Chronic Kidney Disease Definition, 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 comorbid conditions Discuss how early intervention improves outcomes during CKD progression Review measurements of kidney disease

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

Patients Who Are Aware of Weak or Failing Kidneys* (%)
20 18.6 17.9 15

10 5.5 5 1.1 0 1.6 3.9 2.4 2.9

Albuminuria: eGFR:

<30 90+

30+

<30

30+

<30

30+ Sex: F

M 30-59

60-89

30-59

*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. 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?
Age 20 20 55 20 55 50 Gende Race r M M M F F F B* W W W B W SCr
(mg/dL)

eGFR
(mL/min/1.73 m2 )

CKD Stage 1 2 2 3 3 3

1.3 1.3 1.3 1.3 1.3 1.3

91 75 61 56 55 46

*B = black; W = all ethnic groups other than black.

GFR calculator available at: www.kidney.org/index.cfm?index=professionals. Accessed 3/28/05.

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
100 80 No Events ESRD, CKD Stage 5 Death 67.6 84.0 6.1 32.3
+ DM, + CKD

Patients (%)

61.6

60 40

2.9 20 0 15.7
+ DM, - CKD

0.3

29.5
- DM, +CKD

Medical Cohort
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. 2005 The Johns Hopkins University School of Medicine.

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

Outcome Creatinine >2 mg/dL Dialysis or Transplant Intensive
(n = 676)

Conventional
(n = 673)

5* (0.7%) 4 (0.6%)

19 (2.8%) 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
Prot <150 mg/L Prot 150-300 mg/L
40
P<0.001

Prot >300 mg/L

1.0

Survival Curves for CV Mortality

0.9 0.8 0.7 0.6 0.5 0 0 20 40 60 80 100

Overall: P<0.001

Incidence (%)

30 20 10 0

Stroke

Follow-Up (mo)
Miettinen et al. Stroke. 1996;27:2033-2039.

CHD Events

CHD = coronary heart disease; Prot = urinary protein excretion; CV = cardiovascular.

2005 The Johns Hopkins University School of Medicine.

Evidence for Effects of Good Glycemic Control on Complications, Including Nephropathy

Trial Complication DCCT A1C: (9 7%) N = 1441 76% 54% 60% Kumamoto (9 7%) N = 110 69% 70% UKPDS (8 7%) N = 5102 17-21% 24-33%

Retinopathy Nephropathy Neuropathy

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. 2005 The Johns Hopkins University School of Medicine.

Hypertension
The Second Leading cause of Kidney Failure

Recommendations for BP and RAS Management in CKD

Patient Group
+ Diabetes Diabetes + Proteinuria Diabetes Proteinuria

Goal BP
(mm Hg) <130/80 <130/80 <130/80

First Line

Adjunctive

ACE-I or ARB Diuretics then CCB or BB ACE-I or ARB Diuretics then CCB or BB No specific preference: Diuretics then ACE-I, ARB, CCB, or BB

EXPECT TO NEED TO USE 3+ AGENTS TO ACHIEVE GOALS

Recommendations largely consistent across JNC 7, ADA, and K/DOQI
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. 2005 The Johns Hopkins University School of Medicine.

ACEI/ARB & Reduced Risk of Rapid GFR Decline, Kidney Failure, or Death
Composite Risk (%)* 0 -10 -20 -30 -40 -50

AASK (N=1094)

RENAAL (N=1513)

IDNT (N=1722)

-16 -22
Ramipril vs Metoprolol P = 0.04 Losartan vs Placebo P = 0.02

-20
Irbesartan

-23

-38

vs Placebo Irbesartan P = 0.02 vs Amlodipine P = 0.006

Ramipril vs Amlodipine P = 0.004

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.]
2005 The Johns Hopkins University School of Medicine.

Patients Reaching End Point* (%)

ACEIs, ARBs, and Combination Therapy Effects in Nondiabetic Nephropathy

30 25 20 15 10 5 0 0 6 12 18 24 Follow-Up (mo) 30 36

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

P = 0.02

*Primary end point: doubling of SCr or kidney failure.

Nakao et al. Lancet. 2003;361:117-124. 2005 The Johns Hopkins University School of Medicine.

