La Nefropatia Diabetica

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1 La Nefropatia Diabetica storia naturale e nuovi aspetti patogenetici Salvatore De Cosmo IRCCS CSS San Giovanni Rotondo

2 Diabetes: The Most Common 7 Cause of ESRD Primary Diagnosis For Patients Who Start Dialysis Other Glomerulonephritis Diabetes 50.1% 10% 13% Hypertension 27% No of Patients Projection 95% CI Number of Dialysis Patients United States Renal Data System. Annual data report , , ,240 R 2 = 99.8%

3 Storia naturale della Nefropatia Diabetica Storia naturale della Nefropatia Diabetica Nefropatia incipiente Predittori: Iperfiltrazione? EUA PA HbA1c Fumo Diagnosi di DM Proteinuria creatinina ESRD Modificazioni funzionali: FR EUA Volume renale Modificazioni strutturali: Spessore della MBG Espansione del mesangio

4 Diabete di tipo 1 Studi originali ~80% in 10 anni Normoalbuminuria 30-40% in 10 anni 20-30% in 10 anni Microalbuminuria 30-50% in 10 anni Proteinuria

5 Baseline risk factors by progression: The EURODIAB PCS. PCS Progression to microalbuminuria YES (n. 143) NO (n. 972) p value HbA1c (%) 7.1± ± Cholesterol (mmol/l) 5.3± ± Fasting triglyceride (mmol/l) 1.05 (0.75, 1.50) 0.87 (0.64, 1.08) HDL (mmol/l) 1.44± ± LDL (mmol/l) 3.6± ± BMI (kg/m 2 ) 24.1± ± WHR 0.86± ± AER (µg/min) 9.6 (6.8, 13.8) 7.7 (5.4, 11.3) Peripheral neuropathy (%) Any retinopathy (%) The EURODIAB Prospective Complications Study Group, Kidney Int 60: , 2001.

6 Diabete di tipo 1 Studi originali ~80% in 10 anni Normoalbuminuria 30-40% in 10 anni 20-30% in 10 anni Microalbuminuria 30-50% in 10 anni Proteinuria

7 Regression of Microalbuminuria in Type 1 Diabetes Probability of regression (Hazard Ratio) No. of Factors at salutary levels Salutary levels: 1. HbA1c <8% 2. sbp <115 mmhg 3. A combination of: Total-Ch <198 mg/dl Triglycerides<145 mg/dl Perkins BA, NEJM, 2003.

8 Diabete di tipo 2 Lavori originali ~20% in 10 anni Normoalbuminuria 28-40% in 10 anni 20-30% Microalbuminuria Proteinuria 30-40%

9 Determinants of Microalbuminuria in Type 2 Diabetes HOPE Study DIABHYCAR Study N HbA1c sbp dbp Tabacco Age Duration DEMAND Study Gerstein HC et al., the HOPE Study. Diabetes Care 23 (suppl 2): B35-B39, 2000 Marre M et al., the DIABHYCAR Study. Diabetes Care 23 (suppl 2): B40-B48, 2000 Parving HH et al., the DEMAND Study Group. Diabetologia 47 (suppl 1): A167, 2004

10 Diabete di tipo 2 Lavori originali ~20% in 10 anni Normoalbuminuria 28-40% in 10 anni 20-30% Microalbuminuria Proteinuria 30-40%

11 0 Patients who obtained remission 0 Patients who obtained 50% remission/regression Patients progressing to overt nephropathy Normo % of patietnts % 28% -8 Diabetes 54: , 2005

12 Baseline risk factors by progression: The EURODIAB PCS. PCS Progression to microalbuminuria YES (n. 143) NO (n. 972) p value HbA1c (%) 7.1± ± Cholesterol (mmol/l) 5.3± ± Fasting triglyceride (mmol/l)1.05 (0.75, 1.50) 0.87 (0.64, 1.08) HDL (mmol/l) 1.44± ± LDL (mmol/l) 3.6± ± BMI (kg/m 2 ) 24.1± ± WHR 0.86± ± AER (µg/min) 9.6 (6.8, 13.8) 7.7 (5.4, 11.3) Peripheral neuropathy (%) Any retinopathy (%) The EURODIAB Prospective Complications Study Group, Kidney Int 60: , 2001.

13 Insulin resistance and diabetic nephropathy in patients with T1D Glucose disposal rate (mg/kg.min) * * P<0.05 Glucose disposal rate (mg/kg.min) * * 0 UAE + - UAE T1D T1D C + - Lancet, 1993 Nephrol Dial Transplant, 1998

14 Association between insulin resistance and diabetic nephropathy in T2D Author Journal Year N Association L. Groop Diabetologia YES J.S. Yudkin J Diabetes Compl YES C.E. Mogensen Diabetes Care NO R. Nosadini Diabetes YES G.M. Reaven Metabolism NO C.D.A. Steatouwer Diabetologia (174 T2D) NO

15 Risk to develop micro-macroalbuminuria according to quartiles of HOMA IR in 712 T2D 2.0 ORs 2,5 2 1,5 0.9 ( ) 1.3 ( ) ( ) 1 0,5 0 I II III IV Quartiles of HOMA IR De Cosmo et al. Diabetes Care 2005

16 Glucose disposal rate p = M-value (mg/kg/min) Normo Micro Parvanova AL et al Diabetes, 2006

17 Definizioni delle anormalità dell AER Raccolta 24 ore (mg/24 die) Raccolta overnight (μg/min) Campione del mattino (μg/mg creatinina) Normale < 30 < 20 <30 Microalbuminuria Albuminuria clinica > 300 >200 >300

