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La Nefropatia Diabetica:

La Nefropatia Diabetica: nuove acquisizioni epidemiologiche e loro significato clinico dopo i risultati dello Studio RIACE. Giuse pp e Penno Dipartimento di Medicina Clinica e Sperimentale Azienda Ospedaliera Universitaria di Pisa.

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La Nefropatia Diabetica:

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  1. La Nefropatia Diabetica: nuove acquisizioni epidemiologiche e loro significato clinico dopo i risultati dello Studio RIACE Giuseppe Penno Dipartimento di Medicina Clinica e Sperimentale Azienda Ospedaliera Universitaria di Pisa

  2. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study • RIACE is a multicentre observational prospective study that is being conducted in 19 collaborating centres in Italy • Recruitment of patients with T2DM (n. 15,993) started in 2007 and was completed in 2008 • 160 subjects were excluded due to missing or implausible values; data from the remaining 15,773 patients were than analyzed • Age: 66.0±10.3 years (median 67 years) • Diabetes duration: 13.2±10.2 years (median 11 years) • 56.8% male and 43.2% female • 13.593 subjects (86%) completed the 4 to 6 year follow-up • NCT00715481; URL http://clinicaltrials.gov/show/NCT00715481

  3. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Albuminuria eGFR <30 1.7% Macro 4.7% 30-59 17.1% ≥90 29.6% Micro 22.2% Normo 73.1% 60-89 51.7% Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011

  4. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Renal Dysfunction is Common in Patients with T2DM 1.7% 17.1% 12.0% 62.5% 6.7% Approximately 40% of patients with T2DM show signs of CKD Approximately 20% of patients with T2DM show reduced eGFR 15,773 patients with type 2 diabetes from Italy

  5. Prevalence of nephropathy in the German diabetes population Pommer W. NDT Plus 1 (suppl 4) iv2-iv5, 2008

  6. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 15,773 patients with type 2 diabetes from Italy No CKD eGFR ≥60 & no-albuminuria n. 9,865 (62.5%) CKD stages 1-2 eGFR ≥60 & albuminuria n. 2,949 (18.7%) + + CKD stages 3-5 eGFR <60; n. 2,959 (18.8%) Micro-albuminuria n. 2,585 (87.7%) Macro-albuminuria n. 364 (12.3%) Non-albuminuric CKD stages 3-5 n. 1,673 (56.6%) Albuminuric CKD stages 3-5 n. 1,286 (43.4%) Micro-albuminuria n. 912 (30.8%) Macro-albuminuria n. 374 (12,6%) Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011

  7. The RenalInsufficiencyAnd CardiovascularEvents (RIACE) ItalianMulticentreStudy Independent correlates of Chronic Kidney Disease phenotypes 15,773 patients with type 2 diabetes from Italy Variable excluded: LDL-cholesterol Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011

  8. The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study 15,773 patients with T2DM: CKD phenotypes by age quartiles CKD stages 3-5 non-albuminuric CKD stages 3-5 albuminuric CKD stages 1-2 100 80 53.8% 60 Percent 39.1% 40 31.7% 25.4% 20 0 1st n. 1,013 (25.4%) n. 3,995 age ≤59 2nd n. 1,195 (31.7%) n. 3,767 age 60-66 3rd n. 1,622 (39.1%) n. 4,151 age 67-73 4th n. 2,078 (53.8%) n. 3,860 age ≥74 The RIACE Study Group, unpublished data

  9. The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study 15,773 patients with T2DM: CKD phenotypes by age quartiles CKD stages 3-5 non-albuminuric CKD stages 3-5 albuminuric CKD stages 1-2 100 80 M F 60 M Percent F M 40 M F F 20 0 Age, quartiles M: CKD+ n, (%) F: CKD+ n, (%) n, M/F 1st 691 (27.6%) 322 (21.6%) 2,506/1,489 2nd 854 (33.9%) 441 (28.6%) 2,225/1,542 3rd 960 (41.3%) 662 (36.2%) 2,324/1,827 4th 1029 (54.0%) 1049 (53,7%) 1,905/1,955 The RIACE Study Group, unpublished data

