Chronic Kidney Disease: Definitions and Optimal … managementAAP… · 7/3/2008 1 Chronic Kidney Disease: Definitions and Optimal Management Jai Radhakrishnan, MD, MS, MRCP, FACC,

7/3/2008 1

Chronic Kidney Disease:Definitions and Optimal Management

Jai Radhakrishnan, MD, MS, MRCP, FACC, FASNAssoc Professor of Clinical MedicineColumbia University, New York, NY

2

Objectives

Definition of CKDPrevalence and Scope of CKDOptimal management

Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease

Kidney Disease Outcomes Quality InitiativeK/DOQI

http://www.kidney.org/

3

Does she have CKD?

At what level of creatinine does a 65-year-old diabetic, hypertensive white woman weighing 50 kilograms have CKD?

1. 1.0 mg/dL2. 1.3 mg/dL3. 1.5 mg/dL4. 1.7 mg/dL

4

Chronic >3 months

Kidney Damage Hematuria/AlbuminuriaBiopsyAbnormal imaging tests

Glomerular Filtration Rate < 60ml/min

Definitions and Stages of Chronic Kidney Disease

5

Good news NO MORE 24-HOUR URINES!

Spot urines are adequate.

6

Quantification of Proteinuria (positive dipstick):

Normal Abnormal

24 H Urine Protein < 300mg/24h >300mg/24h

Urine SPOTprotein/

Creat. ratio (mg/gm)

< 200mg/g >200mg/g

7

Quantification of Proteinuria:(Negative Dipstick)

Normal “Micro”-albuminuria

Urine AER(μg/min) < 20 20 - 200

Urine AER(mg/24h) < 30 30 - 300

Spot albumin/Cr# ratio (mg/gm)

< 30 30 - 300

8

Methods of Estimating GFRInulin/iothalamate clearance “GOLD STANDARD”Creatinine Clearance (24 h urine)Equations base on serum creatinine

Cockroft-GaultMDRD

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Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999

MDRD equation for predicting GFR

MDRD not validated in:•Diabetic kidney disease•serious comorbid conditions•normal persons •> 70 years old

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www.nephron.com www.medcalc.com

90 60 30 15GFR

Stage

1 2 3 4 5

Renal Replacement

ComplicationsEvident

ComplicationsPossible

Other markers kidney disease: proteinuria, hematuria, anatomic

K/DOQI CKD StagingK/DOQI CKD StagingRequires 2 or more GFR, 3 or more months apartRequires 2 or more GFR, 3 or more months apart

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Does she have CKD?

At what level of creatinine does a 65-year-old diabetic, hypertensive white woman weighing 50 kilograms have CKD?

1. 1.0 mg/dL2. 1.3 mg/dL3. 1.5 mg/dL4. 1.7 mg/dL

•Creatinine = 1.0 for GFR = 59 mL/min/1.73 m2

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Objectives

Definition of CKDPrevalence and Scope of CKDOptimal management

Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease

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Incidence & Prevalence of ESRD

USRDS 2004

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19.2

5.9

5.3

7.6

0.4

0.3

0 5 10 15 20 25

Total

Stage 1 (albuminuria)

Stage 2 (GFR 60-89)

Stage 3 (GFR 30-59)

Stage 4 (GFR 15-29)

Stage 5 (GFR <15 or ESRD)

Number (in Millions)

Prevalence of CKD: NHANES III

Coresh J.. Am J Kidney Dis. 2003 Jan;41(1):1-12.

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Median age by race/ethnicity

USRDS 2004

17

44.4

26.6

9.9

2.3 3.9 3.3 2.07.6

0

20

40

60

Diabetes Hyper- Glomerulo- Secondary Interstitial Cystic/ Neoplasms/ Miscel-tension nephritis GN/ Vascu- Nephritis Hereditary/ Tumors laneous

litis Pyelo- CongenitalNephritis

USRDS 1999

Etiology of ESRD

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Objectives

Definition of CKDPrevalence and Scope of CKDOptimal management

Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease

Kidney Disease Outcomes Quality InitiativeK/DOQI

http://www.kidney.org/

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What can be done to slow progression of renal disease?

