Metabolic Syndrome & CKD

Risk Factors in CKDRisk Factors in CKD

Tevfik Ecder, MDIstanbul Faculty of Medicine

Department of Internal MedicineDivision of Nephrology

••

Therapy of uremia is wholly palliative.Therapy of uremia is wholly palliative.••

If a patient is depleted of salt and water, saline solution shouIf a patient is depleted of salt and water, saline solution should be ld be

infused.infused.••

The chief indication for active treatment of acidosis is the The chief indication for active treatment of acidosis is the

presence of distressing hyperpnea.presence of distressing hyperpnea.••

Tetani is an indication for intravenous calcium therapy.Tetani is an indication for intravenous calcium therapy.

••

The only effective treatment for the anemia is transfusion.The only effective treatment for the anemia is transfusion.••

When cardiac insufficiency complicates the uremic state, it is When cardiac insufficiency complicates the uremic state, it is

unwise to bleed a uremic patient with anemia unless there is a unwise to bleed a uremic patient with anemia unless there is a grave emergency.grave emergency.

••

In recent years the use of peritonal lavage or of some form of tIn recent years the use of peritonal lavage or of some form of the he soso‐‐called artificial kidney has been recommended in the called artificial kidney has been recommended in the

treatment of uremia.treatment of uremia.

Cecil Textbook of MedicineCecil Textbook of Medicine 19511951

( X 1000 )

( X 1000 )

8 63 159 272426

695

1,065

2,095

0

500

1000

1500

2000

2500

1970 1975 1980 1985 1990 1995 2000 2010

Dialysis Patients WorldwideDialysis Patients WorldwideThe Emerging EpidemicThe Emerging Epidemic

of Chronic Kidney Disease !of Chronic Kidney Disease !

Lysaght: J Am Soc Nephrol 13: S37Lysaght: J Am Soc Nephrol 13: S37‐‐S40, 2002S40, 2002


0

200

400

600

800

1000

1200

1971-1980 1981-1990 1991-2000 2001-2010

$ B

illio

ns$

Bill

ions

$ 30 Billion$ 30 Billion $ 155 Billion$ 155 Billion

$ 470 Billion$ 470 Billion

$ 1.1 Trillion$ 1.1 Trillion

Medical Costs of Dialysis PopulationMedical Costs of Dialysis Population


9900%%

Dialysis Patients WorldwideDialysis Patients Worldwide

Burden of Mortality from Kidney Disease Burden of Mortality from Kidney Disease Illustrated by Relative Country SizeIllustrated by Relative Country Size

Nugent et al.: Nephron Clin Pract 118: c269Nugent et al.: Nephron Clin Pract 118: c269‐‐c277, 2011 c277, 2011

05

10152025303540455055

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

Prevalence of Dialysis PatientsPrevalence of Dialysis Patientsin Turkeyin Turkey

Num

ber o

f Patients (x100

0)

49794979 71637163 811881181067210672 1261812618136261362616364

163642114121141

23698236982661526615

HemodialysisHemodialysis

Peritoneal DialysisPeritoneal Dialysis

28641286413188831888

3805338053

4457444574

Turkish Society of Nephrology DatabaseTurkish Society of Nephrology Database

4603846038

5206852068

0 5 10 15 20 25 30

Diabetes mellitusDiabetes mellitus

Chronic glomerulonephritisChronic glomerulonephritis

HypertensionHypertension

Cystic kidney diseasesCystic kidney diseases

Chronic pyelonephritisChronic pyelonephritis

Renal vascular diseaseRenal vascular disease

Unknown etiologyUnknown etiology

4.7

3.4

7.2

16.1

Percent (%)

27.627.6

Other causesOther causes

8.28.2

1.0

AmyloidosisAmyloidosis

No informationNo information

2.0

1.3

30.630.6

Turkish Society of Nephrology Database (2009) Turkish Society of Nephrology Database (2009)

Etiology in Prevalent HD PatientsEtiology in Prevalent HD Patientsin Turkeyin Turkey

58.2%58.2%

60,000 Patients with ESRD60,000 Patients with ESRD

7,500,000 Patients 7,500,000 Patients with Chronic Kidney Diseasewith Chronic Kidney Disease

