Post on 22-Dec-2015
La Nefropatia Diabetica:nuove acquisizioni
epidemiologiche e loro significato clinico dopo i
risultati dello Studio RIACE
GiuseGiuseppppe Pennoe Penno Dipartimento di Medicina Clinica e SperimentaleDipartimento di Medicina Clinica e Sperimentale
Azienda Ospedaliera Universitaria di PisaAzienda Ospedaliera Universitaria di Pisa
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
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Macro4.7% Normo
73.1%Micro22.2%
Albuminuria
30-5917.1%
60-8951.7%
≥9029.6%
<301.7%
eGFR
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011
15,77315,773 patients with type 2 diabetes from Italy patients with type 2 diabetes from Italy
62.5%12.0%
6.7%
17.1%
1.7%
Approximately 40% of patients with T2DM show signs of CKDApproximately 40% of patients with T2DM show signs of CKDApproximately 20% of patients with T2DM show reduced eGFRApproximately 20% of patients with T2DM show reduced eGFR
Renal Dysfunction is Common in Patients with T2DMRenal Dysfunction is Common in Patients with T2DM
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Prevalence of nephropathy in the German Prevalence of nephropathy in the German diabetes populationdiabetes population
Pommer W. NDT Plus 1 (suppl 4) iv2-iv5, 2008
CKD stages 3-5CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)eGFR <60; n. 2,959 (18.8%)
Non-albuminuric CKD Non-albuminuric CKD stages 3-5stages 3-5
n. 1,673 (56.6%)n. 1,673 (56.6%)
Albuminuric CKD stages 3-5Albuminuric CKD stages 3-5n. 1,286 (43.4%)n. 1,286 (43.4%)
No CKDNo CKD eGFR ≥60 & no-albuminuriaeGFR ≥60 & no-albuminuria
n. 9,865 (62.5%)n. 9,865 (62.5%)
CKD stages 1-2CKD stages 1-2eGFR ≥60 & albuminuriaeGFR ≥60 & albuminuria
n. 2,949 (18.7%)n. 2,949 (18.7%)+
+
Micro-albuminuriaMicro-albuminurian. 912 (30.8%)n. 912 (30.8%)
Macro-albuminuriaMacro-albuminurian. 374 (12,6%)n. 374 (12,6%)
Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011
Micro-albuminuriaMicro-albuminurian. 2,585 (87.7%)n. 2,585 (87.7%)
Macro-albuminuriaMacro-albuminurian. 364 (12.3%)n. 364 (12.3%)
15,773 patients with type 2 diabetes from Italy15,773 patients with type 2 diabetes from Italy
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
CKD stages 1-2CKD stages 3-5
albuminuricCKD stages 3-5non-albuminuric
OR 95% CI OR 95% CI OR 95% CIAge (x year) 1.019 1.014-1.024 1.092 1.083-1.101 1.101 1.093-1.109
Diabetes duration (x year) 1.026 1.020-1.032 1.019 1.012-1.026 1.006 1.000-1.012
BMI (x unit) 1.035 1.026-1.034 1.034 1.020-1.049 1.027 1.015-1.039
Triglycerides (x 10 mg/dl) 1.027 1.020-1.034 1.070 1.059-1.081 1.046 1.036-1.056
Variable excluded: LDL-cholesterol
HDL-cholesterol (x 5 mg/dl) - - 0.936 0.910-0.963 0.942 0.919-0.965
Lipid-lowering treatment - - - - 1.216 1.082-1.367
Smoking Ex 1.075 0.969-1.193 - - - -
Current 1.409 1.247-1.592 - - - -
Male gender 2.089 1.891-2.308 1.365 1.182-1.576 0.444 0.392-0.503
HbA1c 1.179 1.144-1.214 1.061 1.014-1.110 - -
Hypertension 1.804 1.576-2.065 2.534 1.922-3.340 1.612 1.317-1.974
Retinopathy Nonadvanced 1.400 1.229-1.594 1.944 1.624-2.327 1.086 0.910-1.297
Advanced 2.252 1.953-2.597 3.927 3.261-4.730 1.447 1.184-1.769
Previous CVD 1.211 1.090-1.345 2.274 1.982-2.610 1.661 1.454-1.898
Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian Multicentre Study) Italian Multicentre Study
Independent correlates of Chronic Kidney Disease phenotypes15,773 patients with type 2 diabetes from Italy15,773 patients with type 2 diabetes from Italy
The RIACE Study Group, unpublished data
CKD stages 1-2CKD stages 3-5 non-albuminuric
CKD stages 3-5 albuminuric
0
20
40
60
80
100
1stn. 1,013 (25.4%)
n. 3,995age ≤59
2ndn. 1,195 (31.7%)
n. 3,767age 60-66
3rdn. 1,622 (39.1%)
n. 4,151age 67-73
4thn. 2,078 (53.8%)
n. 3,860age ≥74
Per
cent
The RIACE (Renal Insufficiency and The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter StudyCardiovascular Events) Italian Multicenter Study
15,773 patients with T2DM: CKD phenotypes by age quartiles15,773 patients with T2DM: CKD phenotypes by age quartiles
25.4%31.7%
39.1%
53.8%
0
20
40
60
80
100
