emerging risk factors and markers of ckd progression · emerging risk factors and markers of ckd...

Emerging risk factors and markers of CKD progression

Florian KronenbergInnsbruck Medical University, Division of Genetic Epidemiology

CKD: Relevance of the problem

Initiation and progression of CKD

Chronic KidneyDisease

ProgressionGFR decline

ESRD

Traditional progression factors or markers:

• Age• Gender• Ethnicity• Family history of CKD• Diabetes mellitus• Metabolic syndrome• Hyperfiltration states• High normal urinary

albumin excretion• Dyslipidemia• Nephrotoxins• Primary kidney disease• Urological disorders• Cardiovascular disease

Initiating factors:

?Emerging progression factors or markers:

Nature Rev. Nephrol. 5:677-89, 2009

Definition of CKD progression

■ Surrogates of GFR slope ► Doubling of baseline serum creatinine level► Need of renal replacement therapy (dialysis and/or transplantation)► Particular relative increase from baseline serum creatinine level► Yearly or monthly decline in GFR► GFR reduction to 50% of baseline► Graft loss

■ Indices of renal damage► Worsening of proteinuria► Appearance of albuminuria in patients with diabetes

Mild to Moderate Kidney Disease Study

■ 227 patients with primary non-diabetic CKD

■ Patients with nephrotic syndrome excluded

■ Recruited 1996/97

■ Age 46 ± 13 years

■ Iohexol clearance at baseline: average GFR 64 ± 39 ml/min

■ Followed for 7 years

■ Endpoint: doubling of serum creatinine and/or ESRD

■ 177 completed follow-up

■ 65 reached endpoint (36 Crea-doubling, 29 ESRD)

ADMA: Asymetric Dimethylarginine

■ Potent and long-lasting endogenous inhibitor of NO synthase → less NO production

■ NO is a potent vasodilatator and regulator of the vascular tone and blood flow

■ Kidney is the main site of ADMA removal

■ ADMA markedly increased in renal patients

■ High ADMA levels related to atherosclerotic complications

ADMA

L-arginine

NO

NO synthase

DDAH

Dimethlyamine + Citrulline

Renal excretion

LDL cholesterolHomocysteineHyperglycemiaHypertension

SmokingInflammation

Aging

Proteins with ADMA residues

Consequences of decreased NO•Decreased renal plasma flow•Increased renovascular resistance•Increased blood pressure•Endothelial damage•Progression of chronic kidney disease

80%

20%

ADMA: Biochemical Pathway

DDAH, dimethylarginine dimethylaminehydrolase


ADMA and progression of CKD: MMKD-Study

►Cox regression: HR 1.47 (95% CI 1.12-1.93) for 0.1 µM/L increase

Fliser et al.: J.Am.Soc.Nephrol. 16:2456-61, 2005

ADMA and progression of CKD and death

Ravani et al.: J.Am.Soc.Nephrol. 16: 2449-55, 2005

ADMA<0.76 µM/L

ADMA≥0.76 µM/L

ADMA<0.76 µM/L

ADMA≥0.76 µM/L

n=131, age 71±11yrs, GFR 8-77 ml/min, follow-up 27 mos

n=29 n=31

ADMA and progression of CKD

Hanai et al: NDT 24:1884-8, 2009:•Progression of diabetic nephropathy•37 of 225 patients with T2DM

p<0.001

Lajer et al: Diabetes care 31:747-52, 2008:•397 patients with T1DM and nephropathy•Yearly decline in GFR

Calcium-phosphate metabolism

■ Progression of CKD in animal models:► High phosphate► High PTH► Lack of active vitamin D

■ Ca-Ph metabolism and progression of CKD in humans:► High phosphate (5 of 5 studies) and high Ca*Ph (3 of 4 studies)► High PTH levels (2 of 2 studies)

■ Fibroblast Growth Factor 23 (FGF23):► Recently identified “phosphatonin”► Regulator of phosphate balance► Under physiological conditions: high phosphate load results in

increased FGF23 secretion and phosphaturia

Calcium-phosphate metabolism and progression

Non-progressors(n=112)

Progressors (n=65)

p-value

FGF 23 c-terminal (rU/mL) 92 ± 113 351 ± 394 <0.001 FGF 23 intact (pg/mL) 35 ± 28 69 ± 70 <0.001 Phosphate (mmol/L) 1.04 ± 0.38 1.25 ± 0.27 <0.001 Ca x P product (mmol2/L2) 2.46 ± 0.85 2.90 ± 0.65 <0.001 Parathormone (pmol/L) 6.5 ± 5.3 22.5 ± 20.0 <0.001