(15.7% of the Adult Population)(15.7% of the Adult Population)

The CREDIT Study: Nephrol Dial Transplant, 2010

Morbidity & Mortality in CKDMorbidity & Mortality in CKD

Go et al.: N Engl J MedGo et al.: N Engl J Med

351351::

12961296‐‐13051305, 200, 2004 4

The Kaiser Permanente Renal Registry (n=1,120,295)The Kaiser Permanente Renal Registry (n=1,120,295)

DeathDeath Cardiovascular EventsCardiovascular Events

0

5

10

15

20

25

Klag et al: N Engl J Med 334Klag et al: N Engl J Med 334::1313‐‐1818, 19, 199696

Adjusted

Relative Risk

<120<80

>210>120

180‐209110‐119

160‐179100‐109

140‐15990‐99

130‐13985‐89

120‐12980‐84

SBP (mm Hg)DBP (mm Hg)

1 1.2 1.93.1*

6.0*

11.2*

22.1*

*P<0.001

Blood Pressure & ESRDBlood Pressure & ESRD

332,544 Males332,544 MalesAge: 35Age: 35‐‐5757

Multiple Risk Factor Intervention Trial (MRFIT)Multiple Risk Factor Intervention Trial (MRFIT)

Hsu et al: Arch Inten Med 165Hsu et al: Arch Inten Med 165::923923‐‐928928, , 2005 2005

Hypertension & ESRDHypertension & ESRDKaiser Permanente of Northern California (n=316,675)*Kaiser Permanente of Northern California (n=316,675)*

JNC VJNC V

*1964*1964‐‐19851985

Hsu et al: Arch Inten Med 165Hsu et al: Arch Inten Med 165::923923‐‐928928, , 2005 2005

JNC VJNC V

*1964*1964‐‐19851985

Hypertension & ESRDHypertension & ESRDKaiser Permanente of Northern California (n=316,675)*Kaiser Permanente of Northern California (n=316,675)*

9595 9898 101101 104104 107107 110110 113113 116116 119119

r = 0.69; P

< 0.05

MAP (mmHg)

GFR

(mL/min/year)

GFR

(mL/min/year)

130/85 140/90

UntreatedHTN

00

‐‐22

‐‐44

‐‐66

‐‐88

‐‐1010

‐‐1212

‐‐1414Parving HH, et al. Br Med J. 1989.Parving HH, et al. Br Med J. 1989.

Moschio G, et al. N Engl J Med. 1996.Moschio G, et al. N Engl J Med. 1996.Viberti GC, et al. JAMA. 1993.Viberti GC, et al. JAMA. 1993.

Bakris GL, et al. Kidney Int. 1996.Bakris GL, et al. Kidney Int. 1996.Klahr S, et al. N Eng J. Med 1994.Klahr S, et al. N Eng J. Med 1994.

Bakris GL. Hypertension. 1997.Bakris GL. Hypertension. 1997.Hebert L, et al. Kidney Int. 1994.Hebert L, et al. Kidney Int. 1994.

The GISEN Group. Lancet. 1997.The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.Lebovitz H, et al. Kidney Int. 1994.

Bakris GL et alBakris GL et al::

Am J Kidney Dis. 36(3):646Am J Kidney Dis. 36(3):646‐‐661661, 2000, 2000

Lower MAP Results in Slower Rates of DeclineLower MAP Results in Slower Rates of Declinein GFR in Diabetics and Nonin GFR in Diabetics and Non‐‐DiabeticsDiabetics

0

10

20

30

40

50

60

4 8 12 16 20

Retarding Progression of CKDRetarding Progression of CKDwith Blood Pressure Controlwith Blood Pressure Control

Time (years)Time (years)

GFR

(ml/m

in)

GFR

(ml/m

in)

8 ml/min/yr8 ml/min/yr

6 ml/min/yr6 ml/min/yr4 ml/min/yr4 ml/min/yr

2 ml/min/yr2 ml/min/yr1 ml/min/yr1 ml/min/yr

Gender Number Mean SD24 hour NaCl intake (gr/day)

