La Nefropatia Diabetica:

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

RIACE is a multicentre 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 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 subjects (86%) completed the 4 to 6 year follow-up NCT ; URL 2

The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study
Albuminuria eGFR <30 1.7% Macro 4.7% Micro 22.2% 30-59 17.1% ≥90 29.6% Normo 73.1% 60-89 51.7% Penno G, et al., The RIACE Study Group. J Hypertens 29: , 2011 4 4

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

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

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%) By the National Kidney Foundation classification, 62 percent of our people had no CKD, about 19 percent had CKD stages 1-2, and as many had CKD stages 3 to 5. Of the about 3 thousands patients with renal function impairment, about 56 percent were normoalbuminuric and about 44 percent were micro (thirty percent) or macroalbuminuric (about 13%). Micro-albuminuria n. 912 (30.8%) Macro-albuminuria n. 374 (12,6%) Penno G, et al., The RIACE Study Group. J Hypertens 29: , 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 Independent correlates of the three CKD phenotypes were age, diabetes duration, BMI and triglycerides. HDL-cholesterol was inversely associated to stage 3-5 CKD, but not to stages 1-2, which was related to smoking status. Male gender, and HbA1c correlated with albuminuric CKD (independent of stage), while female gender, correlated with nonalbuminuric CKD. ORs for hypertension and retinopathy were higher in subjects with CKD with albuminuria (the highest in subjects with stages 3-5 CKD) than in those without albuminuria. Finally, OR for CVD in subjects with nonalbuminuric stages 3-5 CKD was higher than in subjects with stages 1-2 CKD, but lower than in patients with albuminuric stages 3-5 CKD. Variable excluded: LDL-cholesterol Penno G, et al., The RIACE Study Group. J Hypertens 29: , 2011

15,773 patients with T2DM: CKD phenotypes by age quartiles
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% Patients with normoalbuminuric stages 3-5 CKD had lower rate of cardiovascular disease than those with albuminuric stages 3-5 CKD but higher rate than subjects with stages 1-2 CKD. 25.4% 20 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

15,773 patients with T2DM: CKD phenotypes by age quartiles
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 60 F M Percent F M 40 M F Patients with normoalbuminuric stages 3-5 CKD had lower rate of cardiovascular disease than those with albuminuric stages 3-5 CKD but higher rate than subjects with stages 1-2 CKD. F 20 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

Cardiovascular events, death
“Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms Normoalbuminuria Normal GFR Microalbuminuria Cardiovascular events, death Macroalbuminuria By the National Kidney Foundation classification, 62 percent of our people had no CKD, about 19 percent had CKD stages 1-2, and as many had CKD stages 3 to 5. Of the about 3 thousands patients with renal function impairment, about 56 percent were normoalbuminuric and about 44 percent were micro (thirty percent) or macroalbuminuric (about 13%). Reduced eGFR ESRD Natural history of diabetic nephropathy: “non-albuminuric” pathway Natural history of diabetic nephropathy: “albuminuric” pathway

“Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms
Patients n. DM % Follow-up years Renal impairment No-albuminuric renal impairment Renal impairment with no albuminuria nor retinopathy UKPDS Diabetes 55: , 2006 4,006 100 15 28% 67% (51%) --- DCCT/EDIC Diabetes Care 33: , 2010 1,439 (type 1) 19 6.2% 24% MacIsaac RJ et al., Diabetes Care 27: , 2004 301 36% 39% 29% Kramer HJ et al., NHANES III JAMA 289: , 2003 1,197 13% 30% Thomas MC et al., NEFRON Diabetes Care 32: , 2009 3,893 23% 55% Ninomiya T et al., ADVANCE J Am Soc Nephrol 20: , 2009 10,640 19% 62% Bakris GL et al., ACCOMPLISH Lancet 375: , 2010 11,482 60 9.5% 46.8% Tube SW et al., ONTARGET/ TRASCEND Circulation 123: , 2011 23,422 37 68% Drury PL et al., FIELD Diabetologia 54: 32-43, 2011 9,765 5.3% 59.0% RIACE Study Group, RIACE J Hypertens 29: , 2011 15,773 18.8% 56.6% 43.2% In agreement with these prospective trials, and after the studies by MacIsaac and Kramer, several recent large cross-sectional evaluations from NEFRON, ADVANCE, ACCOMPLISH and the pooled analysis of ONTARGET and TRASCEND studies, suggest that nonalbuminuric renal impairment has becoming a predominant phenotype of stages 3-5 CKD.