Fliser, Kollerits et al.: J.Am.Soc.Nephrol. 18:2600-8, 2007

Results from the MMKD Study

Multiple Cox regression analysis


Adjusted for age, sex, GFR, proteinuria and the other

variables of this table

Variable (increment) HR (95% CI) p

Phosphate (0.1 mmol/L) 1.052 (0.952-1.162) 0.322

Ca x P product (0.1 mmol2/L2) 1.024 (0.981-1.068) 0.279

Parathormone (1 pmol/L) 1.009 (0.993-1.025) 0.273

FGF23 c-terminal (10 rU/mL) 1.014 (1.005-1.024) 0.002

FGF23 intact (10 pg/mL) 1.061 (1.018-1.106) 0.005

Multiple Cox regression analysis


Adjusted for age, sex, GFR, proteinuria and the other

variables of this table

Variable (increment) HR (95% CI) p

Phosphate (0.1 mmol/L) 1.052 (0.952-1.162) 0.322

Ca x P product (0.1 mmol2/L2) 1.024 (0.981-1.068) 0.279

Parathormone (1 pmol/L) 1.009 (0.993-1.025) 0.273

FGF23 c-terminal (10 rU/mL) 1.014 (1.005-1.024) 0.002

FGF23 intact (10 pg/mL) 1.061 (1.018-1.106) 0.005

FGF23 c-terminal +250 rU/mL35% increased risk

(adjusted for age, sex, GFR and proteinuria)

FGF23 and progression of CKD in MMKD


Progression

10%

60%

Vitamin D and CKD progression

■ 168 newly referred patients with CKD stages 2-5

■ Follow-up median 57 mos.

■ Endpoint: dialysis treatment in 48 cases

■ 10 ng/ml increase in 25-hydroxy vitamin D level was associated with a 40% decrease in hazard ratio for CKD progression

Ravani et al.: Kidney Int. 75:88-95, 2009

Adiponectin

■ Produced in adipocytes

■ Central role in glucose and lipid metabolism (insulin sensitizer)

■ An anti-inflammatory, anti-atherosclerotic and vasculo-protective cytokine

■ A large number of studies showed an association between low adiponectin levels and negative outcomes

■ Adiponectin is elevated in patients with kidney impairment

High adiponectin and CKD progression

Study Study

population End points Specific

observation Follow-

up

MMKD Study 2007

177 nondiabetic patients with primary CKD

Doubling of serum creatinine and / or ESRD

(n=65)

Observed only in men

Median 53 mos.

EURAGEDIC Case-Control Study 2008

198 patients with T1DM with

nephropathy

Dialysis or kidney transplantation (n=40) Median

8.1 yrs.

Finish Diabetic Nephropathy Study 2008

1330 patients with T1DM

Progression to ESRD (83/296 patients with macroalbuminuria)

No association in patients with

normo- or microalbuminuria

Mean 5 yrs.

Kollerits et al.: Kidney Int. 71:1279-86, 2007Jorsal et al.: Kidney Int. 74:649-54, 2008

Saraheimo et al.: Diabetes care 31:1165-9, 2008

Adiponectin association "reshaped"

■ High adiponectin in other studies predicted …► lower risk for cardiovascular events in ESRD (Zoccali et al. 2002)► mortality in CKD 3 and 4 in the MDRD Study (Menon et al. 2006)► mortality in patients with CHF (Kistorp et al. 2005)► all-cause and CVD mortality in CAD patients (Pilz et al. 2006)► and several other studies

Adiponectin association "reshaped"

■ High adiponectin in other studies predicted …► lower risk for cardiovascular events in ESRD (Zoccali et al. 2002)► mortality in CKD 3 and 4 in the MDRD Study (Menon et al. 2006)► mortality in patients with CHF (Kistorp et al. 2005)► all-cause and CVD mortality in CAD patients (Pilz et al. 2006)► and several other studies

The association of adiponectin might turn in the opposite direction in the presence of severe disease conditions

A compensatory attempt to attenutae endothelial and vascular damage?

Adiponectin resistance?