WholeGroup

1767 18.04 8.34

Males 857 19,31 8,67Females 910 16,83 7,86

Gender Number Mean SD24 hour urinary Na+ (mEq/day)

Whole Group

1767 306.7 142.1

Male 857 328.4 147.5Female 910 286.2 133.7

SALTurk TrialSALTurk Trial

www.turkhipertansiyon.orgwww.turkhipertansiyon.org

AtherosclerosisAtherosclerosis

Type 2Type 2DiabetesDiabetesMellitusMellitus

HypertensionHypertension

HyperlipidemiaHyperlipidemia

InsulinInsulinResistanceResistance

NephropathyNephropathy

OBESITYOBESITY

••

There was a tenThere was a ten‐‐fold fold increase in the incidence increase in the incidence

of obesityof obesity‐‐related related glomerulopathy over 15 glomerulopathy over 15

years. years.

••

80% of the cases were 80% of the cases were due to FSGS.due to FSGS. 0

1

2

1986 2000Kambham et al: Kidney Int 59: 1498Kambham et al: Kidney Int 59: 1498‐‐1509, 20011509, 2001

%%

Analysis of 6818 Kidney BiopsiesAnalysis of 6818 Kidney Biopsies

ObesityObesity‐‐related Glomerulopathyrelated Glomerulopathy

Wang et al: Kidney Int 73: 19Wang et al: Kidney Int 73: 19‐‐33, 2008 33, 2008

Obesity & Kidney DiseaseObesity & Kidney Disease

Renal Effects of AdipocyteRenal Effects of Adipocyte‐‐Derived FactorsDerived Factors

Saxena, ChopraSaxena, Chopra: : Dial Transplant 33Dial Transplant 33::

1111‐‐2020, , 2004 2004

BMI is Associated with Altered RenalBMI is Associated with Altered RenalHemodynamics in NonHemodynamics in Non‐‐Obese Healthy SubjectsObese Healthy Subjects

Bosma et al: Kidney Int 65: 259‐265, 2004

P<0.001P<0.001 P<0.001P<0.001

102 healthy, non102 healthy, non‐‐obese subjects (59 males, 43 females)obese subjects (59 males, 43 females)

PREVENDPREVEND(Prevention of REnal and Vascular ENdstage Disease)(Prevention of REnal and Vascular ENdstage Disease)

de Jong et al: International Journal of Obesity 26: Suppl 4, S21de Jong et al: International Journal of Obesity 26: Suppl 4, S21‐‐S24, 2002 S24, 2002

NonNon‐‐Diabetic and NonDiabetic and Non‐‐Hypertensive Subjects (n=8050)Hypertensive Subjects (n=8050)

de Jong et al: International Journal of Obesity 26: Suppl 4, S21de Jong et al: International Journal of Obesity 26: Suppl 4, S21‐‐S24, 2002 S24, 2002

9.5%9.5%

18.3%18.3%

29.3%29.3%

6.6%6.6%9.2%9.2%

16.0%16.0%

PREVENDPREVEND(Prevention of REnal and Vascular ENdstage Disease)(Prevention of REnal and Vascular ENdstage Disease)

NonNon‐‐Diabetic and NonDiabetic and Non‐‐Hypertensive Subjects (n=8050)Hypertensive Subjects (n=8050)

0

24

68

1012

1416

18

Chen et al.: Ann Intern MedChen et al.: Ann Intern Med

140140::

167167‐‐174174, 200, 20044

P re va le n

c e of

P re va le n

c e of

Microalbu

minuria (%

)Microalbu

minuria (%

)

Blood PressureBlood Pressure>>130/85 mm Hg130/85 mm Hg

HDL CholesterolHDL Cholesterol<40 mg/dL (M)<40 mg/dL (M)<50 mg/dL (F)<50 mg/dL (F)

TriglycerideTriglyceride>>150 mg/dL150 mg/dL

GlucoseGlucose>>110 mg/dL110 mg/dL

Waist CircumferenceWaist Circumference>>102 cm (M)102 cm (M)>>88 cm (F)88 cm (F)