Hypertension control ACE-Inhibitors/A2R-BlockersBlood sugar controlModerate protein restriction

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Early Aggressive Antihypertensive Treatment in Diabetic Nephropathy (n=10)

Parving HH... Lancet 1:1175-1179, 1983

144/97

128/84

Albuminuria GFR Decline

metoprolol, hydralazine, and furosemide or thiazide

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Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics

9595 9898 101101 104104 107107 110110 113113 116116 119119

r = 0.69; P < 0.05

MAP (mmHg)

GFR

(mL/

min

/yea

r)

130/85 140/90

UntreatedHTN

00

--22

--44

--66

--88

--1010

--1212

--1414

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. www.hypertensiononline.org

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Blood Pressure Targets

Clinical Status BP GoalHypertension(no diabetes or renal disease)

<140/90 mmHg(JNC 7)

Diabetes Mellitus <130/80 mmHg(ADA, JNC 7)

Renal Diseasewith proteinuria >1 gram/24 hours, or diabetic kidney disease

<130/80 mmHg<125/75 mmHg

(NKF)

Chobanian AV et al. JAMA. 2003;289:2560–2571.American Diabetes Association. Diabetes Care. 2002;25:134–147.National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.

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SCORECARD: Awareness, Treatment and Control of Blood Pressure 1976-2000 (JNC-VII)

01020304050607080

1976-1980 1988-1991 1991-1994 1999-2000

AwarenessTreatmentControl

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Clinical Practice Guidelines for Management of Hypertension in CKD

Type of Kidney Disease Blood Pressure Target

(mm Hg)

Preferred Agents for CKD, with or

without Hypertension

Other Agentsto Reduce CVD Risk

and Reach Blood Pressure Target

Diabetic Kidney Disease

Nondiabetic Kidney Disease with Urine Total

Protein-to-Creatinine Ratio ≥200 mg/g

ACE inhibitoror ARB

Diuretic preferred, then BB or CCB

Nondiabetic Kidney Disease with Spot Urine

Total Protein-to-Creatinine ratio <200

mg/g

Diuretic preferred, then ACE inhibitor, ARB, BB

or CCB

Kidney Disease in Kidney Transplant Recipient

CCB, diuretic, BB, ACE inhibitor, ARB

None preferred

<130/80

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SCORECARD: ACE-I/ARB Use in Proteinuric Patients

32% 26%

91% 85%

0%10%20%30%40%50%60%70%80%90%

100%

1997 2005

DIABETESNO DIABETES

McClellan WM, et al. Am J Kidney Dis. 1997 Mar;29:368-75Nephrology Dialysis Transplantation 2005 20(6):1110-1115 .

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Diabetes Control and Complications Trial

1441 patients with IDDM 726 without retinopathy at base line (the primary-prevention cohort)715 with mild retinopathy (secondary-intervention cohort)

Conventional (2 insulin injections/day vs Intensive (insulin pump or > 3 insulin injections/day)mean F/U =6.5 yrs

DCCT Research Group. N Engl J Med 1993;329:977-86.

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Diabetes Control and Complications TrialPrevention of Microalbuminuria

Microalbuminuria reduced by 39 percent (95 % C.I.=21 – 52 %)

DCCT Research Group. N Engl J Med 1993;329:977-86.

28ukpds

UKPDS: MicroalbuminuriaUKPDS: MicroalbuminuriaUrine albumin >50 mg/L

0.890.830.880.760.670.70

0.240.0430.130.000620.0000540.033

BaselineThree yearsSix yearsNine yearsTwelve yearsFifteen years

RR p 0.5 1 2

Relative Risk& 99% CI

Favoursconventional

Favoursintensive

<

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ACCORD Glycemic Trial(Overarching trial)

10,000Age-eligible, high risk people with type 2 diabetes

5,000 toIntensive Group

(A1c Target < 6.0%)

5,000 toStandard Group(A1c Target 7.0 -7.9%)

Treated and followedfor > 4 years (mean 5.5 yrs)

MAJOR CVD EVENTS

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ACCORD: Deaths in Intensive vsStandard Glycemic Control Groups

Deaths Standard GlycemicControl

Intensive GlycemicControl

n 203 (11/1000/y) 257 (14/1000/y)

Despite 10% lowering of primary outcome (MI rates) there was a 20% higher death rate

http://www.nhlbi.nih.gov/health/prof/heart/other/accord/q_a.htm

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CKD and Mortality

Salvador Dali - Premonition of Civil War

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Go, A. S. et al. N Engl J Med 2004;351:1296-1305

Go AS.. NEJM, 351:1296-1305, 2004

Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization

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0.76 1.08

4.76

11.36

0

2

4

6

8

10

12

14

≥60 45-59 30-44 15-29 <15

Rat

e of

Dea

th F

rom

Any

Cau

se*

Rates of Death and Cardiovascular Events in Patients According to eGFR

CV = cardiovascular. N = 1,120,295 adults. *Age-standardized rates per 100 person-years; †CV event defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years. Go et al. N Engl J Med. 2004;351:1296-1305.

