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La Nefropatia Diabetica: nuove acquisizioni

epidemiologiche e loro significato clinico dopo i

risultati dello Studio RIACE

Giuseppe Penno Dipartimento di Medicina Clinica e Sperimentale

Azienda Ospedaliera Universitaria di Pisa

RIACE is a multicentre 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

http://clinicaltrials.gov/show/NCT00715481

Macro 4.7% Normo

73.1% Micro 22.2%

Albuminuria

30-59 17.1%

60-89 51.7%

≥90 29.6%

<30 1.7%

eGFR


Penno G, et al., The RIACE Study Group. J Hypertens 29: 1802-1809, 2011

15,773 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 CKD Approximately 20% of patients with T2DM show reduced eGFR

Renal Dysfunction is Common in Patients with T2DM


Prevalence of nephropathy in the German diabetes population

Pommer W. NDT Plus 1 (suppl 4) iv2-iv5, 2008

CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)

Non-albuminuric CKD stages 3-5

n. 1,673 (56.6%)

Albuminuric CKD stages 3-5 n. 1,286 (43.4%)

No CKD eGFR ≥60 & no-albuminuria

n. 9,865 (62.5%)

CKD stages 1-2 eGFR ≥60 & albuminuria

n. 2,949 (18.7%) +

+

Micro-albuminuria n. 912 (30.8%)

Macro-albuminuria n. 374 (12,6%)


Micro-albuminuria n. 2,585 (87.7%)

Macro-albuminuria n. 364 (12.3%)



Variable excluded: LDL-cholesterol


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

0

20

40

60

80

100

1st 691 (27.6%) 322 (21.6%) 2,506/1,489

2nd 854 (33.9%) 441 (28.6%) 2,225/1,542

3rd 960 (41.3%) 662 (36.2%) 2,324/1,827

4th 1029 (54.0%) 1049 (53,7%) 1,905/1,955

Perc

ent

Age, quartiles M: CKD+ n, (%) F: CKD+ n, (%)

n, M/F The RIACE Study Group, unpublished data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 CKD stages 3-5 non-albuminuric

CKD stages 3-5 albuminuric

M F

M F

M F

M F

Normoalbuminuria Normal GFR

“Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms

Microalbuminuria

Macroalbuminuria

Reduced eGFR ESRD

Natural history of diabetic nephropathy: “albuminuric” pathway

Natural history of diabetic nephropathy: “non-albuminuric” pathway

Car

diov

ascu

lar e

vent

s, d

eath

Patients n.

DM %

Follow-up years

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/EDIC Diabetes 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., NEFRON Diabetes Care 32: 1497-1502, 2009

3,893 100 --- 23% 55% ---

Ninomiya T et al., ADVANCE J Am Soc Nephrol 20: 1813-1821, 2009

10,640 100 --- 19% 62% ---

Bakris GL et al., ACCOMPLISH Lancet 375: 1173-1181, 2010

11,482 60 --- 9.5% 46.8% ---

Tube SW et al., ONTARGET/ TRASCEND Circulation 123: 1098-1107, 2011

23,422 37 --- 24% 68% ---

Drury PL et al., FIELD Diabetologia 54: 32-43, 2011

9,765 100 --- 5.3% 59.0% ---

RIACE Study Group, RIACE J Hypertens 29: 1802-1809, 2011

15,773 100 --- 18.8% 56.6% 43.2%

“Natural” history of Diabetic Nephropathy in type 1 and type 2 diabetes: new paradigms


Results: stratification by CKD NKF’s KDOQI stage and retinopathy

No-retinopathy n. 2,027 (68.5%)

Retinopathy n. 932 (31.5%)

+

Non advanced Ret n. 472 (16.0%)

Advanced Ret n. 459 (15.5%)

No-retinopathy n. 2,067 (70.1%)

Retinopathy n. 882 (29.9%)


n. 9,865 (62.5%)


n. 2,949 (18.7%) +

CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)


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



Results: stratification by CKD NKF’s KDOQI stage and retinopathy

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%)