P<0.001P<0.001

P=0.039P=0.039

P<0.001P<0.001YesYes

NoNo

Metabolic Syndrome & MicroalbuminuriaMetabolic Syndrome & Microalbuminuria

0

5

10

15

20

25

0 1 2 3 4 5

Pre valen

ce (%

)Pre valen

ce (%

)

3.03.04.94.9

6.86.89.89.8

14.614.6

20.120.1

Metabolic Syndrome Risk Factors (n)Metabolic Syndrome Risk Factors (n)


140140::

167167‐‐174174, 200, 20044

Metabolic Syndrome & MicroalbuminuriaMetabolic Syndrome & Microalbuminuria

0

1

2

3

4

5

6

7

8

P re va le n

c e of C

K D (%

)P re va le n

c e of C

K D (%

) P<0.001P<0.001

P=0.002P=0.002P=0.004P=0.004

P=0.044P=0.044

P<0.001P<0.001

YesYes

NoNo


140140::

167167‐‐174174, 200, 20044

Metabolic Syndrome & CKDMetabolic Syndrome & CKD

Blood PressureBlood Pressure>>130/85 mm Hg130/85 mm Hg

HDL CholesterolHDL Cholesterol<40 mg/dL (M)<40 mg/dL (M)<50 mg/dL (F)<50 mg/dL (F)

TriglycerideTriglyceride>>150 mg/dL150 mg/dL

GlucoseGlucose>>110 mg/dL110 mg/dL

Waist CircumferenceWaist Circumference>>102 cm (M)102 cm (M)>>88 cm (F)88 cm (F)

0123456789

10

0 1 2 3 4 5

0.3 0.9

2.9

4.9

7.0

9.2


140140::

167167‐‐174174, 200, 20044

Metabolic Syndrome Risk Factors (n)Metabolic Syndrome Risk Factors (n)

Metabolic Syndrome & CKDMetabolic Syndrome & CKDPre valen

ce (%

)Pre valen

ce (%

)

0

20

40

60

NonNon‐‐Metabolic SyndromeMetabolic Syndrome(n=823)(n=823)

Metabolic SyndromeMetabolic Syndrome(n=802)(n=802)

P=0.01P=0.01

Microalb u

minu ri a

Mi cr oa lb u

minu ri a

mg /2 4

ho u

r smg /2 4

ho u

r sHypertensive Renal Damage in Metabolic Syndrome is Hypertensive Renal Damage in Metabolic Syndrome is

Associated with Glucose Metabolism DisturbancesAssociated with Glucose Metabolism Disturbances

1625 Patients with Essential Hypertension1625 Patients with Essential Hypertension

Segura et al: J Am Soc Nephrol 15: S37Segura et al: J Am Soc Nephrol 15: S37‐‐S42, 2004 S42, 2004

0

20

40

60

80

NormoglycemiaNormoglycemia(n=319)(n=319)

Impaired FastingImpaired FastingGlucose (n=237)Glucose (n=237)

DiabetesDiabetes(n=246)(n=246)

Microalbu

minuria

Microalbu

minuria

mg /2 4

ho u

r smg /2 4

ho u

r s

P=0.001P=0.001

Patients with Metabolic Syndrome (n=802)Patients with Metabolic Syndrome (n=802)


Hypertensive Renal Damage in Metabolic Syndrome is Hypertensive Renal Damage in Metabolic Syndrome is Associated with Glucose Metabolism DisturbancesAssociated with Glucose Metabolism Disturbances

40

60

80

100

DiabetesDiabetes(n=246)(n=246)

Creatin

i ne C le ar an ce

C re at in

i ne C le ar an ce

ml/ m

in/ 1.73 m

ml/ m

in/ 1.73 m

22

P=0.0007P=0.0007


Hypertensive Renal Damage in Metabolic Syndrome is Hypertensive Renal Damage in Metabolic Syndrome is Associated with Glucose Metabolism DisturbancesAssociated with Glucose Metabolism Disturbances

Patients with Metabolic Syndrome (n=802)Patients with Metabolic Syndrome (n=802)

NormoglycemiaNormoglycemia(n=319)(n=319)

Impaired FastingImpaired FastingGlucose (n=237)Glucose (n=237)