1st691 (27.6%)322 (21.6%)2,506/1,489
2nd854 (33.9%)441 (28.6%)2,225/1,542
3rd960 (41.3%)662 (36.2%)2,324/1,827
4th1029 (54.0%)1049 (53,7%)1,905/1,955
Per
cent
Age, quartilesM: CKD+ n, (%)F: CKD+ n, (%)
n, M/FThe RIACE Study Group, unpublished data
The RIACE (Renal Insufficiency and The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter StudyCardiovascular Events) Italian Multicenter Study
15,773 patients with T2DM: CKD phenotypes by age quartiles15,773 patients with T2DM: CKD phenotypes by age quartiles
CKD stages 1-2CKD stages 3-5 non-albuminuric
CKD stages 3-5 albuminuric
MF
MF
MF
M F
NormoalbuminuriaNormoalbuminuriaNormal GFRNormal GFR
““Natural” history of Diabetic Nephropathy in Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigmstype 1 and type 2 diabetes: new paradigms
MicroalbuminuriaMicroalbuminuria
MacroalbuminuriaMacroalbuminuria
Reduced eGFRReduced eGFRESRDESRD
Natural history of diabetic nephropathy: “albuminuric” pathway
Natural history of diabetic nephropathy: “non-albuminuric” pathway
Ca
rdio
vasc
ula
r e
ven
ts, d
eath
Ca
rdio
vasc
ula
r e
ven
ts, d
eath
Patientsn.
DM%
Follow-upyears
Renal impairment
No-albuminuric renal
impairment
Renal impairment with no albuminuria nor retinopathy
UKPDS Diabetes 55: 1832-1839, 2006
4,006 100 15 28% 67% (51%) ---
DCCT/EDICDiabetes Care 33: 1536-1543, 2010
1,439 100(type 1)
19 6.2% 24% ---
MacIsaac RJ et al., Diabetes Care 27: 195-200, 2004
301 100 --- 36% 39% 29%
Kramer HJ et al., NHANES III JAMA 289: 3273-3277, 2003
1,197 100 --- 13% 36% 30%
Thomas MC et al., NEFRONDiabetes Care 32: 1497-1502, 2009
3,893 100 --- 23% 55% ---
Ninomiya T et al., ADVANCEJ Am Soc Nephrol 20: 1813-1821, 2009
10,640 100 --- 19% 62% ---
Bakris GL et al., ACCOMPLISHLancet 375: 1173-1181, 2010
11,482 60 --- 9.5% 46.8% ---
Tube SW et al., ONTARGET/ TRASCENDCirculation 123: 1098-1107, 2011
23,422 37 --- 24% 68% ---
Drury PL et al., FIELDDiabetologia 54: 32-43, 2011
9,765 100 --- 5.3% 59.0% ---
RIACE Study Group, RIACEJ Hypertens 29: 1802-1809, 2011
15,773 100 --- 18.8% 56.6% 43.2%
““Natural” history of Diabetic Nephropathy in Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigmstype 1 and type 2 diabetes: new paradigms
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian Multicentre Study) Italian Multicentre Study
Results: stratification by CKD NKF’s KDOQI stage and retinopathy
No-retinopathyNo-retinopathyn. 2,027 (68.5%)n. 2,027 (68.5%)
RetinopathyRetinopathyn. 932 (31.5%)n. 932 (31.5%)
+
Non advanced RetNon advanced Retn. 472 (16.0%)n. 472 (16.0%)
Advanced RetAdvanced Retn. 459 (15.5%)n. 459 (15.5%)
No-retinopathyNo-retinopathyn. 2,067 (70.1%)n. 2,067 (70.1%)
RetinopathyRetinopathyn. 882 (29.9%)n. 882 (29.9%)
No CKDNo CKD eGFR ≥60 & no-albuminuriaeGFR ≥60 & no-albuminuria
n. 9,865 (62.5%)n. 9,865 (62.5%)
CKD stages 1-2CKD stages 1-2eGFR ≥60 & albuminuriaeGFR ≥60 & albuminuria
n. 2,949 (18.7%)n. 2,949 (18.7%)+
CKD stages 3-5CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)eGFR <60; n. 2,959 (18.8%)
Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011
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
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 The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian Multicentre Study) Italian Multicentre Study
Results: stratification by CKD NKF’s KDOQI stage and retinopathy
No-albuminuriaNo-albuminuriano-retinopathyno-retinopathy
n. 1,280 (43.2%)n. 1,280 (43.2%)
No-albuminuriaNo-albuminuriaretinopathyretinopathy
n. 393 (13.3%)n. 393 (13.3%)
AlbuminuriaAlbuminuriano-retinopathyno-retinopathyn. 747 (25.3%)n. 747 (25.3%)
AlbuminuriaAlbuminuriaretinopathyretinopathy
n. 538 (18.2%)n. 538 (18.2%)
+
No CKDNo CKD eGFR ≥60 & no-albuminuriaeGFR ≥60 & no-albuminuria
n. 9,865 (62.5%)n. 9,865 (62.5%)
CKD stages 1-2CKD stages 1-2eGFR ≥60 & albuminuriaeGFR ≥60 & albuminuria
n. 2,949 (18.7%)n. 2,949 (18.7%)+
CKD stages 3-5CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)eGFR <60; n. 2,959 (18.8%)
Penno G, et al., The RIACE Study Group. Diabetes Care 35: 2317-2323, 2012
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%.