Apolipoprotein A-IV and CKD progression

■Activates LPL and LCAT

■Stimulates cholesterol efflux from peripheral cells

■Reverse cholesterol transport

■Antioxidative properties

■Strong association with kidney function

Boes et al.: J.Am.Soc.Nephrol. 17:528-36, 2006

Median = 26 mg/dL

p<0.0001

MMKD Study

Apolipoprotein A-IV and CKD progression

■Activates LPL and LCAT

■Stimulates cholesterol efflux from peripheral cells

■Reverse cholesterol transport

■Antioxidative properties

■Strong association with kidney function

Boes et al.: J.Am.Soc.Nephrol. 17:528-36, 2006

Median = 26 mg/dL

p<0.0001

MMKD Study

ApoA-IV +10 mg/dL 60% increase in risk

of CKD progression

Natriuretic peptides and CKD progression: MMKD

■Potent hypotensive, diuretic and natriuretic peptides involved in maintaining cardiovascular and renal homeostasis

■Produced in the kidney

■ Increased concentrations associated with CVD and renal disease

■Renoprotective properties → compensatory increase in CKD

Dieplinger et al.: Kidney Int. 75:408-14, 2009

Variable (1 SD increment) HR (95% CI) p-value NT-pro BNP (527 ng/L) 1.15 (0.96-1.38) 0.13 A-type natriuretic peptide (131 pmol/L) 2.11 (1.59-2.80) <0.001 Adrenomedullin (0.42 nmol/L) 2.60 (1.85-3.64) <0.001

Adjusted for age, sex, GFR, and proteinuria

Calculating the gain in information

ADMA

FGF23

ANP

Adrenomedullin

NT-proBNP

ApoA-IV

GFR

Proteinuria

Problem of correlation of variables (multicollinearity)

MMKD Study: Comparison of parameters


adjusted for age, sex, GFR and proteinuria

Genomewide association studies (GWAS)

Phenotype(e.g. CKD, CKD progression, GFR)

23 pairs of chromosomes

Genotyping of up to 1 million single nucleotide polymorphisms(SNPs) in thousands of persons

Association analysis

Genetic factors for CKD progression■ Advantages of polymorphisms:

► Stability: inherited at conception and do not change with disease► Causality is likely (no reverse causation)

EndphenotypeProgressive CKD

Intermediate phenotype

Plasma adiponectinconcentrations

GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%







GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%


Weak association explains 0.8% (0.08 x 0.10)

Mendelian

Randomization

EndphProgres



GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%

Na






GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%



Mendelian

Randomization

EndphProgres



GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%

Na

Requires large sample sizes






GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%



Mendelian

Randomization

EndphProgres



GeneADIPOQ

(adiponectin)

Strong association

explains 8%

Strong association

explains 10%

Na

Requires large sample sizes

No reverse causation

GWAS on kidney function

Köttgen et al.: Nat.Genet. (online)

■ Meta-analysis: CKDGen consortium► 20 population-based cohort studies► >90,000 persons► 20 new genetic loci for renal function and chronic kidney disease

Uromodulin (UMOD): codes for Tamm-Horsefall protein

► Association with prevalent and incident CKD and eGFRcreatinine

► Rare mutations cause monogenic forms of kidney diseases

Future developments


Combination of GWAS and metabolomics:Gieger et al.: PLoS Genetics 2008Illig et al.: Nature Genetics 2010

Personalized health-care

system

Summary

■ They are independent from GFR and proteinuria.■ Many of them are independent from each other.■ Some of them might also reflect a cardiorenal syndrome.■ Large studies are urgently required.

Chronic KidneyDisease

ProgressionGFR decline

ESRD

Emerging progression factors or markers:

(number of studies)

The MMKD Study Group

Barbara Kollerits Eberhard RitzEva Boes Gerhard MüllerPaul König Günter KraatzKarl Lhotta Johannes MannUlrich Neyer Werner RiegelDanilo Fliser Vedat SchwengerJan Kielstein Katharina-Susanne SpanausIris M. Heid Arnold von EckardsteinBenjamin Dieplinger Peter Riegler

Renal Units: Innsbruck, Feldkirch, Greifswald, Heidelberg, München-Schwabing,Göttingen, Homburg/Saar, Bozen

Project Support: GEN-AU (Austrian Genome Project)Austrian Science Fund, Austrian National BankAustrian Academy of SciencesAustrian Heart FundElse Kröner-Fresenius Stiftung

emerging risk factors and markers of ckd progression · emerging risk factors and markers of ckd...

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