36.60

2.113.65

11.29

21.80

0

5

10

15

20

25

30

35

40

≥60 45-59 30-44 15-29 <15eGFR (mL/min/1.73 m2)

14.14

Rat

e of

CV

Even

ts†

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HOPE TRIAL:Predictive Variables for CV Death, MI, and Stroke

Variable Hazard Ratio

Microalbuminuria 1.59

Creatinine > 1.4 mg/dL 1.40

CAD 1.51

PVD 1.49

Diabetes Mellitus 1.42

Male 1.20

Age 1.03

Waist-Hip Ratio 1.13

Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636. www.hypertensiononline.org

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45.7%

24.3%19.5%10.2%

19.9%

1.2%1.0%

27.8%

64.2%63.3%

74.8%

10.3%16.2%14.9%6.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Stage 2 (noproteinuria)

Stage 2 (withproteinuria)

Stage 3 Stage 4

Patie

nts Discontinued

Event freeRRTDied

CKD Patients Are More Likely to Die Than Progress to ESRD

Keith D et al. Arch Int Med 2004;164:659-663.

RRT = renal replacement therapy

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Risk Factors for CVDTRADITIONAL

AgeMale genderMenopauseFamily historyHypertensionSmokingLow HDL, high LDLDiabetesInactivity, ObesityLVH

NON TRADITIONAL CaxPO4 productAnemiaInflammationHypoalbuminemia

“REVERSE” EPIDEMIOLOGYLow cholesterolLow body weightLow blood pressure

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Malnutrition, Inflammation and Atherosclerosis (MIA syndrome)

Stenvinkel P .. Nephrol Dial Transplant. 2000 Jul;15(7):953-60.

38

ESRD PATIENTS

CONTROLS FOLD INCREASE

MCP-1* 2.3±1.0x10-1 1.4±0.8x10-5 >15,000x

RAGE* 1.2±1.0x10-1 1.6±0.3x10-5 7,000x

Endothelial Cell Gene Expression ESRD Patients Vs. Controls:

Increased Inflammation and Oxidative Stress

* mRNA Relative Copy Number via Real-Time PCR

Anjali Ganda, .. Jai Radhakrishnan. Submitted to American Society of Nephrology, November, 2008, Philadelphia, PA.

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0.48

0.5

0.52

0.54

0.56

0.58

0.6

0.62

NITROTYROSINE (arbitrary units)

ESRD PATIENTSCONTROLS

Endothelial Cell Protein Expression ESRD Patients Vs. Controls:

Increased Nitrotyrosine (Oxidative Stress)

*Quantitative Immunofluorescence Analysis

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0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

0.045

EPC (%)

ESRD PATIENTSCONTROLS

4 Fold Reduction in Circulating Endothelial Progenitor Cells ESRD Patients Vs. Controls

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Endothelial Dysfunction: The Cardiovascular Disease Continuum

Elevated BP Target-Organ Damage

Vascular Dysfunction

EndothelialDysfunction

Angina PectorisStroke

LVH?

Renal Damage

Cardiovascular Disease ProgressionCardiovascular Disease Progression

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Management of Comorbidities

AnemiaRenal OsteodystrophyHyperlipidemia

43

What is the prevalence of anemia in CKD ?Is the pt’s GFR too good to explain anemia?

Am J Kidney Dis 34:125-134, 1999

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Raising Hematocrit to 30-36% improves:

Brain and cognitive functionQuality of LifeExercise capacity/muscle function?LVH?Survival

Benefits of Correction of Hb

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Principles of Anemia Treatment

ErythropoietinEpoetin alfa :Procrit ® , Epogen®Darbepoietin Alpha: ARANESP ®

TargetsHgb=11g/dL (caution when intentionally maintaining Hb>13g/dL)

Sufficient iron should be administered to maintain

TSAT of >20%, Serum ferritin level of >200 ng/mL

46

CHOIR StudyPrimary EndpointL MI, CVA, CHF, Death

High hemoglobin group

Low hemoglobin group

N Engl J Med. 2006 Nov 16;355(20):2085-98

47

Renal Osteodystrophy

48

Metastatic Coronary Calcification

49

Relationship between Moderate to Severe Kidney Disease and Hip Fracture

Nickolas TL.. J Am Soc Nephrol. 2006 Nov;17(11):3223-32

50

Serum Phosphate Levels and Mortality Risk

J Am Soc Nephrol 16: 520-528, 2005

51

Oral Calcitriol with Improved Survival

J Am Soc Nephrol. 2008 May 7.

