La Nefropatia Diabetica nuove acquisizioni epidemiologiche e loro

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

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study l RIACE is a multicentre observational prospective study that is being conducted in 19 collaborating centres in Italy l Recruitment of patients with T 2 DM (n. 15, 993) started in 2007 and was completed in 2008 l 160 subjects were excluded due to missing or implausible values; data from the remaining 15, 773 patients were than analyzed l Age: 66. 0± 10. 3 years (median 67 years) l Diabetes duration: 13. 2± 10. 2 years (median 11 years) l 56. 8% male and 43. 2% female l 13. 593 subjects (86%) completed the 4 to 6 year follow-up NCT 00715481; URL http: //clinicaltrials. gov/show/NCT 00715481

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Albuminuria Micro 22. 2% Macro 4. 7% Normo 73. 1% e. GFR 30 -59 17. 1% <30 1. 7% ≥ 90 29. 6% 60 -89 51. 7% Penno G, et al. , The RIACE Study Group. J Hypertens 29: 1802 -1809, 2011

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study Renal Dysfunction is Common in Patients with T 2 DM 1. 7% 17. 1% 12. 0% 62. 5% 6. 7% Approximately 40% of patients with T 2 DM show signs of CKD Approximately 20% of patients with T 2 DM show reduced e. GFR 15, 773 patients with type 2 diabetes from Italy

Prevalence of nephropathy in the German diabetes population Pommer W. NDT Plus 1 (suppl 4) iv 2 -iv 5, 2008

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 15, 773 patients with type 2 diabetes from Italy No CKD e. GFR ≥ 60 & no-albuminuria n. 9, 865 (62. 5%) + CKD stages 1 -2 e. GFR ≥ 60 & albuminuria n. 2, 949 (18. 7%) + CKD stages 3 -5 e. GFR <60; n. 2, 959 (18. 8%) Non-albuminuric CKD stages 3 -5 n. 1, 673 (56. 6%) Micro-albuminuria n. 2, 585 (87. 7%) Macro-albuminuria n. 364 (12. 3%) 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

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study 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

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study 15, 773 patients with T 2 DM: CKD phenotypes by age quartiles CKD stages 3 -5 CKD stages 1 -2 non-albuminuric 100 Percent 80 53. 8% 60 39. 1% 40 25. 4% 31. 7% 20 0 1 st 2 nd 3 rd 4 th n. 1, 013 (25. 4%) n. 1, 195 (31. 7%) n. 1, 622 (39. 1%) n. 2, 078 (53. 8%) n. 3, 995 n. 3, 767 n. 4, 151 n. 3, 860 age ≤ 59 age 60 -66 age 67 -73 age ≥ 74 The RIACE Study Group, unpublished data

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study 15, 773 patients with T 2 DM: CKD phenotypes by age quartiles CKD stages 1 -2 100 CKD stages 3 -5 non-albuminuric CKD stages 3 -5 albuminuric Percent 80 M 60 M 40 M M F F 20 0 Age, quartiles 1 st 2 nd M: CKD+ n, (%) F: CKD+ n, (%) n, M/F 691 (27. 6%) 322 (21. 6%) 2, 506/1, 489 854 (33. 9%) 441 (28. 6%) 2, 225/1, 542 3 rd 4 th 960 (41. 3%) 1029 (54. 0%) 662 (36. 2%) 1049 (53, 7%) 2, 324/1, 827 1, 905/1, 955 The RIACE Study Group, unpublished data

