Chronic Kidney DiseaseDefinition, Early Intervention &

Measurement

Andrea Easom Ma, MNSc, APN, BC. CNN

University of Arkansas for Medical Sciences

Instructor, College of Medicine, Nephrology Division

Educational Objectives

• Define chronic kidney disease (CKD)

• Identify risk factors for progression and co-morbid conditions

• Discuss how early intervention improves outcomes during CKD progression

• Review measurements of kidney disease

1.1 1.62.4 2.9

3.95.5

17.918.6

0

5

10

15

20

Pat

ien

ts W

ho

Are

Aw

are

of

Wea

k o

r F

ailin

g K

idn

eys*

(%

)

Awareness of Early-Stage CKD Is Low in the US Population

*Proportion of patients who were told they had weak or failing kidneys, eGFR (mL/min/1.73 m2). Coresh et al. J Am Soc Nephrol. 2005:16:180-188.

<30 30+ <30 30+ <30 30+ F MSex: Albuminuria:

eGFR: 90+ 60-89 30-59 30-59

© 2005 The Johns Hopkins University School of Medicine.

Definition of Chronic Kidney Disease

AJKD 2002: 39(2)

Stages of Chronic Kidney Disease

AJKD 2002: 39(2)

Definition and Stages of Chronic Kidney Disease

AJKD 2002: 39(2)

Stages in Progression of CKD and Therapeutic Strategies

AJKD 2002: 39(2)

Risk Factors for Adverse Outcomes of CKD

AJKD 2002: 39(2)

Potential Risk Factors for Susceptibility to and

Initiation of CKD

AJKD 2002: 39(2)

AJKD 2002: 39(2)

Why Estimate GFR From SCr, Instead of Using SCr for Kidney Function?

*B = black; †W = all ethnic groups other than black. GFR calculator available at: www.kidney.org/index.cfm?index=professionals. Accessed 3/28/05.

AgeGend

er RaceSCr

(mg/dL)

eGFR (mL/min/1.73

m2)

CKD Stage

20 M B* 1.3 91 1

20 M W† 1.3 75 2

55 M W 1.3 61 2

20 F W 1.3 56 3

55 F B 1.3 55 3

50 F W 1.3 46 3

Stages of CKD: A Clinical Action Plan

AJKD 2002: 39(2)

Evaluation of Proteinuria in Patients

Not Known to Have Kidney Disease

AJKD 2002: 39(2)

Diabetes

The Leading Cause of Kidney Failure

Increased Mortality in Patients With Diabetes and CKD: 2-Year Clinical Outcomes

CKD identified as ICD-9-CM diagnosis code, includes CKD from diabetes, hypertension, obstructive uropathy, and other diagnosis codes reported on USRDS ESRD registration forms.DM = diabetes mellitus; ESRD = end-stage renal disease; ICD-9-CM = International Statistical Classification of Diseases, 9th Revision, Clinical Modification.Collins et al. Kidney Int. 2003;64(suppl 87):S24-S31.

+ DM, - CKD

- DM,+CKD

+ DM,+ CKD

Medical Cohort

Pat

ien

ts (

%)

0

20

40

60

80

100

84.067.6 61.6

No Events

29.515.7

32.3

DeathESRD, CKD Stage 5

0.3

2.96.1

© 2005 The Johns Hopkins University School of Medicine.

Advanced Kidney Outcomes by Year 8 of EDIC Reduced by Intensive Treatment

OutcomeIntensive

(n = 676)Conventional

(n = 673)

Creatinine >2 mg/dL

5* (0.7%) 19 (2.8%)

Dialysis or Transplant

4 (0.6%) 7 (1.0%)

EDIC = Epidemiology of Diabetes Interventions and Complications.*P = 0.004. Writing team for the DCCT/EDIC Research Group. JAMA. 2003;290:2159-2167.

© 2005 The Johns Hopkins University School of Medicine.

