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

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
Events (RIACE) Italian Multicenter Study
Albuminuria
Micro
22.2%
Macro
4.7%
eGFR
Normo
73.1%
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 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
The Renal Insufficiency and Cardiovascular
Events (RIACE) Italian Multicenter Study
15,773 patients with type 2 diabetes from Italy
No CKD
eGFR ≥60 & no-albuminuria
n. 9,865 (62.5%)
+
CKD stages 1-2
eGFR ≥60 & albuminuria
n. 2,949 (18.7%)
+
CKD stages 3-5
eGFR <60; n. 2,959 (18.8%)
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
CKD st ages 1-2
Age (x year)
Diabetes duration (x year)
BMI (x unit)
Triglycerides (x 10 mg/dl)
HDL-cholesterol (x 5 mg/dl)
Lipid-lowering treatment
Smoking
Ex
Current
Male gender
HbA1c
Hypertension
Retinopathy
Nonadvanced
Advanced
Previous CVD
CKD st ages 3-5
albuminuric
OR
95% CI
CKD st ages 3-5
non-albuminuric
OR
95% CI
OR
95% CI
1.019
1.026
1.035
1.027
1.014-1.024
1.020-1.032
1.026-1.034
1.020-1.034
1.092
1.019
1.034
1.070
1.083-1.101
1.012-1.026
1.020-1.049
1.059-1.081
1.101
1.006
1.027
1.046
1.093-1.109
1.000-1.012
1.015-1.039
1.036-1.056
-
-
0.936
-
0.910-0.963
-
0.942
1.216
0.919-0.965
1.082-1.367
1.075
1.409
0.969-1.193
1.247-1.592
-
-
-
-
2.089
1.179
1.891-2.308
1.144-1.214
1.365
1.061
1.182-1.576
1.014-1.110
0.444
-
0.392-0.503
-
1.804
1.576-2.065
2.534
1.922-3.340
1.612
1.317-1.974
1.400
2.252
1.229-1.594
1.953-2.597
1.944
3.927
1.624-2.327
3.261-4.730
1.086
1.447
0.910-1.297
1.184-1.769
1.211
1.090-1.345
2.274
1.982-2.610
1.661
1.454-1.898
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 T2DM: CKD phenotypes by age quartiles
CKD stages 1-2
CKD stages 3-5
non-albuminuric
CKD stages 3-5
albuminuric
100
Percent
80
53.8%
60
39.1%
40
31.7%
25.4%
20
0
1st
2nd
3rd
4th
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 T2DM: 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
F
F
20
0
Age, quartiles
1st
2nd
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
3rd
4th
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 eGFR
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
MacIsaac 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%
---
(type 1)
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%
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
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. 2,027 (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
eGFR ≥60 & no-albuminuria
n. 9,865 (62.5%)
+
CKD stages 1-2
eGFR ≥60 & albuminuria
n. 2,949 (18.7%)
+
CKD stages 3-5
eGFR <60; n. 2,959 (18.8%)
No-albuminuria
no-retinopathy
n. 1,280 (43.2%)
No-albuminuria
retinopathy
n. 393 (13.3%)
Albuminuria
no-retinopathy
n. 747 (25.3%)
Albuminuria
retinopathy
n. 538 (18.2%)
Penno G, et al., The RIACE Study Group. Diabetes Care 35: 2317-2323, 2012
The Renal Insufficiency And Cardiovascular Events
(RIACE) Italian multicentre study
4,062 subjects with at least two UAE measurements
Intra-individual CV:
32.5% (14.3-58.9)
Concordance rate between a
single UAE and the geometric
mean:
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
No CKD
1
2
Total
3
4-5
234
(1.5%)
9,821
(62.3%)
10,055
(63.8%)
1
977
(6.2%)
283
(1.8%)
2
75
(0.5%)
1,591
(10.1%)
77
(0.5%)
23
(0.1%)
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%)
3
44
(0.3%)
4-5
Total
9,865
(62.5%)
1,052
(6.7%)
1,897
(12.0%)
1,260
(8.0%)
Subjects
moved by the
CKD-EPI
equation
above
belove
1,743
(11.1%)
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
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
eGFR 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 eGFR
Reference
category
Excess risk significant for eGFR
values < 78 ml/min/1.73m2
Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012
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/24h
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/24h
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 T2DM of the RIACE
cohort have AER <30 mg/24h
AER <10 mg/24h
n. 5,515
(47.8%)
n. 6,023
(52.2%)
AER 10-29 mg/24h
The RIACE Study Group. Unpublished data.
Logistic regression 1 (n. 11,538)
Age, x 1 year
Gender, male
Waist circumference, x 1 cm
HbA1c, x 1%
Diastolic BP, x 1 mmHg
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
Family history for hypertension
Family history for CVD
1.158
1.237
1.325
0.891
Retinopathy (no ret, REF)
non advanced
advanced
1.141
1.095
Smoking habits (no, REF):
ex-smokers
smokers
p
<0.0001
0.004
0.070
<0.0001
<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 T2DM of the RIACE
cohort have AER <30 mg/24h and eGFR >60 ml/min
AER <10 mg/24h
n. 4,654
(47.28%)
n. 5,211
(52.8%)
AER 10-29 mg/24h
The RIACE Study Group. Unpublished data.
