Screening for DKD

ISPAD, ADA and NICE guidelines recommend annual screening for DKD using ACR, and suggest using an early-morning urine sample to help minimise effects of exercise and postural variation on urinary albumin excretion, which can cause it to rise later in the day.4–6 Screening for DKD and other complications is recommended from age 10 to 12 years due to relatively low risk before puberty.7 In addition, ACR can be more variable in children at a younger age.8 Screening should be based on laboratory ACR and cannot be replaced by a urine dipstick test due to the limited sensitivity and specificity of the latter for albuminuria.9

During his annual review, our young person was found to have an increased ACR of 16.8 mg/mmol in an early-morning urine sample. Raised ACR can be an early sign of DKD, although it can also have other causes, as highlighted in Box 1. The young person did not have any active infection at the time of the assessment and his blood pressure and serum lipid levels were within normal ranges. Increased ACR can often occur during puberty due to suboptimal glycaemic control, pubertal hormonal changes and other risk factors, and it can be transient, intermittent or persistent.10 Due to biological variability, albuminuria should be confirmed in repeated samples, with detection in at least two out of three samples collected over 3–6 months indicating the need for further management (figure 1).4

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Figure 1

Comparison of ISPAD, ADA and NICE guidelines for investigation and management of raised albuminuria.4–6 ACEi, ACE inhibitor; ACR, albumin/creatinine ratio; ADA, American Diabetes Association; ARB, angiotensin receptor blocker; BP, blood pressure; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; ISPAD, International Society for Pediatric and Adolescent Diabetes; NICE, National Institute for Health and Care Excellence.

Glomerular filtration rate

In addition to urinary ACR, glomerular filtration rate (GFR) is a useful marker of kidney function. The ISPAD and ADA guidelines also recommend including estimated GFR (eGFR) in DKD screening for children and young people with diabetes, although with the limitation of a lack of validated formula to calculate this in youth with T1D. A simplified version of the Chronic Kidney Disease in Children (CKiD) equation, also known as the updated Schwartz formula,11 is commonly used for eGFR calculation in children (Box 2). A recent study comparing methods to estimate GFR in young people with T1D suggested that a sex-adjusted version of the CKiD equation, CKiD1 (Box 2), was more accurate, although this study included no young people aged <17 years and very few with eGFR <90 mL/min/1.73 m².11 Another study focusing on children with T2D developed and validated the iCARE equation (Box 2) to estimate GFR, although again the prevalence of eGFR <90 mL/min/1.73 m² in the study was very low, and the equation has not yet been validated in young people with T1D.12

For our young person, eGFR using the CKiD1 equation, based on his age, sex, height and serum creatinine level, was 127 mL/min/1.73 m² (normal).

Investigations

Two subsequent early-morning urine samples were tested 1 and 2 months later, in accordance with ISPAD, ADA and NICE guidelines (figure 1). Both revealed elevated ACRs, at 15.7 mg/mmol and 36.9 mg/mmol, respectively. The latter ACR, at ≥30 mg/mmol (severely increased albuminuria), indicated an additional need for further nephrological investigations according to the ISPAD and NICE guidelines (figure 1). The young person underwent a renal ultrasound scan to exclude non-DKD causes of proteinuria, which showed no pathological findings, and a referral was made to paediatric nephrology.

Management

With three out of three urinary ACRs elevated, increased albuminuria was confirmed, prompting management as outlined in figure 1. It has been demonstrated that achieving good glycaemic control is associated with a reduced risk of progression to, and even regression of, albuminuria.10 13 Since this young person’s HbA1c was elevated (62 mmol/mol), while his blood pressure and lipid levels were normal, the first step was to optimise his glycaemia, before considering starting an ACE inhibitor or angiotensin receptor blocker (ARB). With education and support, 3 months later, his HbA1c had fallen to 54 mmol/mol and three further repeated ACR samples were all <3 mg/mmol. The young person was therefore returned to annual urinary ACR screening and his referral to paediatric nephrology was rescinded.

The decision to commence a child or young adult on an ACE inhibitor or ARB is not straightforward. While adult studies show that ACE inhibitors and ARBs prevent DKD and reduce progression to, and increase regression of, albuminuria,14 long-term studies in young people with diabetes without hypertension are still sparse. The best available evidence for adolescents with T1D and a mildly elevated ACR (top tertile for the study population, but <3 mg/mmol in >99% of participants) suggests that ACE inhibitors given for 2–4 years can reduce the cumulative incidence of moderately increased albuminuria by ~40%.15 Furthermore, these drugs may have various adverse effects, including hyperkalaemia, hypotensive headache, cough and erectile dysfunction16; this is a particularly important problem in young people as they may end up taking such medications for decades. However, a recent clinical trial investigating ACE inhibitor treatment in adolescents with T1D reported few drug side effects after 2–4 years of treatment, illustrating its safety in the short term.15 To our knowledge, there are no studies on the use of ARBs in children and young people with diabetes. However, a randomised, double-blind, controlled study showed that treatment with ARBs can reduce albuminuria in children without diabetes with chronic kidney disease and established an acceptable safety profile.17 Finally, ACE inhibitors and ARBs have potential teratogenic effects,18 which must be considered when treating adolescent girls. Females of childbearing age should receive appropriate contraception counselling prior to starting treatment.