Proteinuria Predicts Stroke and CHD Events in Patients With Type 2

Diabetes

P<0.001

40

30

20

10

0Stroke CHD

Events80604020

0

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al C

urv

es f

or

CV

Mo

rtal

ity

Overall: P<0.001

Inci

den

ce (

%)

Follow-Up (mo)

CHD = coronary heart disease; Prot = urinary protein excretion; CV = cardiovascular.Miettinen et al. Stroke. 1996;27:2033-2039.

Prot 150-300 mg/LProt <150 mg/L Prot >300 mg/L

0 100

© 2005 The Johns Hopkins University School of Medicine.

Evidence for Effects of Good Glycemic Control on Complications, Including

Nephropathy

DCCT = The Diabetes Control and Complications Trial.DCCT Study Group. N Engl J Med. 1993;329:977-986; Ohkubo. Diabetes Res Clin Prac. 1995;28:103-117; UKPDS Study Group. Lancet. 1998;352:837-853.

Trial

Complication

DCCTA1C: (9

7%)N = 1441

Kumamoto

(9 7%)N = 110

UKPDS(8 7%)N = 5102

Retinopathy 76% 69% 17-21%

Nephropathy 54% 70% 24-33%

Neuropathy 60% – –

© 2005 The Johns Hopkins University School of Medicine.

Hypertension

The Second Leading cause of Kidney Failure

Recommendations for BP and RAS Management in CKD

BP = blood pressure; RAS = renin angiotensin system; CCB = calcium channel blocker; BB = -blocker; JNC 7 = The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.ADA. Diabetes Care. 2005;28(suppl 1); Chobanian et al. JAMA. 2003;289:2560-2572; Kidney Disease Outcomes Quality Initiatives (K/DOQI). Am J Kidney Dis. 2004;43(5 suppl 1):S1-S290.

PatientGroup

Goal BP(mm Hg) First Line Adjunctive

+ Diabetes <130/80 ACE-I or ARB Diuretics then CCB or BB

Diabetes + Proteinuria

<130/80 ACE-I or ARB Diuretics then CCB or BB

Diabetes Proteinuria

<130/80 No specific preference:

Diuretics then ACE-I, ARB, CCB, or BB

EXPECT TO NEED TO USE 3+ AGENTS TO ACHIEVE GOALSRecommendations largely consistent across JNC 7, ADA, and K/DOQI

© 2005 The Johns Hopkins University School of Medicine.

ACEI/ARB & Reduced Risk of Rapid GFR Decline, Kidney Failure, or Death

-50

-40

-30

-20

-10

0

Co

mp

osi

te R

isk

(%)*

Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431. [AASK - African American Study of Kidney Disease and Hypertension]Brenner et al for the RENAAL Study Investigators. N Engl J Med. 2001;345:861-869. [RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan]Lewis et al for the Collaborative Study Group. N Engl J Med. 2001;345:851-860.[IDNT = Irbesartan in Diabetic Nephropathy Trial.]

Ramipril vs Amlodipine

P = 0.004

Ramipril vs Metoprolol

P = 0.04

Losartan vs Placebo P = 0.02

-38

-22

-16

Irbesartan vs Placebo

P = 0.02

-20

Irbesartan vs Amlodipine

P = 0.006

-23

AASK (N=1094) RENAAL (N=1513) IDNT (N=1722)

© 2005 The Johns Hopkins University School of Medicine.

0

5

10

15

20

25

30

0 6 12 18 24 30 36

Follow-Up (mo)

Pat

ien

ts R

each

ing

En

d P

oin

t* (

%)

*Primary end point: doubling of SCr or kidney failure.Nakao et al. Lancet. 2003;361:117-124.

ACEIs, ARBs, and Combination Therapy Effects in Nondiabetic Nephropathy

P = 0.02

Combination (n = 88)Losartan (n = 89)Trandolapril (n = 86)

© 2005 The Johns Hopkins University School of Medicine.