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

“Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms UKPDS Diabetes 55: 1832 -1839, 2006 DCCT/EDIC Diabetes Care 33: 1536 -1543, 2010 Mac. Isaac RJ et al. , Diabetes Care 27: 195 -200, 2004 Kramer HJ et al. , NHANES III JAMA 289: 3273 -3277, 2003 Thomas MC et al. , NEFRON Diabetes Care 32: 1497 -1502, 2009 Ninomiya T et al. , ADVANCE J Am Soc Nephrol 20: 1813 -1821, 2009 Bakris GL et al. , ACCOMPLISH Lancet 375: 1173 -1181, 2010 Tube SW et al. , ONTARGET/ TRASCEND Patients n. DM % Follow-up years Renal impairment No-albuminuric renal impairment Renal impairment with no albuminuria nor retinopathy 4, 006 100 15 28% 67% (51%) --- 1, 439 100 19 6. 2% 24% --- 301 100 --- 36% 39% 29% 1, 197 100 --- 13% 36% 30% 3, 893 100 --- 23% 55% --- 10, 640 100 --- 19% 62% --- 11, 482 60 --- 9. 5% 46. 8% --- 23, 422 37 --- 24% 68% --- 9, 765 100 --- 5. 3% 59. 0% --- 15, 773 100 --- 18. 8% 56. 6% 43. 2% (type 1) Circulation 123: 1098 -1107, 2011 Drury PL et al. , FIELD Diabetologia 54: 32 -43, 2011 RIACE Study Group, RIACE J Hypertens 29: 1802 -1809, 2011

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study Results: stratification by CKD NKF’s KDOQI stage and retinopathy No CKD e. GFR ≥ 60 & no-albuminuria n. 9, 865 (62. 5%) + CKD stages 1 -2 e. GFR ≥ 60 & albuminuria n. 2, 949 (18. 7%) + CKD stages 3 -5 e. GFR <60; n. 2, 959 (18. 8%) No-retinopathy n. 2, 027 (68. 5%) No-retinopathy n. 2, 067 (70. 1%) Retinopathy n. 882 (29. 9%) 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

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

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study Results: stratification by CKD NKF’s KDOQI stage and retinopathy No CKD e. GFR ≥ 60 & no-albuminuria n. 9, 865 (62. 5%) + CKD stages 1 -2 e. GFR ≥ 60 & albuminuria n. 2, 949 (18. 7%) + CKD stages 3 -5 e. GFR <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

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study 4, 062 subjects with at least two UAE measurements ü Intra-individual CV: 32. 5% (14. 3 -58. 9) ü Concordance rate between a single UAE and the geometric mean: UAEtwo values UAEone value Predictive performance for the mean of 3 UAE values • Two UAE: normo: 94. 6%; micro: 83. 5%; macro: 91. 1%; micro/macro: 90. 6%; Reference line • 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

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 No CKD 1 2 3 234 (1. 5%) 9, 821 (62. 3%) 1 977 (6. 2%) 283 (1. 8%) 2 75 (0. 5%) 1, 591 (10. 1%) 3 44 (0. 3%) 23 (0. 1%) 4 -5 Total 9, 865 (62. 5%) 1, 052 (6. 7%) Total 1, 897 (12. 0%) 4 -5 10, 055 (63. 8%) 1, 260 (8. 0%) 77 (0. 5%) Subjects moved by the CKD-EPI equation above belove 1, 743 (11. 1%) 2, 342 (14. 8%) 2 (0. 1%) 2, 411 (15. 3%) 48 (0. 3%) 256 (1. 6%) 304 (1. 9%) 2, 701 (17. 1%) 258 (1. 7%) 15, 773 (100. 0%) Pugliese G et al. , Atherosclerosis 218: 194 -199, 2011

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. , Atherosclerosis 218: 194 -199, 2011

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

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

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%) Major CVD events, % 50 40 794 (26. 9%) 30 20 528 (31. 6%) 1, 756 (17. 8%) 10 0 No CKD stages 1 -2 n. 9, 865 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

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

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

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

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 12, 960 e. GFR by the CKD-EPI equation 15, 368 1, 104, 713 59, 117 Tonelli M et al. , Lancet 380: 807 -814, 2012

age- and sex-adjusted risk for a CVD event The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study CVD risk increases linearly by 12% for each decreasing decile of e. GFR Reference category Excess risk significant for e. GFR values < 78 ml/min/1. 73 m 2 Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143 -149, 2012

Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis Fox CS et al. , Lancet 380: 1662 -1673, 2012

age- and sex-adjusted risk for a CVD event The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study … CVD risk increases linearly by 9% for each increasing decile of albuminuria Reference category Excess risk was significant for AER values ≥ 10. 5 mg/24 h Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143 -149, 2012

Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis Fox CS et al. , Lancet 380: 1662 -1673, 2012

age- and sex-adjusted risk for a CVD event The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study … CVD risk increases linearly by 9% for each increasing decile of albuminuria Reference category Excess risk was significant for AER values ≥ 10. 5 mg/24 h Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143 -149, 2012

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study 11, 538 (73. 1%) of subjects with T 2 DM of the RIACE cohort have AER <30 mg/24 h AER <10 mg/24 h n. 5, 515 (47. 8%) n. 6, 023 (52. 2%) AER 10 -29 mg/24 h The RIACE Study Group. Unpublished data.

Logistic regression 1 (n. 11, 538) Age, x 1 year Gender, male Waist circumference, x 1 cm Hb. A 1 c, x 1% Diastolic BP, x 1 mm. Hg Triglycerides, x 1 mg/dl RAS blockers DHP calcium channel blockers OR 1. 018 1. 238 1. 050 1. 062 1. 014 1. 001 1. 073 1. 171 95%CI 1. 014 -1. 022 1. 070 -1. 432 0. 996 -1. 106 1. 033 -1. 093 1. 010 -1. 018 1. 000 -1. 001 0. 992 -1. 160 1. 053 -1. 302 Glucose lowering agents (diet, REF): OHA insulin + OHA insulin 1. 312 1. 334 1. 495 1. 175 -1. 464 1. 126 -1. 581 1. 288 -1. 734 1. 158 1. 237 1. 325 0. 891 1. 141 1. 095 Smoking habits (no, REF): ex-smokers Family history for hypertension Family history for CVD Retinopathy (no ret, REF) non advanced p <0. 0001 0. 004 0. 070 <0. 0001 0. 011 0. 077 0. 004 M/F M M/F F M M <0. 0001 M/F 1. 058 -1. 267 1. 106 -1. 384 1. 207 -1. 455 0. 792 -1. 003 <0. 0001 M <0. 0001 0. 057 M/F M 1. 010 -1. 288 0. 942 -1. 271 0. 072 F 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.

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 T 2 DM of the RIACE cohort have AER <30 mg/24 h and e. GFR >60 ml/min AER <10 mg/24 h n. 4, 654 (47. 28%) n. 5, 211 (52. 8%) AER 10 -29 mg/24 h The RIACE Study Group. Unpublished data.

Logistic regression 2 (e. GFR >60; n. 9, 865) Age, x 1 year Gender, male Waist circumference, x 1 cm Hb. A 1 c, x 1% Diastolic BP, x 1 mm. Hg Triglycerides, x 1 mg/dl RAS blockers DHP calcium channel blockers OR 1. 018 1. 233 1. 057 1. 066 1. 014 1. 001 1. 069 1. 182 95%CI 1. 014 -1. 022 1. 053 -1. 444 0. 999 -1. 118 1. 034 -1. 099 1. 010 -1. 019 1. 000 -1. 001 0. 982 -1. 163 1. 052 -1. 329 Glucose lowering agents (diet, REF): OHA insulin + OHA insulin 1. 293 1. 277 1. 470 1. 150 -1. 454 1. 062 -1. 536 1. 247 -1. 733 1. 188 1. 286 1. 346 0. 898 1. 163 1. 088 Smoking habits (no, REF): ex-smokers Family history for hypertension Family history for CVD Retinopathy (no ret, REF) non advanced p <0. 0001 0. 009 0. 054 <0. 0001 0. 058 0. 122 0. 005 M/F M M/F F M M <0. 0001 M/F 1. 077 -1. 310 1. 142 -1. 448 1. 218 -1. 487 0. 790 -1. 021 <0. 0001 M <0. 0001 0. 100 M/F M 1. 018 -1. 330 0. 920 -1. 287 0. 067 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.