+


n. 9,865 (62.5%)


n. 2,949 (18.7%) +

CKD stages 3-5 eGFR <60; n. 2,959 (18.8%)


The Renal Insufficiency And Cardiovascular Events (RIACE) 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 4-5 3 2 1 No CKD

Total MDRD Study CKD stage

CKD-EPI CKD Stage

Subjects moved by the

CKD-EPI equation

above

belove

Prevalence of stages 3-5 CKD in type 2 diabetes MDRD Study: 2,959 (18.8%)

CKD-EPI: 2,715 (17.2%)

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study

Pugliese G et al., Atherosclerosis 218: 194-199, 2011

Prevalence of stages 3-5 CKD in type 2 diabetes MDRD 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 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

0

10

20

30

40

50

CKD stages 1-2

n. 2,949

No CKD

n. 9,865

Maj

or C

VD e

vent

s, %

794 (26.9%)

1,756 (17.8%)

Results: Any CVD event by CKD phenotype

Chi square, p<0.0001

CKD stages 3-5 nonalbuminuric

n. 1,673

528 (31.6%)

Solini A. et al, The RIACE Study Group. Diabetes Care 35: 143-149, 2012

CKD stages 3-5 albuminuric

n. 1,286

576 (44.8%)


Logistic regression analysis of all CVD events with 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 bed with CKD phenotypes as covariates



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-

and

sex

-adj

uste

d ris

k fo

r a C

VD e

vent


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-

and

sex

-adj

uste

d ris

k fo

r a C

VD e

vent



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-

and

sex

-adj

uste

d ris

k fo

r a C

VD e

vent



11,538 (73.1%) of subjects with T2DM of the RIACE cohort 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 p Age, x 1 year 1.018 1.014-1.022 <0.0001 M/F Gender, male 1.238 1.070-1.432 0.004 Waist circumference, x 1 cm 1.050 0.996-1.106 0.070 HbA1c, x 1% 1.062 1.033-1.093 <0.0001 M Diastolic BP, x 1 mmHg 1.014 1.010-1.018 <0.0001 M/F Triglycerides, x 1 mg/dl 1.001 1.000-1.001 0.011 F RAS blockers 1.073 0.992-1.160 0.077 M DHP calcium channel blockers 1.171 1.053-1.302 0.004 M 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

<0.0001 M/F

Smoking habits (no, REF): ex-smokers smokers

1.158 1.237

1.058-1.267 1.106-1.384

<0.0001 M

Family history for hypertension 1.325 1.207-1.455 <0.0001 M/F Family history for CVD 0.891 0.792-1.003 0.057 M Retinopathy (no ret, REF) non advanced advanced

1.141 1.095

1.010-1.288 0.942-1.271

0.072 F

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 excluded

9,865 (62.5%) of subjects with T2DM of the RIACE cohort 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 p Age, x 1 year 1.018 1.014-1.022 <0.0001 M/F Gender, male 1.233 1.053-1.444 0.009 Waist circumference, x 1 cm 1.057 0.999-1.118 0.054 HbA1c, 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 M DHP calcium channel blockers 1.182 1.052-1.329 0.005 M 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

<0.0001 M/F

Smoking habits (no, REF): ex-smokers smokers

1.188 1.286

1.077-1.310 1.142-1.448

<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

1.163 1.088

1.018-1.330 0.920-1.287

0.067

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 variability

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


Avoid HbA1c variability

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


The RIACE Study Group. Submitted to NDT.

Independent association of hypertriglyceridemia with renal complications in subjects with type 2 diabetes.