Predictive performance for the mean of 3 UAE values
Reference line
UAEone valueUAEtwo values
4,062 subjects with at least two UAE measurements
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian multicentre study) Italian multicentre study
Pugliese G et al., Nephrol Dial Transplant 26: 3950-3954, 2011
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian multicentre study) Italian multicentre study
Pugliese G et al., Atherosclerosis 218: 194-199, 2011
15,773(100.0%)
258(1.7%)
2,701(17.1%)
1,897(12.0%)
1,052(6.7%)
9,865(62.5%)
Total
304(1.9%)
256(1.6%)
48(0.3%)
4-5
2,411(15.3%)
2(0.1%)
2,342(14.8%)
23(0.1%)
44(0.3%)
3
1,743(11.1%)
77(0.5%)
1,591(10.1%)
75(0.5%)
2
1,260(8.0%)
283(1.8%)
977(6.2%)
1
10,055(63.8%)
234(1.5%)
9,821(62.3%)
No CKD
4-5321No CKD
TotalMDRD StudyCKD stage
CKD-EPICKD Stage
Subjects moved by the
CKD-EPIequation
above
belove
Prevalence of stages 3-5 CKD in type 2 diabetesMDRD Study: 2,959 (18.8%)
CKD-EPI: 2,715 (17.2%)
The The RRenal enal IInsufficiency nsufficiency AAnd nd CCardiovascular ardiovascular EEvents (vents (RIACERIACE) Italian multicentre study) Italian multicentre study
Pugliese G et al., Atherosclerosis 218: 194-199, 2011
Prevalence of stages 3-5 CKD in type 2 diabetesMDRD Study: 2,959 (18.8%)
CKD-EPI: 2,715 (17.2%)
Matsushita K et al, JAMA 307: 1941-1951, 2012
Comparison of risk prediction using the CKD-EPI Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Equation and the MDRD Study Equation for Estimated Glomerular Filtration RateEstimated 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 Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Equation and the MDRD Study Equation for Estimated Glomerular Filtration RateEstimated Glomerular Filtration RateNet reclassification improvements for all-cause mortality, cardiovascular mortality, and ESRD
0
10
20
30
40
50
CKD stages 1-2
n. 2,949
No CKD
n. 9,865
Maj
or C
VD
eve
nts,
%
794(26.9%)
1,756(17.8%)
Results: Any CVD event by CKD phenotype
Chi square, p<0.0001Chi square, p<0.0001
CKD stages 3-5nonalbuminuric
n. 1,673
528(31.6%)
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
CKD stages 3-5albuminuric
n. 1,286
576(44.8%)
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Logistic regression analysis of all CVD eventswith CKD phenotypes as covariates
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (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 The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Logistic regression analysis of CVD events by vascular bedwith CKD phenotypes as covariates
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Risk of coronary events in people with chronic kidney disease Risk of coronary events in people with chronic kidney disease compared with those with diabetes:compared with those with diabetes:a population-level cohort studya population-level cohort study
Tonelli M et al.,Tonelli M et al., LancetLancet 380: 807-814, 380: 807-814, 20122012
1,268,029 participants; median follow-up of 48 months;the Alberta Kidney Disease Network
1,104,71375,87159,11715,36812,960
eGFR by the CKD-EPI equation
Reference category
Excess risk significant for eGFR values < 78 ml/min/1.73m2
CVD risk increases linearly by 12% for each decreasing decile of eGFR
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
age
- a
nd s
ex-
adju
sted
ris
k fo
r a
CV
D e
vent
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Associations of Kidney Disease measures with mortality and Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysisESRD in individuals with and without diabetes: a meta-analysis
