La Nefropatia Diabetica: nuove acquisizioni epidemiologiche e loro significato clinico dopo i risultati dello Studio RIACE Giuseppe Penno Dipartimento

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

http://clinicaltrials.gov/show/NCT00715481





Macro4.7% Normo

73.1%Micro22.2%

Albuminuria

30-5917.1%

60-8951.7%

≥9029.6%

<301.7%

eGFR


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


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%)


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


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


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


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%)


n. 9,865 (62.5%)n. 9,865 (62.5%)


n. 2,949 (18.7%)n. 2,949 (18.7%)+



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



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%)

+


n. 9,865 (62.5%)n. 9,865 (62.5%)


n. 2,949 (18.7%)n. 2,949 (18.7%)+



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


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%)


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%)


Logistic regression analysis of all CVD eventswith CKD phenotypes as covariates



CVD events in type 2 diabetic patients stratified by CKD and Diabetic Retinopathy



Logistic regression analysis of CVD events by vascular bedwith CKD phenotypes as covariates



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


age

- a

nd s

ex-

adju

sted

ris

k fo

r a

CV

D e

vent


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



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



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.


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.


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


Avoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variabilityAvoid HbA1c variability

Penno G et al. Diabetes Care 36: 2301-2310 2013


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.


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




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




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)



Variables Subjects withresistant

hypertension (RH)

Controlsubjects group

1(NoRH1)


2(NoRH2)


3(NoRH3)


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



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)


3-4 (<60) 2 (60-89) 1 (≥90)


3-4 (<60) 2 (60-89) 1 (≥90)


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%)


Macro-albuminurian. 7 (13.2%)


Albuminuric CKD stages 3-5n. 12 (41.4%)

Albuminuric CKD stages 3-5n. 12 (41.4%)





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



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



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%)





Albuminuric stages 3.5 CKDn. 13 (72.2%)

Albuminuric stages 3.5 CKDn. 13 (72.2%)





*

*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!

Documents

La Nefropatia Diabetica: nuove acquisizioni epidemiologiche e loro significato clinico dopo i risultati dello Studio RIACE Giuseppe Penno Dipartimento