eGFR ≥60 & no-albuminuria
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: , 2011

Concordance of CKD and Diabetic Retinopathy in subjects with type 2 diabetes Patients with at least one major acute CVD event had higher prevalence of nonadvanced and advanced retinopathy, higher AER and lower eGFR, higher prevalence of micro- and macroalbuminuria and higher prevalence of subjects with eGFR lower than 60. 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: , 2012

eGFR ≥60 & no-albuminuria
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: , 2012

4,062 subjects with at least two UAE measurements
The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study 4,062 subjects with at least two UAE measurements Intra-individual CV: 32.5% ( ) 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: micro: 84.2%; macro: 86.8%; micro/macro: 90.8%. Predictive performance for the mean of 3 UAE values Reference line UAEone value UAEtwo values Pugliese G et al., Nephrol Dial Transplant 26: , 2011 16

Prevalence of stages 3-5 CKD in type 2 diabetes
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., Atherosclerosis 218: , 2011 17

Prevalence of stages 3-5 CKD in type 2 diabetes
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: , 2011 18

Reclassification across estimated GFR categories
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: , 2012 19 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: , 2012 20 20

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 Patients with normoalbuminuric stages 3-5 CKD had lower rate of cardiovascular disease than those with albuminuric stages 3-5 CKD but higher rate than subjects with stages 1-2 CKD. 10 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: , 2012

Logistic regression analysis of all CVD events with CKD phenotypes as covariates Patients with at least one major acute CVD event had higher prevalence of nonadvanced and advanced retinopathy, higher AER and lower eGFR, higher prevalence of micro- and macroalbuminuria and higher prevalence of subjects with eGFR lower than 60. Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 2012

CVD events in type 2 diabetic patients stratified by CKD and Diabetic Retinopathy Patients with at least one major acute CVD event had higher prevalence of nonadvanced and advanced retinopathy, higher AER and lower eGFR, higher prevalence of micro- and macroalbuminuria and higher prevalence of subjects with eGFR lower than 60. Penno G, et al., The RIACE Study Group. Diabetes Care 35: , 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates Patients with at least one major acute CVD event had higher prevalence of nonadvanced and advanced retinopathy, higher AER and lower eGFR, higher prevalence of micro- and macroalbuminuria and higher prevalence of subjects with eGFR lower than 60. Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 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 In these general population cohorts, decreasing eGFR and increasing albuminuria were associated with all-cause mortality and CV mortality independently of each-other and of traditional CV risk factors. This was true both in studies where ACR was measured as well in other 7 studies were protein dipsticks were available in more than 1 million participants. 75,871 1,104,713 12,960 15,368 59,117 eGFR by the CKD-EPI equation Tonelli M et al., Lancet 380: , 2012

CVD risk increases linearly by 12% for each decreasing decile of eGFR age- and sex-adjusted risk for a CVD event Reference category Patients with at least one major acute CVD event had higher prevalence of nonadvanced and advanced retinopathy, higher AER and lower eGFR, higher prevalence of micro- and macroalbuminuria and higher prevalence of subjects with eGFR lower than 60. Excess risk significant for eGFR values < 78 ml/min/1.73m2 Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 2012

Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis In these general population cohorts, decreasing eGFR and increasing albuminuria were associated with all-cause mortality and CV mortality independently of each-other and of traditional CV risk factors. This was true both in studies where ACR was measured as well in other 7 studies were protein dipsticks were available in more than 1 million participants. Fox CS et al., Lancet 380: , 2012

… CVD risk increases linearly by 9% for each increasing decile of albuminuria age- and sex-adjusted risk for a CVD event Reference category In the RIACE study, CVD risk increases linearly by 9% for each increasing decile of albuminuria. Of interest, excess risk was significant for an AER values higher than 10.5 mg/24 hours. Excess risk was significant for AER values ≥10.5 mg/24h Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 2012 28

Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysis In these general population cohorts, decreasing eGFR and increasing albuminuria were associated with all-cause mortality and CV mortality independently of each-other and of traditional CV risk factors. This was true both in studies where ACR was measured as well in other 7 studies were protein dipsticks were available in more than 1 million participants. Fox CS et al., Lancet 380: , 2012

… CVD risk increases linearly by 9% for each increasing decile of albuminuria age- and sex-adjusted risk for a CVD event Reference category In the RIACE study, CVD risk increases linearly by 9% for each increasing decile of albuminuria. Of interest, excess risk was significant for an AER values higher than 10.5 mg/24 hours. Excess risk was significant for AER values ≥10.5 mg/24h Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 2012 30

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%) About eleven thousands subjects with type 2 diabetes, that is 73% of the whole cohort, have an AER lower than 30 mg/24 hours. Out of these, 52% have an AER lower than 10, and 48% and AER of mg/24h. AER mg/24h The RIACE Study Group. Unpublished data.

Logistic regression 1 (n. 11,538)
OR 95%CI p Age, x 1 year 1.018 <0.0001 M/F Gender, male 1.238 0.004 Waist circumference, x 1 cm 1.050 0.070 HbA1c, x 1% 1.062 M Diastolic BP, x 1 mmHg 1.014 Triglycerides, x 1 mg/dl 1.001 0.011 F RAS blockers 1.073 0.077 DHP calcium channel blockers 1.171 Glucose lowering agents (diet, REF): OHA insulin + OHA insulin 1.312 1.334 1.495 Smoking habits (no, REF): ex-smokers smokers 1.158 1.237 Family history for hypertension 1.325 Family history for CVD 0.891 0.057 Retinopathy (no ret, REF) non advanced advanced 1.141 1.095 0.072 Logistic regression with backward variables selection showed an independent correlation of AER with age and diastolic blood pressure, both in males and in females, with male gender, with glycated hemoglobin A1c and smoking status in males and with triglycerides levels in females. Treatment with oral glucose-lowering agents and mainly insulin, but also treatment with dyhydropyridine calcium channel blocker, as well family history of hypertension were independently related to AER 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.

1,673 patients with non-albuminuric stages 3-5 CKD excluded
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%) The new regression included a little less than 10 thousands subjects, while the distribution of AER strata was unchanged. n. 5,211 (52.8%) AER mg/24h The RIACE Study Group. Unpublished data.

Logistic regression 2 (eGFR >60; n. 9,865)
OR 95%CI p Age, x 1 year 1.018 <0.0001 M/F Gender, male 1.233 0.009 Waist circumference, x 1 cm 1.057 0.054 HbA1c, x 1% 1.066 M Diastolic BP, x 1 mmHg 1.014 Triglycerides, x 1 mg/dl 1.001 0.058 F RAS blockers 1.069 0.122 DHP calcium channel blockers 1.182 0.005 Glucose lowering agents (diet, REF): OHA insulin + OHA insulin 1.293 1.277 1.470 Smoking habits (no, REF): ex-smokers smokers 1.188 1.286 Family history for hypertension 1.346 Family history for CVD 0.898 0.100 Retinopathy (no ret, REF) non advanced advanced 1.163 1.088 0.067 The logistic regression analysis confirmed the independent association of AER with age, male gender, glycated hemoglobin and diastolic blood pressure, marginally with triglycerides, but also with oral glucose lowering treatment, mainly insulin, treatment with dyhydropyridine calcium channel blockers, smoking habits and family history of hypertension. 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.