Logistic regression 2 (eGFR >60; n. 9,865)
Age, x 1 year
Gender, male
Waist circumference, x 1 cm
HbA1c, x 1%
Diastolic BP, x 1 mmHg
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
Family history for hypertension
Family history for CVD
1.188
1.286
1.346
0.898
Retinopathy (no ret, REF)
non advanced
advanced
1.163
1.088
Smoking habits (no, REF):
ex-smokers
smokers
p
<0.0001
0.009
0.054
<0.0001
<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 HbA1c variability
8,260 patients with type 2 diabetes from Italy
Penno G et al. Diabetes Care 36: 2301-2310 2013
Avoid HbA1c 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
The RIACE Study Group. Submitted to NDT.
1
2
3
4
5
6
7
8
9
10
<0.73
0.740.89
0.901.03
1.041.18
1.191.33
1.341.50
1.511.74
1.752.04
2.052.57
>2.58
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=0.004
*
*
p=0.015
*
2
*
*
*
*
*
1
0
The RIACE Study Group. Submitted to NDT.
1
2
3
4
5
6
7
8
9
10
<0.73
0.740.89
0.901.03
1.041.18
1.191.33
1.341.50
1.511.74
1.752.04
2.052.57
>2.58
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=0.001
p=0.045
p=0.048
* p=0.045
p=0.037
*
*
p=0.026
1
0
The RIACE Study Group. Submitted to NDT.
1
2
3
4
5
6
7
8
9
10
<0.73
0.740.89
0.901.03
1.041.18
1.191.33
1.341.50
1.511.74
1.752.04
2.052.57
>2.58
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.
Variables
n
Albuminuria
Normoa lbuminuria
Low-microalbuminuria
Microalbuminuria
Macroalbuminuria
eGFR (MDRD)
і 90 ml/min/1.73 m 2
60-89 ml/min/1.73 m2
30-59 ml/min/1.73 m 2
<30 ml/min/1.73 m2
CKD phenotype
no CKD
stages 1-2 CKD
stage >3 CKD without
albuminuria
stage >3 CKD with
albuminuria
Retinopathy
No retinopathy
Non-advanced retinopathy
Advanced retinopathy
Control
subjects group
2
(NoRH2)
Control
subjects group
3
(NoRH3)
2,363
Control
subjects group
1
(NoRH1)
1,569
1,369
803
Control
subjects group
4
(UH)
7,440
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) ¤
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) ¤
1,032 (43.7)
545 (23.1)
966 (61.6) ¤
331 (21.1)
796 (58.1) ¤
253 (18.5) ¤
433 (53.9) ¤
144 (17.9) 
4,863 (65.4) ¤
1,397 (18.8)¤
390 (16.5)
151 (9.6) ¤
198 (14.5) *
115 (14.3)
702 (9.4) ¤
396 (16.8)
121 (7.7) ¤
122 (8.9) ¤
111 (13.8)
478 (6.4) ¤
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) ¤
Subjects with
resistant
hypertension (RH)
p values
<0.0001
<0.0001
<0.0001
<0.0001
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.
Model 1
Variables
Model 2
Model 3
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
Smoking
Never
Former
Current
Triglycerides, x 1 mg/dl
(0.0113 mmol/L)
Retinopathy
No retinopathy
Non advanced ret.
Advanced retinopathy
Albuminuria
Normal albuminuria
Low-microalbuminuria
Microalbuminuria
Macroalbuminuiria
eGFR (MDRD)
і 90 ml/min/1.73 m 2
60-89 ml/min/1.73 m2
30-59 ml/min/1.73 m2
<30 ml/min/1.73 m2
1.035
1.030-1.040
<0.0001
1.033
1.028-1.038
<0.0001
1.034
1.028-1.039
<0.0001
0.012
1.0
1.152
0.901
1.016-1.307
0.762-1.066
1.001
1.000-1.002
0.013
0.028
0.225
1.0
1.128
0.869
0.993-1.282
0.733-1.031
0.004
---
---
0.063
0.107
0.984-1.272
0.737-1.037
0.087
0.124
---
---
---
---
0.008
1.0
0.983
1.301
0.840-1.152
1.096-1.543
0.834
0.003
<0.0001
1.0
1.340
1.569
2.637
1.173-1.531
1.360-1.810
2.074-3.352
<0.0001
<0.0001
<0.0001
<0.0001
1.0
1.135
1.425
1.692
0.987-1.305
1.205-1.685
1.169-2.449
0.077
<0.0001
0.005
CVD
Variables not in regression
0.022
1.0
1.119
0.875
BMI, total cholesterol, HbA1c,
HDL cholesterol
BMI, total cholesterol, HbA1c, HDL
cholesterol, diabetes dura tion
0.012
1.0
0.971
1.283
0.829-1.138
1.081-1.524
0.717
0.004
<0.0001
1.0
1.343
1.568
2.612
1.176-1.535
1.359-1.809
2.054-3.322
<0.0001
<0.0001
<0.0001
<0.001
1.0
1.136
1.430
1.704
0.987-1.307
1.208-1.693
1.175-2.470
0.075
<0.0001
0.006
1.126
1.000-1.268
0.050
BMI, total cholesterol, HbA1c, HDL
cholesterol, diabetes dura tion,
triglycerides
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
1st quartile by age
CVD
(%)