Muntner et al: Kidney Int 58: 293Muntner et al: Kidney Int 58: 293‐‐301, 2000 301, 2000

Plasma Lipids & Risk of Renal DysfunctionPlasma Lipids & Risk of Renal DysfunctionAtherosclerosis Risk in Communities Study (n=12,728)Atherosclerosis Risk in Communities Study (n=12,728)

Baseline serum creatinine: <2.0 mg/dL (M), <1.8 mg/dL (F)Baseline serum creatinine: <2.0 mg/dL (M), <1.8 mg/dL (F)

The Benefits of Weight Loss in Patients The Benefits of Weight Loss in Patients with CKDwith CKD

Navaneethan et al: Clin J Am Soc Nephrol 4: 1565‐1574, 2009

The Benefits of Weight Loss in Patients The Benefits of Weight Loss in Patients with CKDwith CKD

A prospective observational study of 20A prospective observational study of 20‐‐yr durationyr durationto examine the association between hypertension and to examine the association between hypertension and

smoking on the future risk of CKDsmoking on the future risk of CKD

Stage 2Stage 2

Stage 1Stage 1

Stage 2Stage 2

Stage 1Stage 1

Stage 1Stage 1

Stage 2Stage 2

CurrentCurrentSmokerSmoker

Former/NeverFormer/NeverSmokerSmoker

Ritz et al.: JASN 9:1798‐1804, 1998

80 90 100 110 120 40 60 80 100

Basal

Cigarette

Mean Arterial PressureMean Arterial Pressure

P<0.0001 P<0.001

mm Hg min‐1

Effects of Smoking on Renal HemodynamicsEffects of Smoking on Renal Hemodynamicsin Healthy Volunteersin Healthy Volunteers

Heart RateHeart Rate

0 50 100 150 200 250 300 0 2 4 6 8 10

P<0.01 P<0.01

pg/ml ng/ml

Basal

Cigarette


Ritz et al.: JASN 9:1798‐1804, 1998

EpinephrinEpinephrin Active ReninActive Renin

80 100 120 140 80 100 120 140

P<0.001 P<0.006

ml/min/1.73m2 mmHg.min/ml.1.73m2


Ritz et al.: JASN 9:1798‐1804, 1998

Basal

Cigarette

Glomerular Filtration RateGlomerular Filtration Rate Renovascular ResistanceRenovascular Resistance

Smoking & CKDSmoking & CKD

Proposed Mechanism of Fetal ProgrammingProposed Mechanism of Fetal Programmingof Hypertension and Renal Diseaseof Hypertension and Renal Disease

Zandi-Nejad et al. Hypertension 47: 502-508, 2006

Nephron Number in Patients with Nephron Number in Patients with Primary HypertensionPrimary Hypertension

Keller et al. N Engl J Med 348: 101‐108, 2003

10 Hypertensive & 10 Normotensive Subjects Who Had Died in Accid10 Hypertensive & 10 Normotensive Subjects Who Had Died in Accidentsents

Hypertensive Hypertensive Patients (n=10)Patients (n=10)

Normotensive Normotensive Subjects (n=10)Subjects (n=10)

P P ValueValue

Age (yr)Age (yr) 45.545.5 46.546.5 NS*NS*

Sex (M/F)Sex (M/F) 9/19/1 9/19/1 NSNS

Height (cm)Height (cm) 178178 177177 NSNS

Body Weight (kg)Body Weight (kg) 90.590.5 84.584.5 NSNS

Heart Weight / Body Weight (g/kg) Heart Weight / Body Weight (g/kg) 6.086.08 4.924.92 <0.001<0.001

Absolute Kidney Weight (g)Absolute Kidney Weight (g) 184184 173173 NSNS

Relative Kidney Weight (g/kg)Relative Kidney Weight (g/kg) 2.062.06 1.861.86 NSNS

Weight of Renal CortexWeight of Renal Cortex 120120 102102 NSNS

*NS: Not Significant*NS: Not Significant

Number of GlomeruliNumber of GlomeruliPer KidneyPer Kidney

Volume of Volume of GlomeruliGlomeruli



NormotensiveNormotensiveControlControl

HypertensiveHypertensivePatientPatient



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forfor

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