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

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

OR (95% CI) for CKD stages 3-5 non-albuminuric
Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 subjects not on statins subjects 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. < >

OR (95% CI) for CKD stages 3-5 albuminuric
Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 14.629 subjects not on statins subjects 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. < >

OR (95% CI) for CKD stages 1-2
Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes. 10 9 8 7 6 5 4 3 2 1 subjects not on statins subjects on statins OR (95% CI) for CKD stages 1-2 * p=0.004 p=0.001 * p=0.016 p=0.045 p=0.048 * p=0.037 p=0.045 p=0.026 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)

Solini A et al. J Am Geriatr Soc 61: 1253-1261, 2013
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eGFR category (ml/min/1.73 m2)
CVD (%) 1st quartile by age 2nd quartile by age 3rd quartile by age 4th quartile by age 10 20 30 40 50 3-4 (<60) 2 (60-89) 1 (≥90) Met yes Met no 1,733 561 61 609 267 102 401 411 172 1,118 969 157 682 1,336 312 281 655 370 161 1,100 513 74 826 776 eGFR category (ml/min/1.73 m2) p=0.002 p<0.001 p=0.023 p=0.001 p=0.245 p=0.010 p=0.311 Solini A et al. J Am Geriatr Soc 61: , 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 % In the UKPDS study, over a median of 15-year follow-up, 51% of type 2 diabetic subjects who developed renal impairment did not have preceding albuminuria. 33% had albuminuria before renal impairment. 30 24% 16% 20 12% 10 1534 (38%) developing albuminuria 1132 (28%) developing renal impairment Retnakaran R et al., Diabetes 55: , 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 no albuminuria microalbuminuria microalbuminuria before renal impairment macroalbuminuria macroalbuminuria before renal impairment 70 61% 60 50% 50 42% 40 Patients % Even within type 1 diabetic patients, as recently reported in a median 19-year follow-up of the DCCT/EDIC Study, 24% of subjects developed sustained eGFR less than 60 ml/min with no history of micro- or macroalbuminuria. 30 24% 20 16% 8% 10 1350 (93.8%) with no sustained eGFR <60 89 (6.2%) developing sustained eGFR <60 Molitch ME et al., Diabetes Care 33: , 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 Diabetic nephropathy can be divided into 4 phases: microalbuminuria (urinary albumin excretion mg/24 h), macroalbuminuria or proteinuria (>300 mg/24 h), the nephrotic syndrome, and chronic renal failure (Grundy et al, 1999). Microalbuminuria is the first clinical sign of diabetic damage to the kidney and is a harbinger of progressive kidney damage. Microalbuminuria also reflects a higher risk for cardiovascular disease. Once microalbuminuria is present, it progresses over 5-10 years to macroalbuminuria in 22%-50% of patients (Mogensen, 1984; Cooper et al, 1988; Haneda et al, 1992; Ravid et al, 1992; John et al, 1994; Lebovitz et al, 1994). Macroalbuminuria denotes significant diabetic nephropathy and will be followed by a decline in glomerular filtration rate (GFR). Once a patient with type 2 diabetes develops macroalbuminuria, further decline in renal function appears to be inevitable; GFR declines at a rate of 4-12 mL/min/year (Pugh et al, 1993; Gall et al, 1993; Hasslacher et al, 1993). Some patients develop the nephrotic syndrome, which usually heralds progressive renal insufficiency and end-stage renal disease. In diabetic nephropathy studies, where the time of onset of type 2 diabetes is known, these patients follow a time course similar to that seen in patients with type 1 diabetes. However, the date of onset of type 2 diabetes is often unknown and usually precedes the clinical diagnosis by several years (Grundy et al, 1999). By the time patients are diagnosed with type 2 diabetes, many have already developed hypertension, signs of nephropathy (including microalbuminuria or even macroalbuminuria) and cardiovascular disease (Mogensen et al, 1992; The Hypertension in Diabetes Study Group, 1993a; American Diabetes Association, 1998). Whereas patients with type 1 diabetes are usually normotensive until overt renal disease develops, hypertension commonly occurs in patients with type 2 diabetes before the onset of overt diabetic nephropathy, and about 40% of newly diagnosed patients with type 2 diabetes are already hypertensive (The Hypertension in Diabetes Study Group, 1993a). Both the onset of microalbuminuria and the progression of renal disease after the onset of macroalbuminuria are accelerated by hypertension (Epstein and Sowers, 1992). The majority of patients with type 2 diabetes who have macroalbuminuria also have hypertension (Grundy et al, 1999). In these patients, control of hypertension slows the decline in GFR. The main goal of any treatment for patients with type 2 diabetic nephropathy should be to prevent the natural progression from microalbuminuria to macroalbuminuria to end-stage renal disease. Effective antihypertensive treatment is the best inhibitor of diabetic nephropathy (Ravid et al, 1993). Since reducing albuminuria delays progression of diabetic nephropathy, this parameter can be used as a benchmark for measuring the efficacy of therapeutic interventions (Rossing et al, 1994). Note that the high risk of cardiovascular mortality in patients with type 2 diabetes, even early in their disease, may not allow for the development of nephropathy (Ismail et al, 1999). ESRD MACE Onset of diabetes 2 5 10 20 30 Years * Kidney size , GFR . † GBM thickening , mesangial expansion