Avoid Hb. A 1 c variability 8, 260 patients with type 2 diabetes from Italy Penno G et al. Diabetes Care 36: 2301 -2310 2013

Avoid Hb. A 1 c variability 8, 260 patients with type 2 diabetes from Italy Penno G et al. Diabetes Care 36: 2301 -2310 2013

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

Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 OR (95% CI) for CKD stages 3 -5 non-albuminuric 9 subjects on statins subjects not on statins 8 7 * 6 5 * * 4 p=0. 006 * 3 * * p=0. 04 2 * * 1 0 1 2 3 4 5 6 <0. 73 0. 740. 89 0. 901. 03 1. 041. 18 1. 191. 33 1. 341. 50 7 8 9 10 1. 511. 752. 05>2. 58 1. 74 2. 04 2. 57 The RIACE Study Group. Submitted to NDT.

Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 OR (95% CI) for CKD stages 3 -5 albuminuric 9 14. 629 subjects on statins subjects not on statins * 8 7 * 6 * 5 4 p=0. 004 p=0. 042 3 p=0. 040 p=0. 015 2 p=0. 004 * * * * 9 10 * 1 0 1 2 3 4 5 6 <0. 73 0. 740. 89 0. 901. 03 1. 041. 18 1. 191. 33 1. 341. 50 7 8 1. 511. 752. 05>2. 58 1. 74 2. 04 2. 57 The RIACE Study Group. Submitted to NDT.

Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 subjects on statins subjects not on statins OR (95% CI) for CKD stages 1 -2 8 7 6 5 4 3 p=0. 004 p=0. 016 2 p=0. 045 p=0. 001 p=0. 048 * p=0. 045 p=0. 037 * * p=0. 026 1 0 1 2 3 4 5 6 <0. 73 0. 740. 89 0. 901. 03 1. 041. 18 1. 191. 33 1. 341. 50 7 8 9 10 1. 511. 752. 05>2. 58 1. 74 2. 04 2. 57 The RIACE Study Group. Submitted to NDT.

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 Hypertens 2014, Sept 5 (Epub ahead of print)

Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications. Solini A et al. J Hypertens 2014, Sept 5 (Epub ahead of print)

Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications. Solini A et al. J Hypertens 2014, Sept 5 (Epub ahead of print)

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

1 st quartile by age CVD (%) p=0. 023 p<0. 001 50 267 609 10 1, 733 561 Met yes 3 -4 (<60) 2 (60 -89) 1 (≥ 90) e. GFR category (ml/min/1. 73 m 2) p=0. 010 CVD (%) 50 3 rd quartile by age p=0. 245 655 30 157 0 969 1, 118 p<0. 001 4 th quartile by age p<0. 001 776 p=0. 311 826 30 281 Met yes 3 -4 (<60) 2 (60 -89) 1 (≥ 90) e. GFR category (ml/min/1. 73 m 2) 40 20 74 20 Met no 10 312 0 Met no 50 40 401 10 CVD (%) p<0. 001 370 411 20 Met no 61 172 30 20 0 p<0. 001 40 p=0. 002 102 p<0. 001 50 40 30 2 nd quartile by age p=0. 001 CVD (%) 1, 336 682 3 -4 (<60) 2 (60 -89) 1 (≥ 90) e. GFR category (ml/min/1. 73 m 2) Met yes 10 0 Met no 513 1, 100 161 Met yes 3 -4 (<60) 2 (60 -89) 1 (≥ 90) e. GFR category (ml/min/1. 73 m 2) Solini A et al. J Am Geriatr Soc 61: 1253 -1261, 2013

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 subsequent to renal impairment before albuminuria before renal impairment 70 64% 60 51% Patients % 50 40 30 20 33% 24% 12% 16% 10 0 1534 (38%) developing albuminuria 1132 (28%) developing renal impairment Retnakaran R et al. , Diabetes 55: 1832 -1839, 2006

