Early Detection and Prevention of Renal Failure

Linda Fried, MD, MPH

Scope of the Problem The incidence of End-stage renal disease is growing As of 12/31/98, there were more than 200,000 people in

the US on dialysis* End-stage renal disease care accounted for >16 billion

dollars in 1998* The major causes of ESRD are diabetes (45%) and

hypertension (24%) and are therefore potentially preventable

ESRD disproportionately affects minorities and the elderly

*USRDS

Incident rates of ESRD Due to Diabetes & Hypertension, by RaceRate per million population, adjusted for age & gender

USRDS

Incident Rates, by Age & First Modalityadjusted for gender & race

USRDS

Incident Rates, by Primary Diagnosis & First Modalityadjusted for age, gender, & race

USRDS

Identifying People with Early Renal Disease Proteinuria

– Microalbuminuria– Overt Proteinuria/Albuminuria- associated with

lower Creatinine clearance in population* Serum Creatinine- miss early declines in GFR Creatinine Clearance- difficult to do as screen Estimated glomerular filtration rate (GFR) - formulas

from laboratory/clinical variables

*Pinto-Sietsma et al, Groningen, Netherlands, JASN 2000

Proposed NKF Clinical Practice Guideline for Stages of Kidney Disease

Stage Description GFR

(ml/min/1.73m2)

1 Kidney Damage withnormal or GFR >90

2 Mild GFR 60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure <15 or dialysis

Proposed NKF Clinical Practice Guideline for Stages of Kidney Disease

Marker* No Marker

GFR HTN No HTN HTN No HTN

>90 1 1 HTN Normal

60-89 2 2 2 GFR

30-59 3 3 3 3

15-29 4 4 4 4

<15 or dialysis 5 5 5 5

*Proteinuria, Urinary sediment abnormalities, Structural abnormalities, Alterations in composition of the urine

Proteinuria

The level of proteinuria is a prognostic factor in renal disease

This is true for a wide variety of diseases, including hypertensive renal diseases

Easily performed– Urine dipstick– Albumin sticks– Protein or albumin/creatinine ratio on spot urine

Should we be screening for proteinuria or an elevated creatinine? All diabetics should be screened for microalbuminuria -

ADA and NKF recommendation In the US, the prevalence of proteinuria is low in subjects

without hypertension or diabetes US Preventive Health Services Task Force does not

recommend urinalysis or creatinine as screen in otherwise healthy adults

Are there higher risk groups, such as African Americans or older individuals where screening should be done in asymptomatic individuals without diabetes or hypertension?

Prevalence of Albuminuria in Individuals Without Diabetes: NHANES III

Prevalence by Age Group (years)

Alb/Cr ratio 20-39 40-59 60-69 70+

Normal 93.3% 91.4% 85.4% 72.8%

Microalbuminuria 6.3% 7.9% 13.2% 24.2%

Albuminuria 0.3% 0.7% 1.4% 3.0%

Prevalence of an Increased Creatinine* in Normal, High Normal, and Stage 1 Hypertension : NHANES III

On Medication Not on Medication

NormalHigh-

Normal Stage 1 NormalHigh-

Normal Stage 1Non-HispanicWhite 4.3% 14.2% 12.2% 1.3% 2.3% 3.4%Non-HispanicBlack 19.0 16.2 20.7 2.9 4.6 4.0

Mexican-American 2.0 5.0 3.0 0.3 1.2 1.0

Age 60 2.8 2.5 1.8 5.1 5.8 6.1

*Cr 1.6 men, 1.4 women, Coresh et al, Arch Intern Med 2001

Screening for Renal Disease

Many of those with early renal disease have not been informed of the diagnosis

– In a small pilot study, only 36% (9 of 25) of patients with a creatinine between 1.5 and 3.0 knew of their renal disease

Screening for Renal Disease Microalbuminuria

– Risk factor for cardiovascular events and in nondiabetics this may be a reason to screen, especially in the elderly

– It is a risk factor for progression of diabetic nephropathy, unknown if it is a risk factor in nondiabetics

Overt proteinuria also identifies those at risk for subsequent events*

An elevated creatinine identifies not only those at risk for progression of renal disease, but also those at higher risk for mortality and cardiovascular events

*NHANES 1, Wagener et al Environ Res 1994

Cardiovascular Health Study Population-based, longitudinal study of 5,888 individuals,

age >65 years Random sample from Medicare eligibility lists in:

– Pittsburgh, PA– Forsyth County, NC– Washington County, MD– Sacramento County, CA

Primary objective of CHS is to identify risk factors related to coronary heart disease and stroke

Elderly with Renal Insufficiency

YES

36%NO

64%

YES

28%NO

36%

YES

2%NO

34%

YES

6%NO

28%

N=208 N=370

N=161 N=209

N=14 N=195

N=32 N=163

Clinical CV Disease

Subclinical CV Disease

Diabetes Mellitus

Framingham Risk > 20% / 10 years

N=578

Baseline Cardiovascular Risk in Subjects withan Elevated Creatinine ( 1.5 men or 1.3 women)

Years of follow-up0 2 4 6 8

0.00

0.25

0.50

0.75

1.00

<1.10

1.10-1.29

1.30-1.49

1.50-1.69

1.70+

Survival of Elderly Subjects in CHSby Baseline Creatinine Level

Creatinine

1.1 1.3 1.5 1.7

Rel

ativ

e R

isk

0

1

2

3

4

5

UnadjustedAdjusted

Relative Risk for Cardiovascular Disease: Unadjusted and Fully Adjusted Models

Preventing Decline in Renal Function

Hypertension Control Angiotensin Converting Enzyme Inhibitors/

Angiotensin Receptor Blockers Control of Diabetes Lipid Reduction Smoking cessation- smoking is associated with

a faster decline, no intervention studies Low Protein Diet- falling out of favor

Multifactorial Intervention Slows Progression to Nephropathy in Diabetes: Steno Study

160 Type 2 Diabetes, stratified by level of proteinuria (30-100mg/day, 101-300 mg/day)

Randomized to standard or intensive management Intensive Therapy: behavioral modification (diet,

exercise, smoking cessation) and pharmacologic therapy in step-wise fashion

Primary endpoint was nephropathy (albumin excretion rate >300mg/24 hours)

Lancet 1999

Steno Study Treatment GoalsStandard Intensive

Systolic BP <160 <140

Diastolic BP <95 <85

HbA1c <7.5 <6.5

Triglycerides <2.2 (195 mg/dl) <1.7 (150 mg/dl)

Total chol <6.5 (250 mg/dl) <5.0 (193 mg/dl)

HDL >0.9 (35 mg/dl) >1.1 (42 mg/dl)

ACEI irrespectiveof BP No YesASA in PVD No Yes

ASA in ischemia Yes Yes

Antioxidant vitamins No Yes

Steno Results

8 patients (11%) in intensive vs 19 (25%) in standard therapy grouped developed overt nephropathy after 4 years (p=0.01)

No patient developed end-stage renal disease Lower risk of progression, but not development of

retinopathy Lower risk of progression of autonomic neuropathy No difference in CVD events, though numbers were small Trend towards fewer patients developing a drop in AAI