In the second Joslin Clinic Kidney Study on the Natural History of Microalbuminuria, progressive renal function decline in type 1 diabetes began during normoalbuminuria. This early progressive linear decline can be considered a primary clinical manifestation of disease process leading to impaired renal function and eventually ESRD. The second Joslin Clinic Kidney Study on the Natural History of Microalbuminuria Progressive renal function decline in type 1 diabetes began during normoalbuminuria. This early progressive linear decline can be considered a primary clinical manifestation of disease process leading to impaired renal function and eventually ESRD. Krolewski AS et al., Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 37: , 2014. 50

In the second Joslin Clinic Kidney Study on the Natural History of Microalbuminuria, progressive renal function decline in type 1 diabetes began during normoalbuminuria. This early progressive linear decline can be considered a primary clinical manifestation of disease process leading to impaired renal function and eventually ESRD. Krolewski AS et al., Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 37: , 2014. 51

Non-albuminuric CKD stages 3-5 Albuminuric CKD stages 3-5
Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes No CKD eGFR ≥60 & no-albuminuria n. 695 (89.4%) Micro-albuminuria n. 46 (86.8%) Macro-albuminuria n. 7 (13.2%) CKD stages 1-2 eGFR ≥60 & albuminuria n. 53 (6.8%) Non-albuminuric CKD stages 3-5 n. 17 (58.6%) CKD stages 3-5 eGFR <60 n. 29 (3.7%) In cohort 1, 89.4% of type 1 diabetic subjects had no CKD; 6.8% had stages 1-2 (by definition albuminuric) CKD; 3.7% had stages 3-5 CKD. Out of these, 41% had the albuminuric phenotype and 59% the non-albuminuric one. Albuminuric CKD stages 3-5 n. 12 (41.4%) Micro-albuminuria n. 4 (33.3%) Macro-albuminuria n. 8 (66.7%) Russo E et al., Diabetologia 56 (suppl 1) S472, 2013; EASD, Barcelona, September 2013 52