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 microalbuminuria before renal impairment macroalbuminuria before renal impairment 70 61% 60 Patients % 50 40 50% 42% 30 24% 16% 20 10 0 8% 1350 (93. 8%) with no sustained e. GFR <60 89 (6. 2%) developing sustained e. GFR <60 Molitch ME et al. , Diabetes Care 33: 1536 -1543, 2010

“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 * Kidney size , GFR . † GBM thickening , mesangial expansion Years 20 30

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

Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes No CKD e. GFR ≥ 60 & no-albuminuria n. 695 (89. 4%) Micro-albuminuria n. 46 (86. 8%) CKD stages 1 -2 e. GFR ≥ 60 & albuminuria n. 53 (6. 8%) Macro-albuminuria CKD stages 3 -5 e. GFR <60 n. 29 (3. 7%) Albuminuric CKD stages 3 -5 n. 7 (13. 2%) n. 12 (41. 4%) Micro-albuminuria n. 4 (33. 3%) Macro-albuminuria n. 8 (66. 7%) Russo E et al. , Diabetologia 56 (suppl 1) S 472, 2013; EASD, Barcelona, 23 -27 September 2013

Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes Variables MODEL 2 CKD 1 -2 CKD 3 -5 OR 95%CI p 0. 956 0. 923 -0. 990 0. 012 1. 048 0. 999 -1. 098 0. 054 -- -- -- Hb. A 1 c 1. 354 1. 024 -1. 790 0. 033 -- -- -- Total-C 1. 011 1. 002 -1. 020 0. 015 -- -- -- Gamma-GT 1. 006 1. 001 -1. 012 0. 029 1. 014 1. 003 -1. 026 0. 017 Fibrinogen 1. 004 1. 000 -1. 009 0. 073 1. 010 1. 002 -1. 017 0. 010 Hypertension 4. 260 1. 999 -9. 078 0. 0001 5. 783 0. 960 -34. 833 0. 055 -- -- Age, x year Diabetes Duration, x year PAS -- 1. 025 0. 998 -1. 052 0. 066 Retinopathy No Background Proliferative 0. 0001 0. 002 1. 0 1. 666 0. 660 -4. 207 0. 280 1. 747 0. 367 -8. 314 10. 778 4. 380 -26. 523 0. 0001 7. 684 1. 877 -31. 450 0. 483 0. 005 Variables not in the Equation Sex, BMI, Smokers, PAD, HDL-C, Triglycerides, Uric Acid Russo E et al. , Diabetologia 56 (suppl 1) S 472, 2013; EASD, Barcelona, 23 -27 September 2013

Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes CKD 3 -5 Non-albuminuric Variables MODELLO 2 CKD 3 -5 albuminuric OR 95%CI p Age, x year Hb. A 1 c HDL-C Gamma. GT Fibrinogen 1. 090 --1. 016 -- 1. 030 -1. 153 --1. 002 -1. 030 -- 0. 003 --0. 022 -- 1. 092 2. 262 0. 950 -1. 016 1. 008 -1. 184 1. 020 -5. 016 0. 890 -1. 013 -1. 003 -1. 028 0. 031 0. 044 0. 117 -0. 012 Hypertension 15. 725 1. 432 -172. 655 0. 024 -- -- -- PAD Retinopathy No Background Proliferative Variables not in the Equation -- -- -- 1. 092 0. 996 -1. 198 0. 062 0. 028 1. 0 0. 779 4. 147 0. 137 -4. 417 0. 964 -17. 844 0. 778 0. 056 -- -- -- Sex, Diabetes Duration, BMI, Smokers, PAS, Total-C, Triglycerides, Uric Acid Russo E et al. , Diabetologia 56 (suppl 1) S 472, 2013; EASD, Barcelona, 23 -27 September 2013

