EPIDEMIOLOGY OF - KDIGOGenzyme, MSD Finland, Novartis, Novo Nordisk Grants Eli Lilly, Roche Advisory...

EPIDEMIOLOGY OF DKD

Per-Henrik Groop, MD DMSc FRCPE Abdominal Center Nephrology

University of Helsinki and Helsinki University Hospital, Finland

Vancouver, 6 February 2015

KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada

Disclosures of interest Honoraria

Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, MSD Finland, Novartis, Novo Nordisk

Grants Eli Lilly, Roche

Advisory boards Abbott, AbbVie, Boehringer Ingelheim, Cebix, Eli Lilly, Medscape, Novartis

Board member Medix Laboratories

Stock/shareholder No


Outline of the presentation

•  The diabetes epidemic

•  Consequences of DKD

•  Screening tools (albuminuria)

•  Tools to screen for renal function (eGFR)

•  Prevalence of DKD

•  Take home messages

The diabetes epidemic

0

100

200

300

400

500

1985 1995 2003

30

120

194

552

The diabetes epidemic

2030

Wor

ldwi

de (m

illio

ns)

366

2011

IDF World Atlas of Diabetes 5th Edition 2011 (www.idf.org/diabetesatlas/)

23.0 M 36.2 M ↑57.0%

14.2 M 26.2 M ↑85%

48.4 M 58.6 M ↑21% 43.0 M

75.8 M ↑79%

7.1M 15.0 M ↑111%

39.3 M 81.6 M ↑108%

Diabetes is a global epidemic

Whole world 2003 = 194 M 2025 = 333 M ↑ 72%

AFR

NA

SACA

EUR

SEA WP

19.2 M 39.4 M ↑105%

EMME

2003 2025

IDF World Atlas of Diabetes 2nd Edition 2003 (www.idf.org/diabetesatlas/)

Type 1 diabetes incidence continues to increase, faster than ever before

Harjutsalo et al Lancet 2008, 24; 371, 1777-82

2.8%

4.1%

Diabetic complications

Nephropathy

Neuropathy

Retinopathy

MI, Cardiac failure

Stroke, PVD

Consequences of diabetic nephropathy

and/or DKD

Mortality excess is confined to

those with renal complications

Most patients do very well

Pop

FinnDiane

Groop et al. Diabetes. 2009;58(7):1651-8. ESRD = end-stage renal disease

Mortality in adults with type 1 diabetes

DKD is the major predictor of mortality in type 2 diabetes

Population-based study of 1,565 individuals with known type 2 diabetes who were resident in the town of Casale Monferrato in north-west Italy in 1988. There were 670 deaths during 10,780

person years of follow-up

0

1

2

3

4

5

6

7

Normoalbuminuria Microalbuminuria Macroalbuminuria

Adj

uste

d H

azar

d ra

tio (H

R)

<30

30-45

45-60

60-90

>90

Bruno G et al. Diabetologia 2007;50(5):941-8.

Prob

abili

ty o

f de

ath

Years

Log rank P<0.0001

eGFR >90

eGFR ≤29

eGFR 30-59

eGFR 60-89

0

0.5

1

1.5

2

0 2 4 6 8 10 12

10-year follow-up of 3288 patients in the South Tees Diabetes Mortality Study

Nag S et al. Diabet Med 2007;24(1):10-7. eGFR = estimated glomerular filtration rate

ADVANCE: Cardiovascular events

Ninomiya et al. J Am Soc Nephrol 2009;20:1813–21

Cardiovascular risk is greatest when both diabetes and CKD are present

Incide

nce

per

100

patien

t-ye

ars

x 2.2

x 2.1

x 1.7 x 2.5

Foley et al. J Am Soc Nephrol. 2005, 16,489–495

Among patients with diabetes and CKD, the rate of cardiovascular events is more than twice that among patients with diabetes only

