Emerging risk factors and markers of CKD progression · Emerging risk factors and markers of CKD progression Florian Kronenberg Innsbruck Medical University, Division of Genetic Epidemiology

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

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

Documents

Emerging risk factors and markers of CKD progression · Emerging risk factors and markers of CKD progression Florian Kronenberg Innsbruck Medical University, Division of Genetic Epidemiology