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Diabetes - persistent microalbuminuria in children and young people with diabetes mellitus

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Introduction

Diabetic kidney disease (DKD) occurs in 20-40% of patients with diabetes and is the leading cause of end stage renal disease 1,2. Whilst severe DKD is rarely seen in childhood, structural changes characteristic of DKD on kidney biopsies appear as early as 1 - 1.5 years following diagnosis18. Persistent microalbuminuria (MA) is an early indicator of DKD 1,2, and a well-established marker for increased cardiovascular risk 15. However, the albumin excretion rate (AER) in paediatric populations is extremely variable and can be transient in nature 25, with 30-40% of cases of children with MA regressing to normoalbuminuria with improved glycaemic and BP control21. Young onset type 2 diabetes mellitus is associated with more co-mordities and risk factors and faster progression of DKD than type 1 diabetes mellitus. There is a need for regular surveillance of urine MA in children with diabetes mellitus to detect the presence of persistent MA and hence increased risk for renal complications of diabetes. Identifying persistent MA in children allows for early treatment and assessment of renal disease progression. In the absence of strong paediatric data, recommendations for use of angiotensin-converting-enzyme inhibitor (ACEI) therapy in paediatric patients with persistent MA to prevent progression to proteinuria are based on local expert opinion, consensus guidelines and adult data.

Stages, clinical features and clinical course of diabetic kidney disease

Diabetic nephropathy has been traditionally categorised into stages based on the values of urinary albumin excretion rate (AER), microalbuminuria (MA) and macroalbuminuria (see table below). There is accumulating evidence suggesting that the risk for developing diabetic nephropathy and cardiovascular disease starts when AER values are still within the normoalbuminuric range.

Stage Urinary albumin (mg/L) GFR (eGFR)  (ML/min)
Stage 1
Pre Nephropathy
Normoalbuminuria (<30) ≥30
Stage 2
Incipient Nephropathy
Microalbuminuria (30-299) ≥30
Stage 3
Overt Nephropathy
Macroalbuminuria (≥300) ≥30
Stage 4
Kidney Failure
Any albuminuria <30
Stage 5
Dialysis therapy
Any albuminuria on continued dialysis therapy <30

Measurement of microalbuminuria

Annual screening for microalbuminuria (MA) in children with type 1 diabetes mellitus should start at 5 years post diabetes mellitus diagnosis for children under 10 years of age, or at 2 years post diagnosis for children over 10 years of age.  Annual screening for MA in children with type 2 diabetes should start at time of diagnosis.

Screening can be done by either of these methods:

  • first morning urine samples for urinary albumin/creatinine ratio (ACR) (preferred method)
  • Timed urine collections for albumin excretion rate (AER)

Definition of microalbuminuria

Diagnosis of incipient nephropathy is defined as any of the following:

  • AER between 20 and 200 μg/min
  • AER between 30 and 300 mg/24 hr in 24 hr or timed urine collections
  • Albumin concentration 30-300 mg/L (early morning urine sample)
  • ACR 2.5-25mg/mmol or 30-300 mg/g in males and 3.5-25mg/mmol in females (because of lower creatinine excretion)

A single elevated microalbuminuria (MA) screen does not indicate 'persistent' MA. 

Further investigating the child with a random positive microalbuminuria screen

Albumin excretion ratio (AER) is estimated to be the lowest in children <6 years old, followed by an increase through the adolescent years and a peak at age 15-16 years due possibly to the confounding influence of orthostatic proteinuria.

Further screening must be undertaken to ascertain level of persistency. Microalbuminuria (MA) can regress, remain unchanged or progress to macroalbuminuria.

Risk factors for MA are elevated HbA1c, blood pressure, LDL, triglycerides, high normal urine albumin excretion, obesity and smoking.

Two of three abnormal results of consecutive specimens for ACR (preferred method) or AER collected over a 3-6month period should be used as evidence of persistent MA

In cases where elevated MA is found in the presence of hypertension, collection of further specimens to ascertain persistent MA may be collected over a lesser time period with consideration for further investigating possible renal or cardiovascular causes.

Confounders affecting microalbuminuria screening

The following confounders can affect the results of microalbuminuria and timing of screening samples should be avoided when any of the following are present:

  • Strenuous exercise
  • Menstrual bleeding
  • Infections
  • Fever
  • Kidney diseases
  • Marked hyperglycaemia.

Approach to management of the child with persistent microalbuminuria and diabetes mellitus

Initial assessment and investigations

  • Medical history (duration of diabetes, metabolic control)
  • Family History (renal or cardiovascular disease)
  • Lifestyle assessment (smoking, dietary review)
  • Clinical Examination
    • Abdominal pain (urinary tract infection)
  • Blood Pressure
  • Urinalysis (microscopy & culture)
  • Renal function (U&E, creatinine, uric acid, lipids)

Second line investigations

Loss of nocturnal dipping is an early marker of diabetic renal disease preceding microalbuminuria (MA)4. Consideration for 24 hour ambulatory BP monitoring may be considered where persistent MA is diagnosed in the presence of intermittent or persistent elevated blood pressure measurements >90th centile.