Number of people initiating treatment for ESRD 1980-2006

Rate

s Pe

r M

illion

Popu

lation

0

10000

20000

30000

40000

50000

80 81 82 83 84 85 86 87 88 89 90 91 Year 93 94 95 96 97 98 99 00 01 02 03 04 05 06 92

U.S. Renal Data System, USRDS 2008 Annual Data Report

Changes in the numbers of ESRD cases due to diabetes in the US over 25 years

Declining renal function also increases risk of severe hypoglycaemia

Increased risk most dramatic in patients with renal dysfunction and type 2 diabetes

Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occurs in patients with reduced renal function

Risk

for

sev

ere

hypo

glyc

aem

ia

(inci

denc

e ra

te r

atio

)

0 1 2 3 4 5 6 7 8 9

+CKD / + Diabetes

– CKD / + Diabetes

+ CKD / – Diabetes

– CKD / – Diabetes

+ CKD + Diabetes

– CKD + Diabetes

+ CKD – Diabetes

– CKD – Diabetes

Moen et al. CJASN 2009;4:1121–27; Weir et al. Nephrol Dial Transplant 2011;26:1888–94

Screening tools (albuminuria)

Screening for microalbuminuria

Courtesy of Hans-Henrik Parving

Definitions of albuminuria

Normoalbuminuria: a timed overnight urinary albumin excretion rate (AER) <20 µg/min or <30 mg/24 h or an albumin-creatinine ratio (ACR) of <2.5 mg/mmol for men and <3.5 for women in a first morning urine sample Microalbuminuria: AER 20-200 µg/min or 30-300 mg/24 h or an ACR of 2.5-25 mg/mmol for men and 3.5-35 for women in a first morning urine sample Macroalbuminuria: AER >200 µg/min or >300 mg/24 h or an ACR of >25 mg/mmol for men and >35 for women in a first morning urine sample

Type 1 diabetes

TYPICAL DIABETIC NEPHROPATHY (C2) – 30 %

NEAR NORMAL HISTOLOGY (C1) – 30 %

NON-SPECIFIC FINDINGS (C3) – 40 %

(a) Both normal and totally destroyed glomeruli

(b) Severe arterioliohyalinosis

(c) Tubulointerstitial fibrosis

Microalbuminuria type 2 diabetes

Fioretto et al. Diabetologia 1998;41:233-236

Change in GFR (%) in patients with type 2 diabetes and microalbuminuria

-20

-10

0

+10

∆ %

GFR

/yea

r C3

C1

C2

Nosadini et al. Diabetes 2000;49:476-484

* p<0.05, C2 vs C1 ja C3

*

(n=33, 4 year follow-up)

Progression of diabetic nephropathy GF

R (m

l/m

in)

Biesenbach et al. Nephrol Dial Transplant. 1994; 9:1097-1102

Proteinuria ≥500 mg/24 h and average S-Crea 88 µmol/l at baseline

Year

Type 1 (n=16) Type 2 (n=16)

0 10 20 30 40 50 60 70 80 90

100 110

0 1 2 3 4 5 6 7

Albuminuria: a risk factor for DKD

0

5

10

15

20

25

30

Normal Microalbuminuria Macroalbuminuria

Risk of developing sustained eGFR < 60 mL/min/1.73 m2

Haz

ard

ratio

(9

5% C

I)

Annual % decrease in eGFR (95% CI)

1.2 (1.2–1.3)

1.8* (1.6–1.9)

5.7* (4.5–6.8)

* p < 0.001 versus normal. Moltich ME, et al. Diabetes Care. 2010;33:1536–1543.

*

*

The risk of CV outcomes according to degree of albuminuria in patients with T2DM: The Renal Insufficiency and Cardiovascular Events Study, N = 15,773

Odds ratio (95% CI) for major acute CVD events

*Coronary events (including myocardial infarction and/or coronary revascularization); cerebrovascular events (including stroke and/or carotid revascularization; and peripheral events including ulcer/gangrene/amputation and/or lower limb

revascularization). Solini et al. Diabetes Care. 2012:35:143–149.