Relationship Between Achieved BP and GFR

-14

-12

-10

-8

-6

-4

-2

0

95 98 101 104 107 110 113 116 119

eG

FR

(m

L/m

in/1

.73 m2)

per

y

MAP = Mean Arterial Pressure*

r = 0.69P<0.05

UntreatedHypertension

130/80 140/90

*MAP = [SBP + (2 × DBP)]/3 mm Hg.Summary of 9 studies used in figure.Parving et al. 1989; Viberti et al. 1993; Klahr et al. 1993; Hebert et al. 1994; Lebovitz et al. 1994; Moschio et al. 1996; Bakris et al. 1996; Bakris et al. 1997; GISEN Group. 1997.Bakris et al. Am J Kidney Dis. 2000;36:646-661.

© 2005 The Johns Hopkins University School of Medicine.

Anemia

A Modifiable and Funded Risk Factor

*NHANES participants aged ≥20 y with anemia as defined by WHO criteria: hemoglobin (Hgb) <12 g/dL for women, and Hgb <13 g/dL for men. USRDS 2004 Annual Data Report. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. Available at: www.usrds.org. Accessed 3/28/05.

Anemia Prevalence by CKD Stage

Pat

ien

ts W

ith

An

emia

* (%

)

0

10

20

30

40

50

60

70

1 2 3 4-5

NHANES IIINHANES 1999-2000

CKD Stage

© 2005 The Johns Hopkins University School of Medicine.

Anemia Treatment Eligibility

• Serum Creatinine (2.0 mg/dl or above) or

• Creatinine Clearance (45 ml/min or below) and

• Hemoglobin (11g/dl or below) or

• Hematocrit (33% or below) or

• Symptoms of anemia

Consequences of Anemia in CKD• Reduced oxygen delivery to tissues• Decrease in Hgb compensated by increased cardiac

output• Progressive cardiac damage and progressive renal

damage1

• Increased mortality risk2

• Reduced quality of life (QOL)3

– Fatigue– Diminished exercise capacity– Reduced cognitive function

• Left ventricular hypertrophy (LVH)4

1. Silverberg et al. Blood Purif. 2003;21:124-130. 2. Collins et al. Semin Nephrol. 2000;20:345-349; 3. The US Recombinant Human Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial. 2003;16:101-105.

© 2005 The Johns Hopkins University School of Medicine.

Patients With CHF and Anemia (n = 126, 91% CKD)

NYHA class = New York Heart Association classification; SOB = shortness of breath.Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236-S240.

Clinical Benefit of Anemia Correction: CHF and CKD

Parameter Before AfterHgb (g/dL) 10.3 13.1

Serum creatinine (g/dL) 2.4 2.3

∆GFR (mL/min/mo) -0.95 0.27

NYHA class (0-4) 3.8 2.7Fatigue/SOB index (0-10) 8.9 2.7

Hospitalizations 3.7 0.2

Systolic BP (mm Hg) 132 131

Diastolic BP (mm Hg) 75 76

© 2005 The Johns Hopkins University School of Medicine.

Secondary Hyperparathyroidism

An Early and Modifiable Complication of CKD

Calcitriol Decline and iPTH Elevation as CKD Progresses

N = 150.iPTH = intact PTH. Adapted from Martinez et al. Nephrol Dial Transplant. 1996;11(suppl 3):22-28.

eGFR (mL/min/1.73 m2)

152535455565758595105

100

200

300

400

0

10

20

30

40

50

iPT

H (

pg

/mL

)

Cal

citr

iol

1,25

(OH

) 2D

3 (p

g/m

L)

Stage 37.4 million

Stage 25.7 million

Stage 4300,000

CKD Stage 15.6 million

25

65

Low-Normal

Calcitriol

High-Normal PTH

© 2005 The Johns Hopkins University School of Medicine.

Feedback Loops in SHPT

Ca = calcium; CVD = cardiovascular disease; P = phosphorus.Courtesy of Kevin Martin, MB, BCh.

PTH

Bone DiseaseFracturesBone pain

Marrow fibrosisErythropoietin resistance

Serum P1,25D

Calcitriol

Renal Failure

PTH

Systemic ToxicityCVD

HypertensionInflammationCalcification

Immunological

25D

Ca++

Decreased Vitamin D Receptors and Ca-Sensing Receptors

© 2005 The Johns Hopkins University School of Medicine.