18 Screening della Nefropatia Diabetica Dipstick Urine Positivo Negativo Urine del mattino Valutazione nefrologica Monitoraggio FG Intervento A/C< 2.5M, 3.5F mg/mm A/C >2.5M, 3.5F mg/mm Controllo annuale A/C Valutare e trattare le cause intercorrenti A/C< 2.5M, 3.5F mg/mm A/C >2.5M, 3.5F mg/mm AER (3 in 3-6 mesi) AER <20 μg/min no nefropatia AER >20 e<200μg/min Microalbuminuria, nefropatia incipiente AER >200μg/min Macroalbuminuria, nefropatia conclamata

19 Variabilità dell escrezione escrezione urinaria dell albumina Rilevanza nella pratica clinica 1. Variabilità intra-individuale biologica dell'aer e del si rapporto albuminuria/creatininuria (CV ~30-50%) 2. Diabete in cattivo controllo glicemico o diabete si di nuova diagnosi 3. Esercizio fisico/postura si* 4. Infezione delle vie urinarie si 5. Insufficienza cardiaca verosimile 6. Malattie intercorrenti no 7. Carico idrico (effetto transitorio) no 8. Ematuria, flusso mestruale, infezioni genitali si 9. Carico orale di proteine (effetto transitorio) no * raccolte urinarie overnight o early morning escludono questo problema.

20 Definition of CKD (according to Kidney/Disease Outcomes Quality Initiative) Structural or functional abnormalities of the kidneys for >3 months, as manifested by either: 1. Kidney damage, with or without decreased GFR, as defined by pathologic abnormalities markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests 2. GFR <60 ml/min/1.73 m 2, with or without kidney damage

21 Prognosis declines with progressing CKD Hospitalisation CV Events Death > <15 > <15 > <15 Rates per 100 person years Estimated egfr (ml/min/1.73m 2 ) Estimated egfr (ml/min/1.73m 2 ) Decreasing egfr Go et al. NEJM 2004; 351: Increasing event rate Rates per 100 person years Rates per 100 person years Estimated egfr (ml/min/1.73m 2 )

22 Prevalence of chronic kidney disease (left) and microalbuminuria (right) by number of the metabolic syndrome components 10 9, ,1 Prevalence, % ,0 4,9 2,9 0,3 0, Prevalence, % ,6 9,8 6,8 4,9 3, Metabolic Syndrome Risk Factors, n Metabolic Syndrome Risk Factors, n Chen J et al. Ann Intern Med 140:167, 2004

23 Risk to have CKD according to MS Syndrome score in patients with T2D ( ) ( ) ORs MS r-score MS Syndrome score De Cosmo S. et al., Diabetes Care, 2006

24 Diabetes Care, in press

25 Formule per la stima del GFR formula di Cockroft e Gault: GFR (ml/min) = [(140-età) x peso (kg)] / [72 x creatinina (mg/dl)] (x 0.85 nelle donne) formula di Levey (MDRD modificata): GFR (ml/min/1.73 m 2 ) = 186 x creatinina (mg/dl) x età (anni) x (nelle donne) x (in soggetti di razza nera)

26 Effetti del miglioramento del controllo glicemico nel diabete tipo 1 IL DCCT Retinopatia Nefropatia Neuropatia CVD Prevenzione -38% -22% -36% primaria -40%* Prevenzione -27% -28% -29% secondaria * ns Riduzione del rischio per riduzioni dell 1% della HbA1c Diabetes Control and Complications Trial Research Group, N Engl J Med, 329: , 1993

27 Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors? Progression to Macroalbuminuria 0.38 ( ) Randomized clinical trials of ACEi in microalbuminuric type 1: 8 trials: 240 pts on ACEi, and 234 on placebo Regression to Normoalbuminuria 3.07 ( ) Odds ratio The ACE Inhibitors in Diabetic Nephropathy Trialist Group Ann Intern Med 2001; 134:

28 IRBESARTAN IN HYPERTENSIVE, MICROALBUMINURIC TYPE 2 DIABETIC PATIENTS - IRMA 2 Incidence of macroalbuminuria Change in albuminuria % % % % p = % % % mg 300 mg mg - 30 % 300 mg Placebo Irbesartan Placebo Irbesartan Blood pressure control comparable in the two treatment groups Parving et al., N Engl J Med, 2001

29 -0.47

30 Rosiglitazone and Proteinuria 0% All Randomized Patients Patients With Baseline Microalbuminuria n=64 n=57 n=16 n=14 Comparison to Baseline (% Change) -20% -40% -60% -9% (95% CI: -20.9, 4.6) -26% (95% CI: -44.3, -2.7)* -23% (95% CI: -43.1, 5.1) -54% (95% CI: -77.8, -3.4)* -80% Glyburide RSG 8 mg/day Glyburide RSG 8 mg/day *p<0.05 vs. glyburide Bakris, G., J Hum Hypert 2003, 17: 7 12.

31 Conclusioni La ND è una complicanza frequente e devastante per i pazienti diabetici La microalbuminuria rappresenta un fattore predittivo importante di danno renale avanzato e di evento CV La sindrome metabolica/insulino resistenza appare avere un ruolo importante nel determinismo del danno renale Nuove strategie diagnostiche, preventive e terapeutiche dovranno tenere in considerazione questi nuovi aspetti patogenetici