Categorical increase in albuminuria (deciles), mg/24 h

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0 1

≤ 3.03 RC

2 3.04 -5.65

3 5.66 -7.8

4 7.9- 10.4

5 10.5- 13.6

6 13.7- 17.6

7 17.7- 25.9

8 26.0- 45.2

9 45.3- 117.3

10 > 117.3

Increasing risk

Decreasing risk

Albuminuria: a risk factor for CVD

Significant increase in CV risk albuminuria ≥ 10.5 mg/24 hours

Tools to estimate renal function (eGFR)

Estimation of renal function

The Cockroft-Gault formula provides an estimate of the creatinine clearance (eCCr) The MDRD-4 formula provides an estimate of the glomerular filtration rate (eGFR) The CKD-EPI equation provides an estimate of the glomerular filtration rate (eGFR)

Levey AS et al. Ann Intern Med 1999;130(6):461-70. Levey AS et al. Ann Intern Med 2006;145(4):247-54.

Cockcroft DW, Gault MH. Nephron 1976;16(1):31-41.

Levey AS et al. Ann Intern Med 2009;150(9):604-12.

Stages of renal function Stage 1 - eGFR >90 ml/min + persistent albuminuria Stage 2 - eGFR 60-89 ml/min + persistent albuminuria Stage 3a – eGFR 45-59 ml/min Stage 3b – eGFR 30-44 Stage IV - eGFR 15-29 ml/min Stage V - eGFR <15 ml/min

KDOQI

Prevalence of DKD


Prevalence depends on the definition?

Impossible to make causal inference “so it is clinically defined in patients

with diabetes and an eGFR <60 ml/min/1.73m2 and/or an elevated urinary ACR

(≥30 mg/g) = essentially CKD in diabetes or DKD

Scatter plots for eGFR against ACR in type 1 and type 2 diabetes

Shaded area denotes CKD defined as ACR ≥30 mg/g and/or eGFR < 60 ml/min/1.73 m2

Ohta et al. Diabet. Med. 2010, 27, 1017-1023

Type 1 diabetes Type 2 diabetes

The distribution of albuminuria and an eGFR <60 ml/min/1.73 m2 in patients

with T2D in Australia

Thomas et al. MJA 2006, 185, 140-144

Nefron Study N=3.893 patients with

Type 2 diabetes 52% males

<60 ACR

22%

Global perspective

Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes (DEMAND)

48%

N=24.151

= 56%

Parving HH et al. Kidney Int 2006;69(11):2057-‐63.


Varies considerably across countries and settings > African Americans > Middle Eastern > Hispanic INCREASED RISK > Asian > Polynesian > Indigenous peoples economic, social or educational disadvantage, access to and uptake of care, lower achievement of treatment goals, lower screening rates, suboptimal early treatment of complications, diet and lifestyle factors, smoking, obesity, genetic factors and probably also developmental programming.

Epidemiology of CKD in diabetes

<60 ACR

26%

Latin American perspective

51%

N=22,000

= 61%



<60 ACR

Asian perspective

56% = 65% 22%



N=9.111

ALB

eGFR <60

Epidemiology of CKD in the UKPDS

= 66%

28%

52%

Only 14% developed both

After 15 years of follow-up

UKPDS 74



HOW MANY OF THESE ACTUALLY HAVE DIABETIC KIDNEY DISEASE?

How many have age-related decline, hypertensive

or dyslipidemic nephropathy, obesity-related, glomerular atherosclerosis?

DOES IT MATTER?



Do you need retinopathy to have DKD?

Do you need albuminuria to have DKD?

Do you need histology to have DKD?


Take home messages

•  Diabetes is increasing with epidemic proportions all over the world

•  DKD is a common complication

•  The consequences of DKD are grim •  We have to take action which is the

scope of this controversy meeting

Thank you for your attention [email protected]

www.finndiane.fi

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