Fox CS et al.,Fox CS et al., LancetLancet 380: 1662-1673, 380: 1662-1673, 20122012
Reference category
… CVD risk increases linearly by 9% for each increasing
decile of albuminuria
Excess risk was significant for AER values ≥10.5 mg/24h
age
- a
nd s
ex-
adju
sted
ris
k fo
r a
CV
D e
vent
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
Associations of Kidney Disease measures with mortality and Associations of Kidney Disease measures with mortality and ESRD in individuals with and without diabetes: a meta-analysisESRD in individuals with and without diabetes: a meta-analysis
Fox CS et al.,Fox CS et al., LancetLancet 380: 1662-1673, 380: 1662-1673, 20122012
Reference category
… CVD risk increases linearly by 9% for each increasing
decile of albuminuria
Excess risk was significant for AER values ≥10.5 mg/24h
age
- a
nd s
ex-
adju
sted
ris
k fo
r a
CV
D e
vent
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
11,538 (73.1%) of subjects with T2DM of the RIACE 11,538 (73.1%) of subjects with T2DM of the RIACE cohort have AER <30 mg/24hcohort have AER <30 mg/24h
n. 6,023 (52.2%)
n. 5,515 (47.8%)
AER <10 mg/24h
AER 10-29 mg/24h
The RIACE Study Group. Unpublished data.
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
OR 95%CI pAge, x 1 year 1.018 1.014-1.022 <0.0001 M/FGender, male 1.238 1.070-1.432 0.004Waist circumference, x 1 cm 1.050 0.996-1.106 0.070HbA1c, x 1% 1.062 1.033-1.093 <0.0001 MDiastolic BP, x 1 mmHg 1.014 1.010-1.018 <0.0001 M/FTriglycerides, x 1 mg/dl 1.001 1.000-1.001 0.011 FRAS blockers 1.073 0.992-1.160 0.077 MDHP calcium channel blockers 1.171 1.053-1.302 0.004 MGlucose lowering agents (diet, REF): OHA insulin + OHA insulin
1.3121.3341.495
1.175-1.4641.126-1.5811.288-1.734
<0.0001 M/F
Smoking habits (no, REF): ex-smokers smokers
1.1581.237
1.058-1.2671.106-1.384
<0.0001 M
Family history for hypertension 1.325 1.207-1.455 <0.0001 M/FFamily history for CVD 0.891 0.792-1.003 0.057 MRetinopathy (no ret, REF) non advanced advanced
1.1411.095
1.010-1.2880.942-1.271
0.072 F
Logistic regression 1 (n. 11,538) Logistic regression 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.
1,673 patients with non-albuminuric stages 3-5 CKD excluded1,673 patients with non-albuminuric stages 3-5 CKD excluded
9,865 (62.5%) of subjects with T2DM of the RIACE 9,865 (62.5%) of subjects with T2DM of the RIACE cohort have AER <30 mg/24h and eGFR >60 ml/mincohort have AER <30 mg/24h and eGFR >60 ml/min
n. 5,211 (52.8%)
n. 4,654 (47.28%)
AER <10 mg/24h
AER 10-29 mg/24h
The RIACE Study Group. Unpublished data.
The Renal Insufficiency and Cardiovascular The Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter StudyEvents (RIACE) Italian Multicenter Study
OR 95%CI pAge, x 1 year 1.018 1.014-1.022 <0.0001 M/F Gender, male 1.233 1.053-1.444 0.009Waist circumference, x 1 cm 1.057 0.999-1.118 0.054HbA1c, x 1% 1.066 1.034-1.099 <0.0001 M Diastolic BP, x 1 mmHg 1.014 1.010-1.019 <0.0001 M/F Triglycerides, x 1 mg/dl 1.001 1.000-1.001 0.058 F RAS blockers 1.069 0.982-1.163 0.122 MDHP calcium channel blockers 1.182 1.052-1.329 0.005 M Glucose lowering agents (diet, REF): OHA insulin + OHA insulin
1.2931.2771.470
1.150-1.4541.062-1.5361.247-1.733
<0.0001 M/F
Smoking habits (no, REF): ex-smokers smokers
1.1881.286
1.077-1.3101.142-1.448
<0.0001 M
Family history for hypertension 1.346 1.218-1.487 <0.0001 M/F Family history for CVD 0.898 0.790-1.021 0.100 M Retinopathy (no ret, REF) non advanced advanced
1.1631.088
1.018-1.3300.920-1.287
0.067
Logistic regression 2 (eGFR >60; n. 9,865)Logistic regression 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.
Avoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variability
Penno G et al. Diabetes Care 36: 2301-2310 2013
8,260 patients with type 2 diabetes from Italy8,260 patients with type 2 diabetes from Italy
Avoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variability
Penno G et al. Diabetes Care 36: 2301-2310 2013
8,260 patients with type 2 diabetes from Italy8,260 patients with type 2 diabetes from Italy
The RIACE Study Group. Submitted to NDT.
Independent association of hypertriglyceridemia Independent association of hypertriglyceridemia with renal complications in subjects with type 2 with renal complications in subjects with type 2 diabetes.diabetes.
10
9
8
7
6
5
4
3
2
1
0
OR
(95
% C
I) f
or C
KD
sta
ges
3-5
non-
albu
min
uric
*
**
*
**
**
p=0.006
p=0.04* *
subjects not on statins subjects on statins
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- >2.580.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57
Independent association of hypertriglyceridemia with Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes.renal complications in subjects with type 2 diabetes.
The RIACE Study Group. Submitted to NDT.
10
9
8
7
6
5
4
3
2
1
01 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- >2.580.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57
*
*
*
**
**
**
**
p=0.004
p=0.015p=0.042
p=0.004
p=0.040
14.629
OR
(95
% C
I) f
or C
KD
sta
ges
3-5
albu
min
uric
subjects not on statins subjects on statins
Independent association of hypertriglyceridemia with Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes.renal complications in subjects with type 2 diabetes.
The RIACE Study Group. Submitted to NDT.
10
9
8
7
6
5
4
3
2
1
01 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- >2.580.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57
**
*p=0.016
p=0.004p=0.045 p=0.048
p=0.001
p=0.045 p=0.026p=0.037
OR
(95
% C
I) f
or C
KD
st
ages
1-2
subjects not on statins subjects on statins
Independent association of hypertriglyceridemia with Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes.renal complications in subjects with type 2 diabetes.
The RIACE Study Group. Submitted to NDT.
Resistant hypertension in subjects with type 2 diabetes: Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications.clinical correlates and association with complications.
Resistant hypertension
Normotensive
Non-resistant hypertension
Uncontrolled hypertension
Solini A et al. J Hypertens 2014, Sept 5 (Epub ahead of print)
Resistant hypertension in subjects with type 2 diabetes: Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications.clinical correlates and association with complications.
Solini A et al. J Hypertens 2014, Sept 5 (Epub ahead of print)
Variables Subjects withresistant
hypertension (RH)
Controlsubjects group
1(NoRH1)
Controlsubjects group
2(NoRH2)
Controlsubjects group
3(NoRH3)
Controlsubjects group
4(UH)
p values
n 2,363 1,569 1,369 803 7,440Albuminuria Normoalbuminuria Low-microalbuminuria Microalbuminuria Macroalbuminuria
656 (27.8)766 (32.4)709 (30.0)232 (9.8)
620 (39.5) §497 (31.7)
391 (24.9) §61 (3.9) §
538 (39.3) §456 (33.3)
318 (23.2) §57 (4.2) §
283 (35.2) §265 (33.0)
211 (26.3) *44 (5.5) §
2,862 (38.5) §2,703 (36.3) §1,558 (20.9) §
317 (4.3) §
<0.0001
eGFR (MDRD) ≥90 ml/min/1.73 m2
60-89 ml/min/1.73 m2
30-59 ml/min/1.73 m2
<30 ml/min/1.73 m2
455 (19.3)1,122 (47.5)694 (29.4)
92 (3.9)
469 (29.9) §828 (52.8) §253 (16.1) §
19 (1.2) §
324 (23.7) =725 (53.0) §297 (21.7) §23 (1.7) §
184 (22.9) *393 (48.9)208 (25.9)18 (2.2) *
2,254 (30.3) §4,006 (53.8) §1,084 (14.6) §
96 (1.3) §
<0.0001
CKD phenotype no CKD stages 1-2 CKD stage >3 CKD without albuminuria stage >3 CKD with albuminuria
1,032 (43.7)545 (23.1)
390 (16.5)
396 (16.8)
966 (61.6) §331 (21.1)
151 (9.6) §
121 (7.7) §
796 (58.1) §253 (18.5) §
198 (14.5) *
122 (8.9) §
433 (53.9) §144 (17.9) =
115 (14.3)
111 (13.8)
4,863 (65.4) §1,397 (18.8)§
702 (9.4) §
478 (6.4) §
<0.0001
Retinopathy No retinopathy Non-advanced retinopathy Advanced retinopathy
1,696 (71.8)329 (13.9)338 (14.3)
1,235 (78.7) §194 (12.4)140 (8.9) §
1,043 (76.2) =197 (14.4)129 (9.4) §
610 (76.0) *108 (13.4)85 (10.6) =
5,792 (77.8) §931 (12.5)717 (9.6) §
<0.0001
Resistant hypertension in subjects with type 2 diabetes: Resistant hypertension in subjects with type 2 diabetes: clinical correlates and association with complications.clinical correlates and association with complications.