Sex, BMI, Smokers, PAD, HDL-C, Triglycerides, Uric Acid
Nel modello 2, la presenza e la severità della retinopatia sono state aggiunte quali variabili indipendenti. In particolare, solo la retinopatia proliferante entra come covariata indipendente degli stadi 1-2 che degli stadi 3-5 di CKD. L’aggiunta della retinopatia come covariata esclude la durata del diabete quale fattore di rischio indipendente di CKD 1-2 e l’Hba1c quale fattore associato a CKD 3-5. Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes Variables CKD 1-2 CKD 3-5 MODEL 2 OR 95%CI p Age, x year 0.956 0.012 1.048 0.054 Diabetes Duration, x year -- HbA1c 1.354 0.033 Total-C 1.011 0.015 Gamma-GT 1.006 0.029 1.014 0.017 Fibrinogen 1.004 0.073 1.010 0.010 Hypertension 4.260 0.0001 5.783 0.055 PAS 1.025 0.066 Retinopathy No Background Proliferative 1.0 1.666 10.778 0.280 1.747 7.684 0.002 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) S472, 2013; EASD, Barcelona, September 2013 53

Nel modello 2, l’aggiunta della retinopatia alla regressione logistica non modifica il ruolo di ipertensione ed emoglobina glicata quali covariate indipendenti di CKD 3-5 non albuminurico e, rispettivamente di CKD 3-5 albuminurico. Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes Variables CKD 3-5 Non-albuminuric albuminuric MODELLO 2 OR 95%CI p Age, x year 1.090 0.003 1.092 0.031 HbA1c -- 2.262 0.044 HDL-C 0.950 0.117 GammaGT 1.016 0.022 Fibrinogen 0.012 Hypertension 15.725 0.024 PAD 0.062 Retinopathy No Background Proliferative 1.0 0.779 4.147 0.028 0.778 0.056 Variables not in the Equation Sex, Diabetes Duration, BMI, Smokers, PAS, Total-C, Triglycerides, Uric Acid Russo E et al., Diabetologia 56 (suppl 1) S472, 2013; EASD, Barcelona, September 2013 54

Non-albuminuric stages 3-5 CKD Albuminuric stages 3.5 CKD
Heterogeneity of CKD phenotypes among 936 subjects with type 1 diabetes (EURODIAB-Italy) No CKD eGFR ≥60 & no-albuminuria n. 736 (78.6%) Micro-albuminuria n. 128 (70.3%) Macro-albuminuria n. 54 (29.7%) CKD stages 1-2 eGFR ≥60 & albuminuria n. 182 (19.5%) * *p=0.039 vs cohort 1 Non-albuminuric stages 3-5 CKD n. 5 (27.8%) CKD stages 3-5 eGFR <60 n. 18 (1.9%) In cohort 2, 78.6% of type 1 diabetic subjects had no CKD; 19.5% had stages 1-2 CKD; About 2% had stages 3-5 CKD. Out of these, 72% had the albuminuric phenotype and only 28% the non-albuminuric phenotype. This distribution was significantly different as compared with that of cohort 1 (p=0.39). 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, September 2014 55

