Renal complications of childhood type 1 diabetes

Abstract

Are correlated with glycated haemoglobin, so tight control is needed from the start

The primary goal of managing childhood type 1 diabetes is to prevent or delay retinal and renal microvascular complications. Because lesions are silent for a long time,¹ glycated haemoglobin (HbA_1c) concentrations are used as a surrogate measure of the adequacy of treatment to avoid diabetic complications. Most of our knowledge of the relation between control of diabetes and the risk of renal complications of diabetes comes from data in adults and adolescents, so it is important to have a precise evaluation of the risk in children.

In the accompanying paper, Amin and colleagues report on the risk of diabetic renal disease in the Oxford regional prospective study, a population based cohort study of children with type 1 diabetes.² The prevalence of microalbuminuria was about 25% and 50% after 10 and 20 years of diabetes, respectively. The natural course of microalbuminuria was such that about half of patients reverted at least transiently to normoalbuminuria and 13% progressed to macroalbuminuria. The study answers important questions for those who care for children with diabetes.

The main result of the study is that mean HbA_1c is a strong predictor—and the only modifiable one identified—of microalbuminuria, with a hazard ratio of 1.39 (95% confidence interval 1.27 to 1.52), for each 1% increase of HbA_1c. The study did not directly assess whether an HbA_1c threshold existed, below which the risk of microalbuminuria is null or minimal. However, the group with a mean HbA_1c lower than 8.5%, the best controlled group of patients in the study, was not protected—these patients had around a 15% risk of microalbuminuria at the age of 20 years.

The role of the control of diabetes during childhood—as opposed to later in life—in determining the risk of complications is important because the complications of diabetes are first identified after the onset of puberty, even in patients with early onset of disease. In Amin and colleagues’ study,² the prevalence of microalbuminuria was not influenced by the age of onset of diabetes after 15 years of disease, indicating that the deleterious effect of hyperglycaemia is similar in childhood and later in life. In apparent contradiction, a Finnish study found a lower risk of end stage renal disease after 30 years of diabetes in patients who were diagnosed before the age of 5 years.³ Further studies are needed to evaluate whether the rate of progression from microalbuminuria to macroalbuminuria and renal insufficiency is influenced by the age at onset of diabetes.⁴

Are these results representative of the health of children with diabetes elsewhere? The mean HbA_1c of the cohort (9.8%) is higher than was seen in two large paediatric collaborative studies, which found a mean HbA_1c of 8.6-9%.^{5 6} However, neither of these studies was population based, so Amin and colleagues’ results are probably an unbiased representation of care for childhood diabetes in Europe. They remind us that, in practice, we are far from the HbA_1c threshold of less than 7.5% in teenagers, 8% in children, and 8.5% in toddlers recommended by the American Diabetes Association—in their study, even the best controlled group of patients did not reach these thresholds.⁷

Other important predictors of diabetic kidney disease need to be considered.² Higher glucose variability for a given HbA_1c value has been proposed as an independent predictor of complications.⁸ Although the influence of glucose variability is controversial, it would be worthwhile examining this measure in Amin and colleagues’ study. Individual factors—whether genetic or epigenetic—have an important role in modulating the risk of diabetic complications, and it will be essential to identify them as covariates to HbA_1c.^{9 10}

A small proportion of patients with microalbuminuria in the study were treated with antihypertensive drugs with rather unsatisfactory results. This finding should be interpreted with caution, however, because indications for use of antihypertensive drugs were not controlled, and compliance is often poor in adolescents and young adults with a long history of chronic disease. As discussed by the authors, no data are available on the use of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in adolescents with diabetic nephropathy, and intervention trials are needed to evaluate whether treatments recommended for adults with microalbuminuria are similarly renoprotective in adolescents.¹¹

In summary, Amin and colleagues’ study unequivocally shows that both recent and more remote concentrations of glycated haemoglobin are associated with the risk for microalbuminuria and progression from microalbuminuria to macroalbuminuria. They remind us that the future is dim for children with diabetes unless their disease is rigorously controlled throughout childhood and adolescence by diet, education, adequate delivery of insulin, and control of blood glucose, while avoiding hypoglycaemia. Paediatricians are often torn between the inclination to reduce the pressure on patients and families and the need to use sophisticated but demanding treatments, such as multiple injections, pumps, and—more recently—continuous glucose monitoring.¹² These new data will certainly help doctors counsel their patients and families on treatment options that should more than ever focus on tight diabetes control with targets such as those recommended by the American Diabetes Association.