Solini A et al. J Hypertens 2014, Sept 5 (Epub ahead of print)
Model 1 Model 2 Model 3Variables
OR 95%CI p OR 95%CI p OR 95%CI p
Age, x year 1.034 1.027-1.040 <0.0001 1.027 1.021-1.034 <0.0001 1.026 1.020-1.033 <0.0001
Diabetes duration, x year 1.006 1.000-1.011 0.037 --- --- --- --- --- ---
Gender, male 0.880 0.785-0.986 0.028 0.818 0.727-0.920 0.001 0.820 0.726-0.926 0.001
Waist circumference, x 1 cm 1.035 1.030-1.040 <0.0001 1.033 1.028-1.038 <0.0001 1.034 1.028-1.039 <0.0001
Smoking Never Former Current
1.01.1520.901
1.016-1.3070.762-1.066
0.012
0.0280.225
1.01.1280.869
0.993-1.2820.733-1.031
0.013
0.0630.107
1.01.1190.875
0.984-1.2720.737-1.037
0.022
0.0870.124
Triglycerides, x 1 mg/dl(0.0113 mmol/L)
1.001 1.000-1.002 0.004 --- --- --- --- --- ---
Retinopathy No retinopathy Non advanced ret. Advanced retinopathy
1.00.9831.301
0.840-1.1521.096-1.543
0.008
0.8340.003
1.00.9711.283
0.829-1.1381.081-1.524
0.012
0.7170.004
Albuminuria Normal albuminuria Low-microalbuminuria Microalbuminuria Macroalbuminuiria
1.01.3401.5692.637
1.173-1.5311.360-1.8102.074-3.352
<0.0001
<0.0001<0.0001<0.0001
1.01.3431.5682.612
1.176-1.5351.359-1.8092.054-3.322
<0.0001
<0.0001<0.0001<0.0001
eGFR (MDRD) ≥90 ml/min/1.73 m2
60-89 ml/min/1.73 m2
30-59 ml/min/1.73 m2
<30 ml/min/1.73 m2
1.01.1351.4251.692
0.987-1.3051.205-1.6851.169-2.449
<0.0001
0.077<0.0001
0.005
1.01.1361.4301.704
0.987-1.3071.208-1.6931.175-2.470
<0.001
0.075<0.0001
0.006
CVD 1.126 1.000-1.268 0.050
Variables not in regression BMI, total cholesterol, HbA1c,HDL cholesterol
BMI, total cholesterol, HbA1c, HDLcholesterol, diabetes duration
BMI, total cholesterol, HbA1c, HDLcholesterol, diabetes duration,
triglycerides
Solini A et al. J Am Geriatr Soc 61: 1253-1261, 2013
CVD(%)
1st quartile by age CVD(%)
2nd quartile by age
CVD(%)
CVD(%)
3rd quartile by age 4th quartile by age
0
10
20
30
40
50
3-4 (<60) 2 (60-89) 1 (≥90)
Met yes
Met no
0
10
20
30
40
50
Met yes
Met no
0
10
20
30
40
50
Met yes
Met no
0
10
20
30
40
50
Met yes
Met no
1,73356161
609267102
401411
172
1,118969157
6821,336312
281655
370
1611,100513
74826
776
eGFR category (ml/min/1.73 m2)
3-4 (<60) 2 (60-89) 1 (≥90)
eGFR category (ml/min/1.73 m2)
3-4 (<60) 2 (60-89) 1 (≥90)
eGFR category (ml/min/1.73 m2)
3-4 (<60) 2 (60-89) 1 (≥90)
eGFR category (ml/min/1.73 m2)
p=0.002
p<0.001p=0.023
p<0.001p<0.001
p=0.001
p=0.245
p<0.001
p=0.010
p=0.311
p<0.001
p<0.001
Solini A et al. J Am Geriatr Soc 61: 1253-1261, 2013
Retnakaran R et al.,Retnakaran R et al., Diabetes Diabetes 55: 1832-1839, 55: 1832-1839, 20062006
Challenging conventional paradigms:Challenging conventional paradigms:Diabetic kidney disease with and without albuminuriaDiabetic kidney disease with and without albuminuria
UKPDS; 4006 type 2 DM patientsfollowed over a median of 15 years
0
10
20
30
40
50
60
70
1534 (38%) developing albuminuria
1132 (28%) developing renal impairment
64%
24%
12%
Pat
ient
s %
51%
16%
33%
no renal impairment
renal impairment subsequent to albuminuria
renal impairment before albuminuria
no albuminuria
albuminuria subsequent to renal impairment
albuminuria before renal impairment
Challenging conventional paradigms:Challenging conventional paradigms:Diabetic kidney disease with and without albuminuriaDiabetic kidney disease with and without albuminuria
Molitch ME et al.,Molitch ME et al., Diabetes CareDiabetes Care 33: 1536-1543, 33: 1536-1543, 20102010
DCCT/EDIC; 1439 type 1 DM patientsfollowed over a median of 19 years