10

9

8

7

6

5

4

3

2

1

0

OR

(95%

CI)

for C

KD s

tage

s 3-

5 no

n-al

bum

inur

ic

*

* *

*

* * * *

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- >2.58 0.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57



10

9

8

7

6

5

4

3

2

1

0 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- >2.58 0.89 1.03 1.18 1.33 1.50 1.74 2.04 2.57

*

*

*

* *

* *

* * * *

p=0.004

p=0.015 p=0.042

p=0.004

p=0.040

14.629

OR

(95%

CI)

for C

KD s

tage

s 3-

5 al

bum

inur

ic

subjects not on statins subjects on statins



Resistant hypertension in subjects with type 2 diabetes: 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)





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

1,733 561 61

609 267 102 401

411 172

1,118 969 157

682 1,336 312

281 655

370

161 1,100 513

74 826

776

eGFR category (ml/min/1.73 m2)

3-4 (<60) 2 (60-89) 1 (≥90) eGFR category (ml/min/1.73 m2)



p=0.002

p<0.001 p=0.023

p<0.001 p<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., Diabetes 55: 1832-1839, 2006

Challenging conventional paradigms: Diabetic kidney disease with and without albuminuria

UKPDS; 4006 type 2 DM patients followed 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%

Patie

nts

%

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: Diabetic kidney disease with and without albuminuria

Molitch ME et al., Diabetes Care 33: 1536-1543, 2010

DCCT/EDIC; 1439 type 1 DM patients followed 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%

Patie

nts

%

24% 16%

61%

no albuminuria

microalbuminuria

macroalbuminuria

no albuminuria

microalbuminuria before renal impairment

macroalbuminuria before renal impairment

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%)


n. 695 (89.4%)


n. 53 (6.8%)



Non-albuminuric CKD stages 3-5 n. 17 (58.6%)

Albuminuric CKD stages 3-5 n. 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

Retinopathy No Background Proliferative

1.0

1.666 10.778

0.660-4.207 4.380-26.523

0.0001

0.280 0.0001

1.0

1.747 7.684

0.367-8.314 1.877-31.450

0.002

0.483 0.005

Variables not in the Equation Sex, BMI, Smokers, PAD, HDL-C, Triglycerides, Uric Acid



Variables CKD 3-5 Non-albuminuric

CKD 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

Retinopathy No Background Proliferative

1.0

0.779 4.147

0.137-4.417 0.964-17.844

0.028

0.778 0.056

-- -- --

Variables not in the Equation Sex, Diabetes Duration, BMI, Smokers, PAS, Total-C, Triglycerides, Uric Acid



CKD stages 3-5 eGFR <60

n. 18 (1.9%)


n. 736 (78.6%)


n. 182 (19.5%)



Non-albuminuric stages 3-5 CKD n. 5 (27.8%)

Albuminuric stages 3.5 CKD n. 13 (72.2%)



*

*p=0.039 vs cohort 1 Russo 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 T1DM eGFR MDRD (ml/min/1.73 m2)

Total >90 75-89 60-74 <60 N. 445 232 71 29 ACR (<10 mg/g), n (%) 353 (79.3) 187 (80.6) 50 (70.4) 10 (34.5) 600 (77.2)

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 T1DM eGFR MDRD (ml/min/1.73 m2) Total >90 75-89 60-74 <60

N. 794 84 40 18 ACR (<10 mg/g), n (%) 407 (51.3) 35 (41.7) 13 (32.5) 4 (22.2) 459 (49.0)

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

NA

NA

Garofolo M et al., 25° Congresso Nazionale SID, Bologna, 28-31 Maggio 2014

93,8

82,4

70,6 64,7

90

58,3 58,3

16,7

0

10

20

30

40

50

60

70

80

90

100

Hypertension Treatment with BP-lowering

agents

Treatment with RAS blockers

Treatment with statins

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+

ns ns

ns p = 0.010

ns


38,3

20,6 17,5 15,9

100

87,5

75

12,5

0

10

20

30

40

50

60

70

80

90

100

Hypertension Treatment with BP-lowering

agents

Treatment with RAS blockers

Treatment with statins

22,6 25

75,8

37,5

1,6

37,5

CKD 2b Alb- CKD 2b Alb +

p=0,001 p<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%


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.

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.

Thanksgiving

Thanksgiving

MD Monia Garofolo

Eleonora Russo

Rosalia Bellante

BD Daniela Lucchesi

Laura Giusti

Veronica Sancho-Bornez

Laura Pucci

Thank you for your attention!