1. Diabetic Nephropathy in the Adolescent Age Group Henry Rodriguez, M.D. Associate Professor of Pediatrics Indiana University School of Medicine Director, Pediatric Diabetes Clinical Program James Whitcomb Riley Hospital for Children

2. Occurrence/Epidemiology 1. 1.Leading cause of ESRD in the Western world. Accounts for almost ½ of all new cases of ESRD. Develops in 15-40% of patients with T1DM. Peak incidence after 15-20 years of DM.

3. Diabetic Nephropathy: 5 Stages 1. 1.Increase in renal size & increase in GFR by 20–40%, (hyper-filtration). Seen in 25–50% of patients. Reversible microalbuminuria. BP typically is normal during this period. No histological lesions in glomeruli or vascular structures. 2. 2.Glomerular basement membrane (GBM) thickening & mesangial matrix expansion. Typically occur during the first 2–5 years post-diagnosis. MA is only present during periods of poor metabolic control & with exercise. Patients may continue in this stage for many years or throughout their lives. Urinary albumin excretion begins to rise within the normal range in a set of patients that will ultimately develop MA.

4. Stages of Diabetic Nephropathy (cont.) 3. 3. Microalbuminuria (MA). Found in approx 1/3 of patients. Develops 7– 10 years after diagnosis 1 st clinical sign of DN. In adults with T1DM, the presence of MA indicates a 4- to 5-fold increase in the risk of progression to further stages, but in adolescents with MA detected in the first decade of diabetes, progression is much less predictable. GFR is normal or elevated. May have increased BP within the conventional age-corrected normal range (about 3 mmHg/year) An increase in nocturnal systolic BP in adolescents precedes the development of MA.

5. Stages of Diabetic Nephropathy (cont.) 4. 4. Overt (clinical) proteinuria (>0.5 g/24 h). Found in 15–20% of patients or less after 15–25 years of diabetes. Commonly associated with the presence of other microvascular complications, particularly retinopathy. Increasing albumin excretion rate (AER) is generally accompanied by a steady rise in BP (by about 3 mmHg/ year) and decline in GFR (approx.10 ml/min per year). Proteinuria imparts a 40-fold increase in mortality. 5. 5.End-stage renal disease (ESRD) Usually 5–10 years after the appearance of overt proteinuria.

6. Factors that influence the onset / Progression 1. 1.Metabolic control 2. 2.Duration of diabetes 3. 3.Puberty 4. 4.Age at onset 5. 5.Higher BP 6. 6.Smoking 7. 7.Hyperlipidemia 8. 8.Family history of diabetic complications (genetic factors)

7. Data for Consideration: A1c, BP, Smoking 1. 1. Any level of sustained improvement in glycemic control is associated with risk reduction (DCCT & EDIC). 2. 2. It is total duration of disease rather than duration before or after puberty that affects the rate of progression of GBM and mesangial lesions characteristic of DN (International Diabetic Nephropathy Study Group). 3. 3. Non-dipping of nocturnal blood pressure is related to morphological changes in normoalbuminuric adolescent and young adult T1DM patients.. These may be early predictors of later nephropathy. 4. 4. Cigarette smoking in diabetic children correlates with AER, independent of age and other variables, and is more prevalent in the borderline albuminuria and MA groups (2.8-fold increased risk of MA).

8. Data for Consideration: Lipids & Genetics 4. 4. Serum cholesterol may play an important role in the development and progression of DN. – –In DCCT/EDIC, higher total and LDL cholesterol and higher triglyceride levels were associated with development of MA. – –Large-scale prospective randomized controlled studies in adolescents are lacking. 5. 5. The risk of diabetic complications is most likely partly inherited – –only a portion of patients with T1DM or T2DM will develop DN irrespective of glycemic control. – –The risk that diabetic siblings of diabetic proband with nephropathy will also have nephropathy is 3- to 4-fold increased compared with diabetics whose siblings have no nephropathy. – –Gene linkage analysis and genome wide scans have identified several candidate genes that influence susceptibility to DN.

9. Screening: Options 1. 1. Urine for Microalbumin - -Starting when & how often? - - At dx? At puberty? Five years post-dx? - -If screen positive, when to repeat? - -If persistent, renal evaluation to rule out other causes? 2. 2. Blood Pressure - -Ideally at all clinic visits – at least annually and compared to sex-, age-, and height-appropriate norms. - -Place for 24-h ambulatory BP monitoring? - -Family history of HTN? 3. 3. Lipids - -Starting when & how often? - - At dx? At puberty? Five years post-dx? Follow-up if normal? 4. 4. Smoking - -Prevention is ideal. If not, cessation.

10. Treatment: Options   Prevention must focus on changing potentially modifiable risk factors: optimizing blood glucose, controlling BP, discouraging smoking, encouraging healthy diet, and encouraging healthy exercise.   In those with MA, the goal is to prevent progression of MA to overt proteinuria and the decline of renal function. 1. 1.Glymcemic control. 2. 2.Protein restriction (0.8-1 g/kg/day)? 3.ACE Inhibitors vs. angiotensin ll type 1 receptor blockers? - -possible teratogenic effect 4. 4.Statins?

11. Unanswered Questions 1. 1.Rate and predictors of MA development and factors involved in regression. 2. 2.Unknown fiscal impact of different screening strategies. 3. 3.Unknown patient impact of screening. 4. 4.Need to standardize screening tests – particularly for HTN. 5. 5.Need more long-term studies of statin therapy starting in adolescence. 6. 6.Need long-term randomized studies with ACEI’s* and ARBs in children and adolescents. 7. 7.Need to identify biomarkers that will identify risk for nephropathy prior to the development of MA.