Heterogeneity of CKD phenotypes among 936 subjects with type 1 diabetes (EURODIAB-Italy) No CKD e. GFR ≥ 60 & no-albuminuria n. 736 (78. 6%) CKD stages 1 -2 e. GFR ≥ 60 & albuminuria n. 182 (19. 5%) CKD stages 3 -5 e. GFR <60 n. 18 (1. 9%) *p=0. 039 vs cohort 1 Micro-albuminuria n. 128 (70. 3%) Macro-albuminuria n. 54 (29. 7%) Albuminuric stages 3. 5 CKD n. 13 (72. 2%) Micro-albuminuria n. 4 (30. 8%) * Macro-albuminuria n. 9 (69. 2%) Russo E et al. , Diabetologia 57 (suppl 1), 2014; EASD, Vienna, 15 -19 September 2014

Heterogeneity of CKD phenotypes among subjects with type 1 diabetes 777 T 1 DM N. NA ACR (<10 mg/g), n (%) ACR (10 -29 mg/g), n (%) Microalbuminuria (30 -299 mg/g), n (%) Macroalbuminuria (>300 mg/g), n (%) 936 T 1 DM N. NA ACR (<10 mg/g), n (%) ACR (10 -29 mg/g), n (%) Microalbuminuria (30 -299 mg/g), n (%) Macroalbuminuria (>300 mg/g), n (%) >90 e. GFR MDRD (ml/min/1. 73 m 2) 75 -89 <60 60 -74 Total 445 232 71 29 353 (79. 3) 187 (80. 6) 50 (70. 4) 10 (34. 5) 600 (77. 2) 61 (13. 7) 31 (13. 4) 13 (18. 3) 7 (24. 1) 112 (14. 4) 25 (5. 6) 14 (6. 0) 7 (9. 9) 4 (13. 8) 50 (6. 4) 6 (1. 3) --- 1 (1. 4) 8 (27. 6) 15 (1. 9) >90 e. GFR MDRD (ml/min/1. 73 m 2) 75 -89 <60 60 -74 Total 794 84 40 18 407 (51. 3) 35 (41. 7) 13 (32. 5) 4 (22. 2) 459 (49. 0) 242 (30. 5) 25 (29. 8) 14 (35. 0) 1 (5. 5) 282 (30. 1) 106 (13. 4) 16 (19. 0) 6 (15. 0) 4 (22. 2) 132 (14. 1) 39 (4. 9) 8 (9. 5) 7 (17. 5) 9 (50. 0) 63 (6. 7) *p<0. 0001 *p=0. 006 Russo E et al. , Diabetologia 57 (suppl 1), 2014; EASD, Vienna, 15 -19 September 2014

777 T 1 DM: clinical features CKD 3 -5 Alb- vs CKD 3 -5 Alb+ ns ns 100 90 93, 8 ns 90 11, 8 ns 82, 4 80 25 p = 0. 010 70, 6 70 64, 7 58, 3 60 58, 3 76, 5 50 66, 7 40 30 16, 7 20 10 11, 8 8, 3 CKD 3 -5 Alb- CKD 3 -5 Alb + 0 Hypertension Treatment with BP-lowering agents Treatment with RAS blockers Treatment with statins Hb. A 1 c > 9% Hb. A 1 c 7 -9% Hb. A 1 c < 7% Garofolo M et al. , 25° Congresso Nazionale SID, Bologna, 28 -31 Maggio 2014

777 T 1 DM: clinical features CKD 3 -5 Alb- vs CKD 3 -5 Alb+ p=0, 001 1, 6 p<0, 001 p <0, 001 100 87, 5 90 p <0, 001 37, 5 75 80 70 75, 8 60 50 40 37, 5 38, 3 30 20, 6 20 17, 5 15, 9 ns 12, 5 10 22, 6 25 CKD 2 b Alb- CKD 2 b Alb + 0 Hypertension Treatment with BP-lowering agents Treatment with RAS blockers Treatment with statins Hb. A 1 c > 9% Hb. A 1 c 7 -9% Hb. A 1 c < 7% Garofolo M et al. , 25° Congresso Nazionale SID, Bologna, 28 -31 Maggio 2014

Conclusions (1) l Non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with reduced e. GFR. l Concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions. l The non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary vascular bed. l Even within the normoalbuminuric range, in type 2 diabetic patients, AER is correlated with several risk factors which are potentially susceptible of therapeutic intervention.

