11/9/2006 1

Chronic Kidney Disease:Definitions and Optimal Management

Jai Radhakrishnan, MDAssoc Professor of Clinical Medicine

College of Physicians & Surgeons of Columbia 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

Case

A 78 year old Caucasian female patient presents to her PCP for a routine physical. She has been told of mild HTN but takes no medications.BP=160/90Laboratory

creatinine 1.5mg/dL Hb=10g/dLUrine exam 1+ proteinTchol 220, LDL 138, HDL 40, TG 150

How severily compromised is her renal function?Is she being optimally managed?

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Chronic >3 months

Kidney Damage Hematuria/AlbuminuriaBiopsyAbnormal imaging tests

Glomerular Filtration Rate < 60ml/min

Definitions and Stages of Chronic Kidney Disease

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Good news NO MORE 24-HOUR URINES!

Spot urines are adequate.

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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

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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

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Serum Creatinine Is an Inadequate Screening Test for Renal Failure in Elderly Patients

S. Creatinine > 1.7mg/dL

Swedko PJ…Arch Intern Med. 2003;163:356-360

27% referred to neprhologist

85% incompletely evaluated

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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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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

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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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Angiotensin II: Role in Renal InjuryAngiotensin II: Role in Renal Injury

Angiotensin II

AT1RAT2R

NF-κB

TNFR1

TNFR2

Angiotensinogen

Fibroblasts

Proliferation and differentiation

Matrix

FIBROSIS

Inflammation

Cellular adhesion molecules

Tubule cells

TNF-α

+ +

Profibrotic cytokines

www.hypertensiononline.org

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ACE-I: Preventing Microalbuminuriain Type 2 Diabetes (Benedict Study)

1204 subjects with type 2 DM, HTN and normal urine albumin. Treatment with at least three years of

Trandolapril 2 mg/d + verapamil(SR180mg/dTrandolapril alone 2 mg/dVerapamil SR 240mg/d alone Placebo

The target blood pressure=120/80 mm Hg.The primary end point: development of persistent microalbuminuria

N Engl J Med. 2004 Nov 4;351(19):1941-51.

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ACE-I/ARB in Diabetic Nephropathy

REFERENCE POPULATION Drug/Duration

Viberti et alJAMA 1994; 271: 275-9

92 DM-1 Non- HTNMicroalbuminuria

Captopril3 years

Collaborative Study Grp.N E J M 1993 Nov 11;329(20):1456-62.

419 DM-1UVPr> 0.5g

Captopril3 years

RENAALN E J M. 2001;345:861–869

1513 DM-2UVPr >0.9g, Cr 1-3

Losartan3.4 years

IRMA 2N E J M. 2001;345:870–888.

590 DM-2, HTNMicroalbuminuria

Usual AHTN vs Valsartan2 years

MARVALCirculation. 2002;106:672–678

332 DM-2Microalbuminuria

Valsartan vs Amlodipine24 weeks

IDNTN Engl J Med. 2001 Sep 20;345(12):851-60.

1715 DM-2UVPR>0.5g

Irbesartan vs Amlodipine2.6 years

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ACE-I/ARB in Non-Diabetic Renal Disease

REFERENCE POPULATION Drug/Duration

AIPRI N Engl J Med 1996; 334: 939

REINKidney Int 1998; 53: 1209-16. Lancet 1999; 354: 359-64

AASKJAMA. 2001 Jun 6;285(21):2719-28JAMA. 2002;288(19):2421-31

1094 AA ptsHTN, GFR 20-65ml/min

Amlodipine vs.Ramipril vs Metoprolol

Praga MJASN. 2003 Jun;14(6):1578-83.

Wei AKidney Int. 2003 Oct;64(4):1462-71.

44 HIVANCreatiinine<2.0

Fosinopril5.1 years

583 CRI (DM/Non DM)

Benazepril3 years

352 CRI +/-Nephroticproteinuria

Ramipril2 years

44 IgAN Enalapril~6 years

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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.

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Albuminuria(urinary albumin > 300 mg/24h) reduced by 54%) (95% C.I. 19 – 74%)

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

Diabetes Control and Complications Trial Prevention of Macroalbuminuria

33ukpds

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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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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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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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.

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Management of Comorbidities

AnemiaRenal OsteodystrophyHyperlipidemia

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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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Etiology and Workup of Anemia in Renal Failure

Decreased productionLow EPO (renal failure)Nutritional

(Iron, B12, Folate)Infection, inflammation and malignancy

Blood Loss

Reticulocyte countRed Blood Cell indices: MCV, RDWIron Parameters

Total ironIron binding capacityFerritin

Vitamins:Folate\ B12 levels

Stools for occult bloodErythropoietin levels not indicated

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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=11 to 12 g/dLHct =33% to 36%

Sufficient iron should be administered to maintain

TSAT of >20%, Serum ferritin level of >100 ng/mL

43

lla

illi

lla

illi

Incident ESRD patients with a first service date between May 1995 & June 2003; data from Medical Evidence form.

Scorecard: Mean monthly hemoglobin (g/dl) at initiation

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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®)

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Dyslipidemia in Renal Patients

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

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Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis

Wanner, C. et al. N Engl J Med 2005;353:238-248

Primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in diabetic hemodialysis pts.

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Management of Dyslipidemia in CKD

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

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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

50

lla

illi

lla

illi

AV access (Target 50% Fistulae)

USRDS 2004

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Patient Survival vs Waiting Time

52

Effect of Preemptive Renal Transplant on Allograft Survival

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

53

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

54

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

55

56

57

Awareness/CKD Stage

58

59

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.

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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

•• ““Spot”Spot” 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