  10. “Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms Normoalbuminuria Normal GFR Microalbuminuria Cardiovascular events, death Macroalbuminuria Reduced eGFR ESRD Natural history of diabetic nephropathy: “non-albuminuric” pathway Natural history of diabetic nephropathy: “albuminuric” pathway

  11. “Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms

  12. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study Results: stratification by CKD NKF’s KDOQI stage and retinopathy No CKD eGFR ≥60 & no-albuminuria n. 9,865 (62.5%) CKD stages 1-2 eGFR ≥60 & albuminuria n. 2,949 (18.7%) + + CKD stages 3-5 eGFR <60; n. 2,959 (18.8%) No-retinopathy n. 2,067 (70.1%) Retinopathy n. 882 (29.9%) No-retinopathy n. 2,027 (68.5%) Retinopathy n. 932 (31.5%) Non advanced Ret n. 472 (16.0%) Advanced Ret n. 459 (15.5%) Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011

  13. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Concordance of CKD and Diabetic Retinopathy in subjects with type 2 diabetes Out of 5,908 pts with CKD, only 1,814 (31%) had also retinopathy Penno G, et al., The RIACE Study Group. Diabetes Care 35: 2317-2323, 2012

  14. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study Results: stratification by CKD NKF’s KDOQI stage and retinopathy No CKD eGFR ≥60 & no-albuminuria n. 9,865 (62.5%) CKD stages 1-2 eGFR ≥60 & albuminuria n. 2,949 (18.7%) + + CKD stages 3-5 eGFR <60; n. 2,959 (18.8%) No-albuminuria no-retinopathy n. 1,280 (43.2%) No-albuminuria retinopathy n. 393 (13.3%) Albuminuria no-retinopathy n. 747 (25.3%) Albuminuria retinopathy n. 538 (18.2%) Penno G, et al., The RIACE Study Group. Diabetes Care 35: 2317-2323, 2012

  15. UAEone value UAEtwo values Predictive performance for the mean of 3 UAE values Reference line The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study 4,062 subjects with at least two UAE measurements • Intra-individual CV: • 32.5% (14.3-58.9) • Concordance rate between a single UAE and the geometric mean: • Two UAE: • normo: 94.6%; • micro: 83.5%; • macro: 91.1%; • micro/macro: 90.6%; • Three UAE: • normo: 94.6%; • micro: 84.2%; • macro: 86.8%; • micro/macro: 90.8%. Pugliese G et al., Nephrol Dial Transplant 26: 3950-3954, 2011

  16. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study Prevalence of stages 3-5 CKD in type 2 diabetes MDRD Study: 2,959 (18.8%) CKD-EPI: 2,715 (17.2%) CKD-EPI CKD Stage MDRD Study CKD stage Total Subjects moved by the CKD-EPI equation above belove No CKD 1 2 3 4-5 No CKD 9,821 (62.3%) 234 (1.5%) 10,055 (63.8%) 1 977 (6.2%) 283 (1.8%) 1,260 (8.0%) 2 75 (0.5%) 1,591 (10.1%) 77 (0.5%) 1,743 (11.1%) 3 44 (0.3%) 23 (0.1%) 2,342 (14.8%) 2 (0.1%) 2,411 (15.3%) 4-5 48 (0.3%) 256 (1.6%) 304 (1.9%) Total 9,865 (62.5%) 1,052 (6.7%) 1,897 (12.0%) 2,701 (17.1%) 258 (1.7%) 15,773 (100.0%) Pugliese G et al., Atherosclerosis218: 194-199, 2011

  17. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study Prevalence of stages 3-5 CKD in type 2 diabetes MDRD Study: 2,959 (18.8%) CKD-EPI: 2,715 (17.2%) Pugliese G et al., Atherosclerosis218: 194-199, 2011

  18. Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular Filtration Rate Reclassification across estimated GFR categories Matsushita K et al, JAMA 307: 1941-1951, 2012