0
10
20
30
40
50
60
70
1350 (93.8%) with no sustained eGFR <60
89 (6.2%) developing sustained eGFR <60
50%
42%
8%
Pat
ient
s %
24%
16%
61%
no albuminuria
microalbuminuria
macroalbuminuria
no albuminuria
microalbuminuria before renal impairment
macroalbuminuria before renal impairment
Functional changes*
ESRD
Clinical type 1 diabetes
Structural changes†
Proteinuria
Rising serum creatinine levels
Rising blood pressure
Onset of diabetes 2 5 10 20
Years
* Kidney size , GFR † GBM thickening , mesangial expansion
Microalbuminuria
30
MACE
““Natural” history of Diabetic Nephropathy in Natural” history of Diabetic Nephropathy in type 1 diabetestype 1 diabetes
Krolewski AS et al., Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 37: 226-234, 2014.
CKD stages 3-5 eGFR <60 n. 29 (3.7%)
No CKD eGFR ≥60 & no-albuminuria
n. 695 (89.4%)
CKD stages 1-2eGFR ≥60 & albuminuria
n. 53 (6.8%)
Micro-albuminurian. 46 (86.8%)
Micro-albuminurian. 46 (86.8%)
Macro-albuminurian. 7 (13.2%)
Macro-albuminurian. 7 (13.2%)
Albuminuric CKD stages 3-5n. 12 (41.4%)
Albuminuric CKD stages 3-5n. 12 (41.4%)
Micro-albuminurian. 4 (33.3%)
Micro-albuminurian. 4 (33.3%)
Macro-albuminurian. 8 (66.7%)
Macro-albuminurian. 8 (66.7%)
Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes
Russo E et al., Diabetologia 56 (suppl 1) S472, 2013; EASD, Barcelona, 23-27 September 2013
Variables CKD 1-2 CKD 3-5
MODEL 2 OR 95%CI p OR 95%CI p
Age, x year 0.956 0.923-0.990 0.012 1.048 0.999-1.098 0.054
Diabetes Duration, x year -- -- -- -- -- --
HbA1c 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
PAS -- -- -- 1.025 0.998-1.052 0.066
RetinopathyNoBackgroundProliferative
1.01.66610.778
0.660-4.2074.380-26.523
0.0001
0.2800.0001
1.01.7477.684
0.367-8.3141.877-31.450
0.002
0.4830.005
Variables not in the Equation Sex, BMI, Smokers, PAD, HDL-C, Triglycerides, Uric Acid
Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes
Russo E et al., Diabetologia 56 (suppl 1) S472, 2013; EASD, Barcelona, 23-27 September 2013
VariablesCKD 3-5
Non-albuminuricCKD 3-5
albuminuric
MODELLO 2 OR 95%CI p OR 95%CI p
Age, x year 1.090 1.030-1.153 0.003 1.092 1.008-1.184 0.031
HbA1c -- -- -- 2.262 1.020-5.016 0.044
HDL-C -- -- -- 0.950 0.890-1.013 0.117
GammaGT 1.016 1.002-1.030 0.022 -- -- --
Fibrinogen -- -- -- 1.016 1.003-1.028 0.012
Hypertension 15.725 1.432-172.655 0.024 -- -- --
PAD -- -- -- 1.092 0.996-1.198 0.062
RetinopathyNoBackgroundProliferative
1.00.7794.147
0.137-4.4170.964-17.844
0.028
0.7780.056
-- -- --
Variables not in the EquationSex, Diabetes Duration, BMI, Smokers, PAS, Total-C, Triglycerides, Uric Acid
Heterogeneity of CKD phenotypes among 777 subjects with type 1 diabetes
Russo E et al., Diabetologia 56 (suppl 1) S472, 2013; EASD, Barcelona, 23-27 September 2013
CKD stages 3-5 eGFR <60 n. 18 (1.9%)
No CKD eGFR ≥60 & no-albuminuria
n. 736 (78.6%)
CKD stages 1-2eGFR ≥60 & albuminuria
n. 182 (19.5%)
Micro-albuminurian. 128 (70.3%)
Micro-albuminurian. 128 (70.3%)
Macro-albuminurian. 54 (29.7%)
Macro-albuminurian. 54 (29.7%)
Albuminuric stages 3.5 CKDn. 13 (72.2%)
Albuminuric stages 3.5 CKDn. 13 (72.2%)
Micro-albuminurian. 4 (30.8%)
Micro-albuminurian. 4 (30.8%)
Macro-albuminurian. 9 (69.2%)
Macro-albuminurian. 9 (69.2%)
*
*p=0.039 vs cohort 1Russo E et al., Diabetologia 57 (suppl 1), 2014; EASD, Vienna, 15-19 September 2014
Heterogeneity of CKD phenotypes among 936 subjects with type 1 diabetes (EURODIAB-Italy)