Heterogeneity of CKD phenotypes among subjects with type 1 diabetes
In both cohorts, normoalbuminuria was splitted in ACR lower than 10 mg/g and ACR mg/g. Furthermore, stages 1-2 CKD were stratified in 2a (eGFR 75-89) and 2b (eGFR 60-74). Even in 2b eGFR, normoalbuminuria, the red boxes (88.7% vs 67.5%, p=0.006), and more so ACR lower than 10 mg/g, in green (70.4% vs 32.5%, p<0.0001) were higher in cohort 1 as compared with cohort 2. Tale analisi può rafforzare l’ipotesi che prevede il fenotipo non albuminurico quale pathway alternativa verso la CKD nei pazienti con DMT1. In coorte 1, la percentuale di soggetti normoalbuminurici con filtrato moderatamente ridotto (eGFR ml/min) era del 92,7%, identica a quella osservata nei pazienti con eGFR >90 ml/min. in questi soggetti si potrebbe ipotizzare una iniziale riduzione della funzione renale (early renal function decline, ERFD) quale nuovo fenotipo che può frequentemente comparire nelle fasi iniziali della storia naturale della malattia renale cronica nel diabete. Tale ipotesi è rafforzata dall’osservazione che anche nei soggetti con eGFR stadio 2b rimanangono elevate la percentuale non solo dei soggetti che presentano normoalbuminuria (88.7%), ma anche di quelli che presentano albuminuria normale (70.4%). A conferma di tale osservazione è l’analisi eseguita nei soggetti di coorte 2. La percentuale dei soggetti normoalbuminurici con eGFR tra era del 70.2%, inferiore rispetto a quella osservata nei soggetti con eGFR >90 (81.7%), ma anche più bassa rispetto alla coorte 1. Inoltre, considerando tra i soggetti di coorte 2 quelli che presentavano stadio 2b di eGFR, rimanevano elevate la percentuale non solo dei soggetti che presentavano normoalbuminuria, ma anche di quelli che presentavano normale albuminuria. Tale iniziale riduzione della funzione renale può essere meglio diagnosticata usando misurazioni seriate della cistatina C, valido marker di GFR anche nel range di GFR normale o elevato. Heterogeneity of CKD phenotypes among subjects with type 1 diabetes 777 T1DM eGFR MDRD (ml/min/1.73 m2) Total >90 75-89 60-74 <60 N. 445 232 71 29 ACR (<10 mg/g), n (%) 353 (79.3) 187 (80.6) 50 (70.4) 10 (34.5) 600 (77.2) (10-29 mg/g), n (%) 61 (13.7) 31 (13.4) 13 (18.3) 7 (24.1) 112 (14.4) Microalbuminuria ( mg/g), n (%) 25 (5.6) 14 (6.0) 7 (9.9) 4 (13.8) 50 (6.4) Macroalbuminuria (>300 mg/g), n (%) 6 (1.3) --- 1 (1.4) 8 (27.6) 15 (1.9) NA 936 T1DM eGFR MDRD (ml/min/1.73 m2) Total >90 75-89 60-74 <60 N. 794 84 40 18 ACR (<10 mg/g), n (%) 407 (51.3) 35 (41.7) 13 (32.5) 4 (22.2) 459 (49.0) (10-29 mg/g), n (%) 242 (30.5) 25 (29.8) 14 (35.0) 1 (5.5) 282 (30.1) Microalbuminuria ( mg/g), n (%) 106 (13.4) 16 (19.0) 6 (15.0) 132 (14.1) Macroalbuminuria (>300 mg/g), n (%) 39 (4.9) 8 (9.5) 7 (17.5) 9 (50.0) 63 (6.7) *p<0.0001 NA *p=0.006 Russo E et al., Diabetologia 57 (suppl 1), 2014; EASD, Vienna, September 2014 56

777 T1DM: clinical features
CKD 3-5 Alb- vs CKD 3-5 Alb+ ns ns ns 11,8 100 93,8 90 25 ns 90 82,4 p = 0.010 80 70,6 70 64,7 58,3 58,3 60 76,5 50 66,7 40 30 See previous slide. 16,7 20 10 11,8 8,3 Hypertension Treatment with Treatment with Treatment with CKD 3-5 Alb- CKD 3-5 Alb + BP-lowering RAS blockers statins HbA1c > 9% agents HbA1c 7-9% HbA1c < 7% Garofolo M et al., 25° Congresso Nazionale SID, Bologna, Maggio 2014 57

777 T1DM: clinical features
CKD 3-5 Alb- vs CKD 3-5 Alb+ p=0,001 p <0,001 p<0,001 1,6 100 100 p <0,001 87,5 90 37,5 80 75 70 75,8 60 50 37,5 38,3 40 ns 30 Backup slide. 20,6 17,5 20 15,9 12,5 22,6 25 10 Hypertension Treatment with Treatment with Treatment with CKD 2b Alb- CKD 2b Alb + BP-lowering RAS blockers statins HbA1c > 9% agents HbA1c 7-9% HbA1c < 7% Garofolo M et al., 25° Congresso Nazionale SID, Bologna, Maggio 2014 58