Relationship Between Achieved BP and GFR

MAP = Mean Arterial Pressure*
eGFR (mL/min/1.73 per y ) m 95 0 -2 -4 -6 -8 -10 -12 -14 98 101 104 107 110 113 116 119

r = 0.69 P<0.05 Untreated Hypertension 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

Anemia Prevalence by CKD Stage

70

NHANES III NHANES 1999-2000

Patients With Anemia* (%)

60 50 40 30 20 10 0 1 2 3 4-5

CKD Stage
*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. 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.

Clinical Benefit of Anemia Correction: CHF and CKD

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

Parameter
Hgb (g/dL) Serum creatinine (g/dL) GFR (mL/min/mo) NYHA class (0-4)
Fatigue/SOB index (0-10)

Before
10.3 2.4 -0.95 3.8 8.9 3.7 132 75

After
13.1 2.3 0.27 2.7 2.7 0.2 131 76

Hospitalizations Systolic BP (mm Hg) Diastolic BP (mm Hg)

NYHA class = New York Heart Association classification; 2005 The Johns Hopkins University School of Medicine. SOB = shortness of breath.
Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236-S240.

Secondary Hyperparathyroidism
An Early and Modifiable Complication of CKD

Calcitriol Decline and iPTH Elevation as CKD Progresses

50

Calcitriol 1,25(OH)2D3 (pg/mL)

CKD Stage 1 5.6 million

Stage 2 5.7 million

Stage 3 7.4 million

Stage 4 300,000

40 30 25 20 10 0

400

300 Low-Normal Calcitriol 200

100 High-Normal 65 PTH 105 95 85 75 65 55 45 35 25 15

N = 150. iPTH = intact PTH.

eGFR (mL/min/1.73 m2)

Adapted from Martinez et al. Nephrol Dial Transplant. 1996;11(suppl 3):22-28. 2005 The Johns Hopkins University School of Medicine.

iPTH (pg/mL)

Feedback Loops in SHPT

Decreased Vitamin D Receptors and Ca-Sensing Receptors

PTH

PTH

Ca++
Bone Disease Fractures Serum P Bone pain Marrow fibrosis Erythropoietin resistance

1,25D Calcitriol

Systemic Toxicity CVD Hypertension Inflammation Calcification Immunological

25D
Renal Failure
Ca = calcium; CVD = cardiovascular disease; P = phosphorus.
Courtesy of Kevin Martin, MB, BCh. 2005 The Johns Hopkins University School of Medicine.

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

PTH <60 pg/mL Spine 0.00 -0.25 -0.50 -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 -2.25 PTH 60-120 pg/mL Hip PTH >120 pg/mL Arm Bone Mineral Density, Z-Score

* * *

*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

Observed/Expected Incidence of Hip Fracture*
100 80 20 15 10 5 0 <45 45-54 55-64 65-74 Age (y) 75-84 Total
10 10 7.5 6.4 2.4 2.5 4.4 4.4 87 99 25 20

Overall Male Relative Risk = 4.4 Female Relative Risk = 4.4

*Ratio of observed incidence of hip fracture in patients with kidney failure to expected incidence of hip fracture in the general population.
Adapted from Alem et al. Kidney Int. 2000;58:396-399. 2005 The Johns Hopkins University School of Medicine.

Cardiovascular Outcomes Worsen With CKD Progression: 3-Y Follow-Up by eGFR Levels eGFR (mL/min/1.73 m )
2

60 50 40 30 20 10 0
Composite End Point Death From CV Causes Reinfarction CHF Stroke

Estimated Event Rate (%)

P<0.001

75 60-74 45-59 <45

Resuscitation

CHF = congestive heart failure.

Anavekar et al. N Engl J Med. 2004;351:1285-1295.

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 (contd)

AJKD 2002: 39(2)

Guideline 4. Estimation of GFR (contd)

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)

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)

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

Patients Who Are Aware of Weak or Failing Kidneys* (%)
20 18.6 17.9 15

10 5.5 5 1.1 0 1.6 3.9 2.4 2.9

Albuminuria: eGFR:

<30 90+

30+

<30

30+

<30

30+ Sex: F

M 30-59

60-89

30-59

*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. 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.