52

Treatment of Calcium, Phosphate Levels and Osteodystrophy

AIM: To Normalize-Serum calciumSerum PhosphorusPTH levels

Methods:Oral CalciumVitamin D analogsPhosphate binders (sevelamer-Renagel®)Calcimimetics (cinacalcet-Sensipar®)

53

Dyslipidemia in Renal Patients

Am J Kidney Dis. 1998 Nov;32(5 Suppl 3):S142-56

54

55

TNT (Treating to New Targets) study CKD substudy

J Am Coll Cardiol. 2008 Apr 15;51(15):1448-54

Risk Reduction-32% CKD

(n= 3,107)

-15% normal eGFR(n= 9,656)

56

0

2

4

6

8

Mea

n in

crea

se fr

om b

asel

ine

(mL/

min

)

Atorvastatin 10 mg (n=3977)Atorvastatin 80 mg (n=3988)

MDRD (mL/min/1.73 m2) Cockcroft-Gault (mL/min)eGFR

P<0.0001

(↑ 5.6%)

(↑ 8.4%)

P<0.0001

(↑ 1.2%)

(↑ 3.3%)

TNTeGFR at Last Study Visit

57

?HDL-directed therapies?

My doctor said:“Only 1 glass of alcohol a day.”

I can live with that.!

58

Management of Dyslipidemia in CKD

NCEP guidelines recommended:Cholesterol <200LDL-C <100 (?<70)HDL-C >45 (M), 55(F)Triglycerides<150

59

Preparation for renal replacementChoice of renal replacementTimely access surgeryTimely dialysis initiation

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Preparation for Renal Replacement

When GFR <25ml/minRenal transplant is treatment of first choice

Workup living donors

If no donors availableList patient on cadaver tx. listPlace Angioaccess if HD preferred

61

lla

illi

lla

illi

AV access (Target 50% Fistulae)

USRDS 2004

62

Patient Survival vs Waiting Time

63

Effect of Preemptive Renal Transplant on Allograft Survival

Mange K….N Engl J Med. 2001 Mar 8;344(10):726-31.

64

Renal Transplant Waiting List 1993-2002

0

10,000

20,000

30,000

40,000

50,000

60,000

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002Year

Num

ber o

f Reg

istr

atio

ns

Kidney

65

Kidney Donors Recovered1993-2002

0

1000

2000

3000

4000

5000

6000

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002Year

# of

Don

ors

Rec

over

ed

Deceased Donor Living Donor

7/15/2007:72,355

66

67

68

Awareness/CKD Stage

69

70

Timing Of Nephrology Referral

Patients with chronic kidney disease should be referred to a specialist for consultation and co-management if:

the clinical action plan cannot be preparedthe prescribed evaluation of the patient cannot be carried outthe recommended treatment cannot be carried out. In general, patients with GFR <30 mL/min/1.73 m2

should be referred to a nephrologist.

71

The timing of specialist evaluation in chronic kidney disease and mortality:Cumulative Mortality

Early: > 12 monthsIntermediate: 4-12 monthsLate: <4 months

Kinchen KS….Ann Intern Med 2002 Sep 17;137(6):479-86

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Early Treatment Should Make a Difference

Brenner, et al., 2001

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PCP Must be Engaged

1) 7.6 million people with GFR 30-60 mL/min/1.73 m2

2) About 5,000 full-time nephrologists

3) Nearly 1,500 new patients per nephrologist

Therefore, 7 new patients per day per nephrologist.

Obviously not possible.

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Summary: Definition of CKD

•• ““SpotSpot”” urine albumin/microalbumin to creatinine ratio

• Estimate GFR from serum creatinine using the MDRD prediction equation

Note: 24 hour urine collections are NOT neededDiabetics, HTN: should be tested once a yearOthers at risk: less frequently as long as normal

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SummaryOptimal Management of CKD

Delay ProgressionACE-Inhibitors/ARBBP control (130/85)Blood sugar control?Protein restriction

Treat ComorbiditiesAnemiaRenal osteodystrophyHyperlipidemiaCardiovascular diseaseNutrition, Acidosis

Preparation for renal replacementChoice of Renal ReplacementTimely access surgeryTimely dialysis initiation

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www.columbianephrology.org