Conclusions (2) l CKD is associated with Hb. A 1 c variability more than with average Hb. A 1 c, whereas retinopathy and CVD are not. l CKD is associated with hypertriglyceridemia and with resistant hypertension (likely bidirectional? ). l Non-albuminuric renal function impairment is also detectable in a high proportion of patients with type 1 diabetes.

Thanksgiving The RIACE Steering Committee Giuseppe Pugliese (Coordinator), Giuseppe Penno (Secretariat), Anna Solini, Enzo Bonora, Emanuela Orsi, Roberto Trevisan, Luigi Laviola, Antonio Nicolucci. The Diabetic Nephropathy Study Group, SID Giuseppe Pugliese, Salvatore De Cosmo, Gabriella Gruden, Susanna Morano, Giuseppe Penno, Francesco Pugliese, Giampaolo Zerbini, Luigi Laviola, Anna Solini, Roberto Trevisan. Participating diabetes centers 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Azienda Ospedaliera Sant'Andrea, Roma (Coordinating Center): Giuseppe Pugliese, Paola Simonelli, Laura Salvi, Alessandra Bazuro. Ospedale Le Molinette, Torino: Paolo Cavallo-Perin, Gabriella Gruden, Bartolomeo Lorenzati. Ospedale San Luigi Gonzaga, Orbassano: Mariella Trovati, Giovanni Anfossi, Franco Cavalot, Massimo Chirio. Ospedale San Raffaele, Milan: Gianpaolo Zerbini, Valentina Martina. IRCCS “Cà Granda – Ospedale Maggiore Policlinico”, Milan: Emanuela Orsi, Alessia Dolci. Ospedale San Paolo, Milan: Antonio Pontiroli, Marco Laneri. Ospedale San Giuseppe, Milan: Maura Arosio, Antonio Rossi, Laura Montefusco. Ospedali Riuniti, Bergamo: Roberto Trevisan, Anna Corsi. Università e Azienda Ospedaliera Universitaria Integrata di Verona: Enzo Bonora, Giacomo Zoppini. Policlinico Universitario, Padova: Angelo Avogaro, Monica Vedovato, Elisa Pagnin. Azienda Ospedaliero-Universitaria Pisana, Pisa: Giuseppe Penno, Laura Pucci, Daniela Lucchesi, Eleonora Russo, Monia Garofolo. Ospedale Santa Chiara, Azienda Ospedaliero-Universitaria Pisana, Pisa: Anna Solini. Ospedale Le Scotte, Siena: Francesco Dotta, Cecilia Fondelli, Laura Nigi. Policlinico Umberto I, Roma: Susanna Morano, Alessandra Gatti, Elisabetta Mandosi e Mara Fallarino. Ospedale S. Maria Goretti, Latina: Raffaella Buzzetti, Gaetano Leto. Ospedali Riuniti, Foggia: Mauro Cignarelli, Olga Lamacchia, Sabina Pinnelli. Policlinico Universitario, Bari: Francesco Giorgino, Luigi Laviola, Sebastio Perrini. Policlinico Mater Domini, Catanzaro: Giorgio Sesti, Francesco Andreozzi. Università e Azienda Ospedaliera Universitaria di Cagliari, Policlinico Universitario: Marco Giorgio Baroni, Giuseppina Frau.

Thanksgiving MD BD Monia Garofolo Daniela Lucchesi Eleonora Russo Laura Giusti Rosalia Bellante Veronica Sancho-Bornez Laura Pucci

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