Renal impairment: at the heart of diabetes care

Chairmen: M. Marre (France) S. Liatis (Greece)

Satellite symposium

The burden of renal complications in type 2 diabetes

A. Avogaro (Italy)

Satellite Symposium Servier

The burden of renal complications in Type 2 Diabetes

Angelo Avogaro

DIMED@UNIPD. Italy

Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes

Journal of Diabetes Investigation Volume 6, Issue 1, pages 3-15, 11 JUL 2014 DOI: 10.1111/jdi.12255 http://onlinelibrary.wiley.com/doi/10.1111/jdi.12255/full#jdi12255-fig-0001

Clinical features of diabetic nephropathy

nephrotic syndrome ESRD

1. Impaired barrier function (proteinuria)

→ Podocyte dysfunction/loss → GBM thickening Normoalbuminuria Microalbuminuria Macroalbuminuria

3. Increased systemic blood pressure (BP)

→ Primary (essential) T2DM → Secondary (renal) T1DM Normal BP Borderline BP Hypertension

2. Altered glomerular filtration rate (GFR)

→ Mesangial expansion → Glomerulosclerosis Increased GFR Normal GFR Reduced GFR

The clinical tryad

CKD classification

<15

15-29

30-45

45-59

60-74

75-89

90-104

>105

Kidney failure G5

Severe G4

Moderate-severe G3b

Mild-moderate G3a

Mild

G2

Optimal

High G1

>2000 300-1999 30-299 10-29 <10

Nephrotic Very high High High-normal Optimal

A3 (macro) A2 (micro) A1 (normo)

Albuminuria (mg/g)

eGFR

, ml/

min

/1.7

3 m

2

Levey AS et al, Kidney Int 2011; 80:17–28

Kidney Disease: Improving Global Outcomes (KDIGO)

Progression to ESRD versus death from CVD

Annual transition rates through the stages of nephropathy and to death from any cause.

normoalbuminuria

microalbuminuria

macroalbuminuria

elevated plasma creatinine renal replacement therapy

D E A T H

1.4% (1.3-1.5%)

3.0% (2.6-3.4%)

3.6% (4.6-5.7%)

19.2% (14.0-24.4%)

2.0% (1.9-2.2%)

2.8% (2.5-3.2%)

2.3% (1.5-3.0%)

0.1% (0.1-0.2%)

0.3% (0.1-0.4%)

0.1% (0.0-0.1%)

The United Kingdom Prospective Diabetes Study (UKPDS) 64

Adler AI et al, Kidney Int 2003; 63:225–232

Albuminuria versus reduced eGFR in diabetic subjects

Ninomiya T et al, J Am Soc Nephrol 2009; 20:1813–1821

10,640 T2DM patients - median follow-up of 4.3 years

Adverse CVD and renal events by baseline eGFR and albuminuria

The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) Study

0

10

20

30

40

50

Maj

or a

cute

CVD

eve

nts (

%)

stages 3-5 CKD nonalbuminuric

n. 1,673

528 (31.6%)

stages 3-5 CKD albuminuric

n. 1,286

576 (44.8%)

No CKD

n. 9,865

stages 1-2 CKD

n. 2,949

794 (26.9%)

1,756 (17.8%)

Albuminuria versus reduced eGFR and CVD events

Penno G et al, J Hypertens 2011; 29:1802-1809

The Renal Insufficiency And Cardiovascular Events (RIACE) Study

Solini A et al, Diabetes Care 2012; 35:143-149

The Renal Insufficiency And Cardiovascular Events (RIACE) Study

Albuminuria versus reduced eGFR and CVD events by vascular bed

CKD stages 3-5 nonalbuminuric

CKD stages 3-5 albuminuric CKD stages 1-2

OR 95% CI OR 95% CI OR 95% CI

Total CVD events 1.52 1.34-1.73 1.90 1.66-2.19 1.20 1.08-1.33

Coronary events 1.51 1.30-1.76 1.27 1.08-1.49 0.90 0.79-1.02

Cerebrovascular events 1.22 1.01-1.48 1.69 1.40-2.00 1.41 1.20-1.65

Peripheral events 1.40 1.11-1.76 1.88 1.52-2.34 1.51 1.25-1.82

Logistic regression analysis with stepwise variable selection

Framework for classifying biomarkers of incident CKD

Shlipak, M. G. & Day, E. C. (2013) Biomarkers for incident CKD: a new framework for interpreting the literature

Nat. Rev. Nephrol. doi:10.1038/nrneph.2013.108

Biomarkers of CKD and microalbuminuria in the Framingham Heart Study

Shlipak, M. G. & Day, E. C. (2013) Biomarkers for incident CKD: a new framework for interpreting the literature