p=0.023
p<0.001
50
609
20
1,733
561
Met yes
3-4 (<60)
2 (60-89)
1 (≥90)
eGFR category (ml/min/1.73 m2)
p=0.010
CVD
(%)
50
3rd quartile by age
40
655
0
0
157
969
1,118
p<0.001
4th quartile by age
p<0.001
776
p=0.311
826
281
Met yes
3-4 (<60)
2 (60-89)
1 (≥90)
eGFR category (ml/min/1.73 m2)
40
74
30
20
10
401
Met no
50
p=0.245
30
10
CVD
(%)
p<0.001
370
411
20
Met no
61
0
172
30
267
10
p<0.001
40
p=0.002
102
p<0.001
50
40
30
2nd quartile by age
p=0.001
CVD
(%)
20
Met no
312
1,336
682
3-4 (<60)
2 (60-89)
1 (≥90)
eGFR category (ml/min/1.73 m2)
Met yes
10
0
Met no
513
1,100
161
Met yes
3-4 (<60)
2 (60-89)
1 (≥90)
eGFR category (ml/min/1.73 m2)
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
albuminuria subsequent to renal impairment
renal impairment before albuminuria
albuminuria before renal impairment
70
64%
60
51%
Patients %
50
40
30
20
33%
24%
16%
12%
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
no albuminuria
microalbuminuria
microalbuminuria before renal impairment
macroalbuminuria
macroalbuminuria before renal impairment
70
61%
60
Patients %
50
50%
42%
40
30
24%
16%
20
10
0
8%
1350 (93.8%)
with no sustained eGFR <60
89 (6.2%)
developing sustained eGFR <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
* Kidney size , GFR .
† GBM thickening , mesangial expansion
10
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
eGFR ≥60 & no-albuminuria
n. 695 (89.4%)
CKD stages 1-2
eGFR ≥60 & albuminuria
n. 53 (6.8%)
Micro-albuminuria
n. 46 (86.8%)
Macro-albuminuria
n. 7 (13.2%)
Non-albuminuric CKD stages 3-5
CKD stages 3-5
eGFR <60
n. 29 (3.7%)
n. 17 (58.6%)
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, 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
OR
95%CI
p
0.956
0.923-0.990
0.012
1.048
0.999-1.098
0.054
--
--
--
--
--
--
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
--
--
Age, x year
Diabetes Duration, x year
PAS
Retinopathy
No
Background
Proliferative
Variables not in the Equation
--
1.025
0.998-1.052
0.066
0.0001
0.002
1.0
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
Sex, BMI, Smokers, PAD, HDL-C, Triglycerides, Uric Acid
Russo E et al., Diabetologia 56 (suppl 1) S472, 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
OR
95%CI
p
Age, x year
HbA1c
HDL-C
GammaGT
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) S472, 2013; EASD, Barcelona, 23-27 September 2013
Heterogeneity of CKD phenotypes among 936
subjects with type 1 diabetes (EURODIAB-Italy)
No CKD
eGFR ≥60 & no-albuminuria
n. 736 (78.6%)
CKD stages 1-2
eGFR ≥60 & albuminuria
n. 182 (19.5%)
Micro-albuminuria
n. 128 (70.3%)
Macro-albuminuria
n. 54 (29.7%)
Non-albuminuric stages 3-5 CKD
CKD stages 3-5
eGFR <60
n. 18 (1.9%)
*p=0.039 vs cohort 1
n. 5 (27.8%)
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 T1DM
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 T1DM
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
eGFR MDRD (ml/min/1.73 m2)
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
eGFR MDRD (ml/min/1.73 m2)
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 T1DM: clinical features
CKD 3-5 Alb- vs CKD 3-5 Alb+
ns
ns
100
93,8
ns
90
90
11,8
ns
82,4
25
p = 0.010
80
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
HbA1c > 9%
HbA1c 7-9%
HbA1c < 7%
Garofolo M et al., 25° Congresso Nazionale SID, Bologna, 28-31 Maggio 2014
777 T1DM: clinical features
CKD 3-5 Alb- vs CKD 3-5 Alb+
p=0,001
p <0,001
1,6
p<0,001
100
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
ns
17,5
15,9
12,5
10
22,6
25
CKD 2b Alb-
CKD 2b Alb +
0
Hypertension
Treatment with
BP-lowering
agents
Treatment with
RAS blockers
Treatment with
statins
HbA1c > 9%
HbA1c 7-9%
HbA1c < 7%
Garofolo M et al., 25° Congresso Nazionale SID, Bologna, 28-31 Maggio 2014
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.
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.
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
Thank you for
your attention!