  19. Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular Filtration Rate Net reclassification improvements for all-cause mortality, cardiovascular mortality, and ESRD Matsushita K et al, JAMA 307: 1941-1951, 2012

  20. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Results: Any CVD event by CKD phenotype Chi square, p<0.0001 576 (44.8%) 50 40 528 (31.6%) 794 (26.9%) 30 Major CVD events, % 1,756 (17.8%) 20 10 0 No CKD n. 9,865 CKD stages 1-2 n. 2,949 CKD stages 3-5 nonalbuminuric n. 1,673 CKD stages 3-5 albuminuric n. 1,286 Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  21. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Logistic regression analysis of all CVD events with CKD phenotypes as covariates Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  22. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study CVD events in type 2 diabetic patients stratified by CKD and Diabetic Retinopathy Penno G, et al., The RIACE Study Group. Diabetes Care 35: 2317-2323, 2012

  23. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  24. Risk of coronary events in people with chronic kidney disease compared with those with diabetes:a population-level cohort study 1,268,029 participants; median follow-up of 48 months; the Alberta Kidney Disease Network 75,871 1,104,713 12,960 15,368 59,117 Tonelli M et al.,Lancet380: 807-814, 2012 eGFR by the CKD-EPI equation

  25. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study CVD risk increases linearly by 12% for each decreasing decile of eGFR age- and sex-adjusted risk for a CVD event Reference category Excess risk significant for eGFR values < 78 ml/min/1.73m2 Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  26. Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis Fox CS et al.,Lancet380: 1662-1673, 2012

  27. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study … CVD risk increases linearly by 9% for each increasing decile of albuminuria age- and sex-adjusted risk for a CVD event Reference category Excess risk was significant for AER values ≥10.5 mg/24h Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  28. Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis Fox CS et al.,Lancet380: 1662-1673, 2012

  29. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study … CVD risk increases linearly by 9% for each increasing decile of albuminuria age- and sex-adjusted risk for a CVD event Reference category Excess risk was significant for AER values ≥10.5 mg/24h Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

  30. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 11,538 (73.1%) of subjects with T2DM of the RIACE cohort have AER <30 mg/24h AER <10 mg/24h n. 5,515 (47.8%) n. 6,023 (52.2%) AER 10-29 mg/24h The RIACE Study Group. Unpublished data.

  31. Logisticregression 1 (n. 11,538) Not in regression: diabetes duration, BMI (M), total cholesterol (M), HDL cholesterol, systolic BP (F), family history for diabetes The RIACE Study Group. Unpublished data.

  32. The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 1,673 patients with non-albuminuric stages 3-5 CKD excluded 9,865 (62.5%) of subjects with T2DM of the RIACE cohort have AER <30 mg/24h and eGFR >60 ml/min AER <10 mg/24h n. 4,654 (47.28%) n. 5,211 (52.8%) AER 10-29 mg/24h The RIACE Study Group. Unpublished data.

  33. Logisticregression 2 (eGFR >60; n. 9,865) Not in regression: duration of diabetes, BMI (M), HDL cholesterol, systolic BP (F), RAS blockers (M), family history for diabetes The RIACE Study Group. Unpublished data.

  34. Avoid HbA1c variability 8,260 patients with type 2 diabetes from Italy Penno G et al. Diabetes Care 36: 2301-2310 2013

  35. Avoid HbA1c variability 8,260 patients with type 2 diabetes from Italy Penno G et al. Diabetes Care 36: 2301-2310 2013

  36. Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. The RIACE Study Group. Submitted to NDT.