The baseline data of the RIACE study confirm that albuminuria is a continuous variable.
Even within the normoalbuminuric range, in type 2 diabetic patients, AER is correlated with several risk factors which are potentially susceptible of therapeutic intervention. However, correlations does not necessarily imply causality. Conclusions (1) Non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with reduced eGFR. Concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions. The non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary vascular bed. Even within the normoalbuminuric range, in type 2 diabetic patients, AER is correlated with several risk factors which are potentially susceptible of therapeutic intervention. 59

The baseline data of the RIACE study confirm that albuminuria is a continuous variable.
Even within the normoalbuminuric range, in type 2 diabetic patients, AER is correlated with several risk factors which are potentially susceptible of therapeutic intervention. However, correlations does not necessarily imply causality. Conclusions (2) CKD is associated with HbA1c variability more than with average HbA1c, whereas retinopathy and CVD are not. CKD is associated with hypertriglyceridemia and with resistant hypertension (likely bidirectional?). Non-albuminuric renal function impairment is also detectable in a high proportion of patients with type 1 diabetes. 60

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. Azienda Ospedaliera Sant'Andrea, Roma (Coordinating Center): Giuseppe Pugliese, Paola Simonelli, Laura Salvi, Alessandra Bazuro. 2. Ospedale Le Molinette, Torino: Paolo Cavallo-Perin, Gabriella Gruden, Bartolomeo Lorenzati. 3. Ospedale San Luigi Gonzaga, Orbassano: Mariella Trovati, Giovanni Anfossi, Franco Cavalot, Massimo Chirio. 4. Ospedale San Raffaele, Milan: Gianpaolo Zerbini, Valentina Martina. 5. IRCCS “Cà Granda – Ospedale Maggiore Policlinico”, Milan: Emanuela Orsi, Alessia Dolci. 6. Ospedale San Paolo, Milan: Antonio Pontiroli, Marco Laneri. 7. Ospedale San Giuseppe, Milan: Maura Arosio, Antonio Rossi, Laura Montefusco. 8. Ospedali Riuniti, Bergamo: Roberto Trevisan, Anna Corsi. 9. Università e Azienda Ospedaliera Universitaria Integrata di Verona: Enzo Bonora, Giacomo Zoppini. 10. Policlinico Universitario, Padova: Angelo Avogaro, Monica Vedovato, Elisa Pagnin. 11. Azienda Ospedaliero-Universitaria Pisana, Pisa: Giuseppe Penno, Laura Pucci, Daniela Lucchesi, Eleonora Russo, Monia Garofolo. 12. Ospedale Santa Chiara, Azienda Ospedaliero-Universitaria Pisana, Pisa: Anna Solini. 13. Ospedale Le Scotte, Siena: Francesco Dotta, Cecilia Fondelli, Laura Nigi. 14. Policlinico Umberto I, Roma: Susanna Morano, Alessandra Gatti, Elisabetta Mandosi e Mara Fallarino. 15. Ospedale S. Maria Goretti, Latina: Raffaella Buzzetti, Gaetano Leto. 16. Ospedali Riuniti, Foggia: Mauro Cignarelli, Olga Lamacchia, Sabina Pinnelli. 17. Policlinico Universitario, Bari: Francesco Giorgino, Luigi Laviola, Sebastio Perrini. 18. Policlinico Mater Domini, Catanzaro: Giorgio Sesti, Francesco Andreozzi. 19. Università e Azienda Ospedaliera Universitaria di Cagliari, Policlinico Universitario: Marco Giorgio Baroni, Giuseppina Frau. 61

MD BD Thanksgiving Monia Garofolo Eleonora Russo Rosalia Bellante
Daniela Lucchesi Laura Giusti Veronica Sancho-Bornez Laura Pucci 62

Thank you for your attention!
63

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