Nat. Rev. Nephrol. doi:10.1038/nrneph.2013.108

From: Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline

Ann Intern Med. 2013;158(11):825-830. doi:10.7326/0003-4819-158-11-201306040-00007

Fadini et al. Cardiovasc Res 2010

The balance between damage and repair

Endothelial progenitor cells

EPCs represent an integrated component of

the vascular system involved in vascular repair

Choi et al ATVB 2004

Rookmaker et al, Am J Pathol 2003

GLOMERULAR REPAIR BY BM CELLS

Endothelial Mesangial Monocytes

02468

101214161820

CTRL CRF DM non-DM

EPC

s / m

m2

*

Endothelial progenitor cells repair the glomerulus

Makino et al, Diabetic Medicine 2009

Low CD34+ cell count

High CD34+ cell count

Circulating endothelial and CD34+ progenitors in diabetes

Type 2 diabetes

Fadini et al. JACC 2005

Pre-diabetes

Fadini et al. Diabetologia 2007

EPCs CPCs

Type 1 diabetes

Hörtenhuber et al. DCare 2013

Progenitor cell levels predict microvascular outcomes N=187 type 2 diabetic patients, followed-up for 3.9 years

Fadini et al. JCEM 2015

+

CD34+

CD133

+

CD133

+

CD34

+

KDR+

CD34

+

KDR+

CD133

+

KDR+

CD133

+

CD34

0

100

200

300

400

500 NoYes

Cel

l cou

nt /

106

+

CD34+

CD133

+

CD133

+

CD34

+

KDR+

CD34

+

KDR+

CD133

+

KDR+

CD133

+

CD34

0.0

1.0

2.0

3.0

4.0

5.0

Low (below median)High (above median)

Ons

et /

prog

ress

ion

(% p

er y

r)

UAER

**

**

** ** **

****

+

CD34+

CD133

+

CD133

+

CD34

+

KDR+

CD34

+

KDR+

CD133

+

KDR+

CD133

+

CD34

0.0

1.0

2.0

3.0

4.0

5.0O

nset

/ pr

ogre

ssio

n (%

per

yr)

**

**

CKD

****

+

CD34+

CD133

+

CD133

+

CD34

+

KDR+

CD34

+

KDR+

CD133

+

KDR+

CD133

+

CD34

0

100

200

300

400

500

Cel

l cou

nt /

106

Mean HbA1c at the final visit

7.3%

6.5%

Treatments in intensive control group at the end

of follow-up

Gliclazide MR 91%

Metformin 74%

Insulin 40%

TZD 17%

Glucose control in ADVANCE

Δ 0.67% (95% CI 0.64 - 0.70); p<0.001

Standard Intensive

Mea

n H

bA1c

(%)

6.0

6.5

7.0

7.5

8.0

8.5

9.0

Follow-up (Months)

0 6 12 18 24 30 36 42 48 54 60 66

Patel A et al., N Engl J Med 2008; 358(24): 2560-72

Major microvascular events (glucose arm)

Microvascular 526 605 14% (3 to 23)

New or worsening nephropathy 230 292 21% (7 to 34)

New or worsening retinopathy 332 349 5% (-10 to 18)

Number of patients with event Intensive Standard (n=5,571) (n=5,569)

Relative risk reduction (95% CI)

Favors Intensive

Favors Standard

Hazard ratio 0.5 1.0 2.0

†P=0.01

‡P=0.006

†

‡

Patel A et al., N Engl J Med 2008; 358(24): 2560-72

Multifactorial Intervention and CVD in Patients with Type 2 diabetes. The Steno-2 Study.

Gaede P et al., N Engl J Med 348: 383-393, 2003

160 people with DMT2 and microalbuminuria

Mean follow-up: 7.8 years

Effect of a Multifactorial Intervention on CV events/mortality in Type 2 Diabetes Development or Progression of Diabetic Nephropathy

Gaede P et al., N Engl J Med 348: 383-393, 2003 Gaede P et al., N Engl J Med 358: 580-591, 2008

0.39 (0.17-0.87) p=0.003

31

16

0.44 (0.25-0.77) p=0.004

37

20

STENO-2 Study

Conclusions

1. ESRD is the only long-term diabetic complication, which is not decreased in recent years

2. CKD is associated with a significant CV morbidity and mortality

3. Good metabolic control may reverse the progression from normo- to macroproteinuria

4. The control of all risk factor for CVD without hierarchy may decrease the development and the progression of CKD