Management of persistent microalbuminuria

  • Improvement in metabolic control (HbA1c) is the mainstay in diabetes related microalbuminuria (MA) in childhood, especially during adolescence.
  • Abnormal lipid studies are often detected in adolescents with diabetes mellitus however there is no consensus on the role of statin treatment in the adolescent age group due to the abesence of randomised controlled trial data.
  • Dietary modification with a focus on weight reduction and reduced salt intake is strongly encouraged for those with elevated blood pressure (BP) measurements in addition to persistent MA.
  • Lifestyle changes are integral to the successful treatment of persistent MA.
  • Confirmed hypertension (BP>95% for age, gender and height) or albuminuria should be treated with an ACEI. If not tolerated discuss the use of an angiotensin receptor blocker (ARB) with the Specialist Nephrology Team.
  • Pharmacological renoprotective treatment with ACEI is indicated for all patients with persistent MA regardless of BP measurements. Single agent ACEI suitable for once daily dosing is the preferred choice.
  • Side-effects of ACEI are cough (10%), hyperkalaemia, headache and impotence. In addition, major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in non-diabetic women.
  • There is increased risk of hypoglycaemia related to ACEI-induced increased insulin sensitivity.

During acute illness where there is a high potential for dehydration, ACEI/ARB's must be stopped to avoid acute kidney injury. These can resume once acute illness has resolved.

 

Table 1: ACEI therapy for management of persistent microalbuminuria in children with diabetes aged 1-17 years.

Class Drug Dose Frequency Comments
ACEI  Lisinopril Initial: 0.1 - 0.2 mg/kg/day up to 5mg/day
Max: 1mg/kg/day up to 40mg/day
Once daily Once daily Round doses to tablet size
Tablets can be halved
Soluble in water
 Enalapril Initial: 0.1mg/kg/day up to 5mg/day
Max: 1mg/kg/day up to 40mg/day 
Once or twice daily  Liquid manufactured 1mg/ml
Liquid requires HEC for discharge 
Patients who cannot tolerate ACEI and need to be treated with an angiotensin receptor blocker (ARB) should be discussed with a Paediatric Nephrologist.
Funding: Medications listed above are fully funded as tablets unless specified. Availability of liquid formulations is listed where possible with strength used at ADHB, including any additional funding requirements.

Required monitoring following commencement of ACEI therapy for children with persistent microalbuminuria and diabetes mellitus

Initial monitoring

  • Potassium supplements and potassium sparing diuretics are contraindicated during ACEI therapy
  • Blood pressure (BP) and serum electrolytes (Na+, K+ & creatinine) to be checked within 4 weeks of commencement of ACEI therapy and after each dose change
  • ACEI doses should be adjusted no more frequently than every 4-6 weeks after commencement of treatment therapy or after dose titration
  • First morning ACR is recommended 3 months after commencement of ACEI therapy and after each dose change
  • Assessment of dose effectiveness to be based on individual response (i.e. improvement in % reduction ACR when being used for reno-protection; and/or maintaining target BP when used for anti-hypertensive effect)

Ongoing Monitoring

  • Annual screening of serum electrolytes (Na+, K+, creatinine, uric acid and lipids) needs to be checked alongside BP and ACR as part of routine complications screening

Caveat: Comprehensive sexual health and family planning education must be provided to young females using ACEI therapy to ensure complete understanding of possible adverse effects during pregnancy and the subsequent need for reliable contraception.

Information for Families

Patient Information Pamphlet on ACEI

References

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  6. Brito, P.L., Fioretto, P., Drummond, K., Kim, Y., Steffes, M.W., Basgen, J.M., Sisson-Ross, S., Mauer, M. (1998) Proximal tubular basement membrane width in insulin-dependent diabetes mellitus. Kidney Int 53, 754-761

  7. Bullo, M., Tschumi, S., Bucher, B., Bianchetti, M. & Simonetti, G. (2012). Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 60, 444-450.
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  21. Rudberg, S., Aperia, A., Freyschuss, U., et al. (1990). Enalapril reduces microalbuminuria in young normotensive type 1 (insulin-dependent) diabetic patients irrespective of its hypotensive effect. Diabetologia 33 (8), 470-6.
  22. Rudberg, S., Dahlquist, G. (1996) Determinants of progression of microalbuminuria in adolescents with IDDM. Diabetes Care 19, 369-371
  23. Rudberg, S., Osterby, R., Bangstad, H.J, et al. (1999). 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 42 (5), 589-95.
  24. Salardi, S., Balsamo, C., Zucchini, S., Maltoni, G., Scipione, M., Rollo, A., Gualandi, S., Cicognani, A. (2011) High rate of regression from micromacroalbuminuria to normoalbuminuria in children and adolescents with type 1 diabetes treated or not with enalapril: the influence of HDL cholesterol. Diabetes Care 34, 424-429.
  25. Schultz, C.J., Konopelska-Bahu, T., Dalton, R.N., et al. (1999). 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 22(3), 495-502.
  26. Schwartz, G.J, Work, D.F. (2009). Measurement and estimation of GFR in children and adolescents. Clinical Journal American Society Nephrology 4, 1832-1843
  27. Strippoli, G.F., Craig, M., Deeks, J.J., et al. (2004). Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 329 (7470), 828.
  28. Yuksel, H., Darcan, S., Kabasakal, C., et al. (1998). Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes. Pediatr Nephrol 12 (8), 648-50.
  29. Wong, W. (2015) Hypertension. Starship Clinical Guideline. (2015). Retrieved 9 March, 2016 from: /for-health-professionals/starship-clinical-guidelines/h/hypertension/

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Document Control

  • Date last published: 28 June 2016
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Endocrinology
  • Author(s): Rosalie Hornung, Craig Jefferies, Paul Hofman, William Wong, Fran Mouat
  • Owner: Rosalie Hornung
  • Editor: Greg Williams
  • Review frequency: 2 years

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