  37. Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 0 subjects on statins subjects not on statins * OR (95% CI) for CKD stages 3-5 non-albuminuric * * * p=0.006 * * * * * * p=0.04 The RIACE Study Group. Submitted to NDT. 1 2 3 4 5 6 7 8 9 10 <0.73 0.74- 0.90- 1.04- 1.19- 1.34- 1.51- 1.75- 2.05- >2.58 0.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57

  38. Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 0 14.629 subjects on statins subjects not on statins * * OR (95% CI) for CKD stages 3-5 albuminuric * * * p=0.004 p=0.004 * * * p=0.040 p=0.042 p=0.015 * * * The RIACE Study Group. Submitted to NDT. 1 2 3 4 5 6 7 8 9 10 <0.73 0.74- 0.90- 1.04- 1.19- 1.34- 1.51- 1.75- 2.05- >2.58 0.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57

  39. Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 0 subjects on statins subjects not on statins OR (95% CI) for CKD stages 1-2 * p=0.001 * p=0.004 p=0.045 p=0.016 p=0.048 * p=0.026 p=0.045 p=0.037 The RIACE Study Group. Submitted to NDT. 1 2 3 4 5 6 7 8 9 10 <0.73 0.74- 0.90- 1.04- 1.19- 1.34- 1.51- 1.75- 2.05- >2.58 0.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57

  40. Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications. Normotensive Non-resistant hypertension Uncontrolled hypertension Resistant hypertension Solini A et al. J Hypertens2014, Sept 5 (Epub ahead of print)

  41. Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications. Solini A et al. J Hypertens2014, Sept 5 (Epub ahead of print)

  42. Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications. Solini A et al. J Hypertens2014, Sept 5 (Epub ahead of print)

  43. Solini A et al. J Am Geriatr Soc 61: 1253-1261, 2013

  44. p=0.001 1st quartile by age 2nd quartile by age CVD (%) CVD (%) p=0.023 p<0.001 p<0.001 50 50 p<0.001 172 40 40 p=0.002 411 401 30 30 102 267 609 20 20 Met no Met no 10 10 1,733 157 969 1,118 61 561 Met yes Met yes 0 0 3-4 (<60) 2 (60-89) 1 (≥90) 3-4 (<60) 2 (60-89) 1 (≥90) eGFR category (ml/min/1.73 m2) eGFR category (ml/min/1.73 m2) p<0.001 p=0.010 3rd quartile by age 4th quartile by age CVD (%) CVD (%) p<0.001 p<0.001 50 50 370 776 p=0.245 p=0.311 40 40 826 655 74 281 30 30 20 20 Met no Met no 10 10 513 1,100 161 312 1,336 682 Met yes Met yes 0 0 3-4 (<60) 2 (60-89) 1 (≥90) 3-4 (<60) 2 (60-89) 1 (≥90) eGFR category (ml/min/1.73 m2) eGFR category (ml/min/1.73 m2) Solini A et al. J Am Geriatr Soc 61: 1253-1261, 2013

  45. Challenging conventional paradigms:Diabetic kidney disease with and without albuminuria UKPDS; 4006 type 2 DM patients followed over a median of 15 years no renal impairment no albuminuria renal impairment subsequent to albuminuria albuminuria subsequent to renal impairment renal impairment before albuminuria albuminuria before renal impairment 70 64% 60 51% 50 40 33% Patients % 30 24% 16% 20 12% 10 0 1132 (28%) developing renal impairment 1534 (38%) developing albuminuria Retnakaran R et al.,Diabetes 55: 1832-1839, 2006

  46. Challenging conventional paradigms:Diabetic kidney disease with and without albuminuria DCCT/EDIC; 1439 type 1 DM patients followed over a median of 19 years no albuminuria no albuminuria microalbuminuria microalbuminuria before renal impairment macroalbuminuria macroalbuminuria before renal impairment 70 61% 60 50% 50 42% 40 Patients % 30 24% 16% 20 8% 10 0 89 (6.2%) developing sustained eGFR <60 1350 (93.8%) with no sustained eGFR <60 Molitch ME et al.,Diabetes Care 33: 1536-1543, 2010

  47. “Natural” history of Diabetic Nephropathy in type 1 diabetes Clinical type 1 diabetes Functional changes* Structural changes† Microalbuminuria Proteinuria Rising blood pressure Rising serum creatinine levels ESRD MACE Onset of diabetes 2 5 10 20 30 Years * Kidney size ­, GFR ­. † GBM thickening ­, mesangial expansion ­

  48. Krolewski AS et al., Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria.Diabetes Care 37: 226-234, 2014.

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