-2.25

-2.00

-1.75

-1.50

-1.25

-1.00

-0.75

-0.50

-0.25

0.00Spine Hip Arm

Bo

ne

Min

eral

Den

sity

, Z

-Sco

re

PTH <60 pg/mL PTH 60-120 pg/mL PTH >120 pg/mL

Bone Loss Correlates With Severity of SHPT in CKD Stages 3 and 4

*P<0.05 compared with patients with PTH in the normal range.Z-Score = comparison to the mean value for women at a similar risk, including age, weight, and ethnicity.Rix et al. Kidney Int. 1999;56:1084-1093.

*

**

© 2005 The Johns Hopkins University School of Medicine.

Bone-Fracture Rate Increases as CKD Progresses: Fractures in Patients on

Dialysis

*Ratio of observed incidence of hip fracture in patients with kidney failure to expected incidenceof hip fracture in the general population.Adapted from Alem et al. Kidney Int. 2000;58:396-399.

0

5

10

100

<45 45-54 55-64 65-74 75-84 TotalAge (y)

Ob

serv

ed/E

xpec

ted

In

cid

ence

of

Hip

Fra

ctu

re*

Male Relative Risk = 4.4Female Relative Risk = 4.4

Overall

15

20

80

100 8799

25 20

10 10

7.56.4

2.4 2.54.4 4.4

© 2005 The Johns Hopkins University School of Medicine.

Cardiovascular Outcomes Worsen With CKD Progression: 3-Y Follow-Up by eGFR

Levels

CHF = congestive heart failure.Anavekar et al. N Engl J Med. 2004;351:1285-1295.

0

10

20

30

40

50

60

CompositeEnd Point

Death FromCV Causes

Reinfarction CHF Stroke Resuscitation

Est

imat

ed E

ven

t R

ate

(%)

75 60-74 45-59 <45P<0.001

eGFR (mL/min/1.73 m2)

© 2005 The Johns Hopkins University School of Medicine.

Why Classify Severity as the Level of GFR?

AJKD 2002: 39(2)

Guideline 4.Estimation of GFR

AJKD 2002: 39(2)

Guideline 4.Estimation of GFR (cont’d)

AJKD 2002: 39(2)

Guideline 4.Estimation of GFR (cont’d)

AJKD 2002: 39(2)

Advantages of Estimating GFR Using Equations

AJKD 2002: 39(2)

Serum Creatinine Corresponding to GFR of

60 mL/min/1.73 m2

AJKD 2002: 39(2)

Relationship of Creatinine Clearance

and Serum Creatinine with GFR (Inulin Clearance) in

Patients with Glomerular Disease

AJKD 2002: 39(2)

Estimates of GFR vs. Measured GFR

in MDRD Study Baseline Cohort

AJKD 2002: 39(2)

Accuracy of Different Estimates of GFR in Adults

AJKD 2002: 39(2)

Prevalence of Individuals at Increased Risk for CKD

AJKD 2002: 39(2)

1.1 1.62.4 2.9

3.95.5

17.918.6

0

5

10

15

20

Pat

ien

ts W

ho

Are

Aw

are

of

Wea

k o

r F

ailin

g K

idn

eys*

(%

)

Awareness of Early-Stage CKD Is Low in the US Population

*Proportion of patients who were told they had weak or failing kidneys, eGFR (mL/min/1.73 m2). Coresh et al. J Am Soc Nephrol. 2005:16:180-188.

<30 30+ <30 30+ <30 30+ F MSex: Albuminuria:

eGFR: 90+ 60-89 30-59 30-59

© 2005 The Johns Hopkins University School of Medicine.

Summary

• Over 20 millions Americans have some degree of CKD & few are aware of it.

• There are interventions to slow the progression and treat the complications that are associated with CKD.

• Reporting eGFR can help alert health care providers that their patient may have CKD so further workup, education and interventions can be done.