroprotective effect in ways independent of their effects on blood pressure [18]. In our study, only normotensive type 1 diabetic children were included and although systolic/diastolic pressure in the children who received irbesartan showed a slight reduction, there were no significant differences in blood pressure between the two groups, suggesting that the reduction of creatinine clearance by irbesartan could be independent of its blood pressure-lowering effect. It is necessary to keep in mind, however, that given the small sample size, the non-parametric distribution of systolic and diastolic pressures and the fact that we only measured blood pressure monthly, the suggestion that the reduction in creatinine clearance was independent of irbesartan's effect on blood pressure cannot be supported sufficiently. In addition, we cannot establish if the drop in blood pressure in the irbesartan group was the result of circadian variations or if it represents the effect of irbesartan. Further studies with 24-h measurements of blood pressure will be needed to clarify this matter.

The main goal in the treatment of diabetic nephropathy is the strict control of glycaemia and aggressive antihypertensive treatment [19,20]. In this study, the physician who oversaw the metabolic control of the participants was blinded to the group assignments of patients and the endpoint of the trial. On the other hand, the high glucose levels and elevated HbA1c percentage that participants in both groups showed during the study, although not corresponding to the desirable outcome of metabolic control, closely mirror what frequently occurs in clinical practice. In our cohort, the children who received irbesartan, both those whose diabetes was controlled and those who were not controlled, showed a significant decrease in creatinine clearance, suggesting that the effect of irbesartan was independent of metabolic control. Thus, irbesartan could be useful for reducing hyperfiltration in those type 1 diabetic patients whose glycaemic control cannot be improved. Nonetheless, it is necessary to emphasize that efforts to delay or prevent the development of renal disease and other microvascular complications in diabetic patients should focus on the best possible metabolic control, which must be the overarching goal in the treatment of diabetic patients.

Several potential limitations of this study deserve to be mentioned. First, it was designed as a short-term trial and although the reduction in creatinine clearance was significant from the first month of intervention, and was sustained through the 3 months of the study, longer observations are necessary to determine whether or not this reduction provides nephroprotection and reduces progression to end-stage renal disease. Second, we tested a small number of normotensive diabetic children and although the sample size was enough to adequately demonstrate differences in the primary endpoint of the trial, it will be desirable to conduct a multicentric study to enlarge the sample size and to determine the clinical significance of the early reduction of creatinine clearance. Finally, the short follow-up and the small sample size cannot establish whether or not non-hypertensive, uncontrolled diabetic children with renal hyperfunction should be treated for years with irbesartan. What this study indicates is that renal hyperfunction in children with poor glycaemic control can be reversible in the short term by treatment with irbesartan.

In conclusion, irbesartan has excellent tolerability and it significantly reduces creatinine clearance in non-hypertensive, non-controlled type 1 diabetic patients with renal hyperfunction.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 18. 5.04
Accepted in revised form: 1.12.04





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