777 T1DMeGFR 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)
ACR (10-29 mg/g), n (%)
61 (13.7) 31 (13.4) 13 (18.3) 7 (24.1) 112 (14.4)
Microalbuminuria (30-299 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)
936 T1DMeGFR 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)
ACR (10-29 mg/g), n (%)
242 (30.5) 25 (29.8) 14 (35.0) 1 (5.5) 282 (30.1)
Microalbuminuria (30-299 mg/g), n (%)
106 (13.4) 16 (19.0) 6 (15.0) 4 (22.2) 132 (14.1)
Macroalbuminuria (>300 mg/g), n (%)
39 (4.9) 8 (9.5) 7 (17.5) 9 (50.0) 63 (6.7)
*p=0.006
*p<0.0001
Heterogeneity of CKD phenotypes among subjects with type 1 diabetes
Russo E et al., Diabetologia 57 (suppl 1), 2014; EASD, Vienna, 15-19 September 2014
NA
NA
93,8
82,4
70,664,7
90
58,3 58,3
16,7
0
10
20
30
40
50
60
70
80
90
100
Hypertension Treatment withBP-lowering
agents
Treatment withRAS blockers
Treatment withstatins
11,8 8,3
76,5
66,7
11,8
25
CKD 3-5 Alb- CKD 3-5 Alb +
HbA1c > 9%
HbA1c 7-9%
HbA1c < 7%
777 T1DM: clinical features CKD 3-5 Alb- vs CKD 3-5 Alb+
nsns
nsp = 0.010
ns
Garofolo M et al., 25° Congresso Nazionale SID, Bologna, 28-31 Maggio 2014
38,3
20,617,5 15,9
100
87,5
75
12,5
0
10
20
30
40
50
60
70
80
90
100
Hypertension Treatment withBP-lowering
agents
Treatment withRAS blockers
Treatment withstatins
22,6 25
75,8
37,5
1,6
37,5
CKD 2b Alb- CKD 2b Alb +
p=0,001p<0,001
p <0,001
ns
p <0,001
777 T1DM: clinical features CKD 3-5 Alb- vs CKD 3-5 Alb+
HbA1c > 9%
HbA1c 7-9%
HbA1c < 7%
Garofolo M et al., 25° Congresso Nazionale SID, Bologna, 28-31 Maggio 2014
Conclusions (1)Conclusions (1)
Non-albuminuric renal impairment is the predominant Non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with clinical phenotype in patients, particularly women, with reduced eGFR.reduced eGFR.
Concordance between CKD and diabetic retinopathy is low, Concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions.presenting with any or advanced retinal lesions.
The non-albuminuric form is associated with a significant The non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary prevalence of CVD, especially at the level of the coronary vascular bed.vascular bed.
Even within the normoalbuminuric range, in type 2 diabetic Even within the normoalbuminuric range, in type 2 diabetic patients, AER is correlated with several risk factors which patients, AER is correlated with several risk factors which are potentially susceptible of therapeutic intervention.are potentially susceptible of therapeutic intervention.
Conclusions (2)Conclusions (2)
CKD is associated with HbA1c variability more than with CKD is associated with HbA1c variability more than with average HbA1c, whereas retinopathy and CVD are not.average HbA1c, whereas retinopathy and CVD are not.
CKD is associated with hypertriglyceridemia and with CKD is associated with hypertriglyceridemia and with resistant hypertension (likely bidirectional?).resistant hypertension (likely bidirectional?).
Non-albuminuric renal function impairment is also Non-albuminuric renal function impairment is also detectable in a high proportion of patients with type 1 detectable in a high proportion of patients with type 1 diabetes.diabetes.
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.
ThanksgivingThanksgiving
ThanksgivingThanksgiving
MDMonia Garofolo
Eleonora Russo
Rosalia Bellante
BDDaniela Lucchesi
Laura Giusti
Veronica Sancho-Bornez
Laura Pucci
Thank you Thank you for your for your
attention!attention!