Managing Chronic Kidney

Disease in the Elderly

Veteran
Ann M. OHare, MA MD
Staff Physician, VAPSHCS
Assistant Professor of Medicine
University of Washington

For Ann OHares financial disclosure statement:

http://depts.washington.edu/greccva/OHare_Disclosure.doc

Generalizability of RCTs

Gross, C. P. et. al. Ann Intern Med 2002;137:10-16

RCTs in high impact medical

journals

Van Spall, JAMA 2007

Mean age of participants in heart

failure trials

Heiat et al, Archives of Internal Medicine, 2002

Exclusion criteria of heart failure

trials

Acute MI
A total of 214 trials met inclusion criteria,
involving 150,920 study subjects.
Over 60% of trials excluded persons over
the age of 75 years.
Studies published after 1980 were more
likely to have age-based exclusions
compared with studies published before
1980
Gurwitz, JAMA, 1992

Cancer treatment trials

Hutchins, NEJM 1999

Exclusion of elderly in clinical

trials
National Institutes of Health Revitalization
Act of 1993 (Public Law 103-143)
Requirements for the inclusion of women and
minorities in clinical trials but not the elderly

Randomized Aldactone Evaluation Study

(RALES)

Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
N Engl J Med 1999;341:709-717. [

Rates of spironolactone
prescription

Juurlink et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
N Engl J Med. 2004 Aug 5;351(6):543-51.

Rates admission for hyperkalemia

Rates of death

Action to Control Cardiovascular

Risk in Diabetes (ACCORD)
10,251 adults with established type 2
diabetes
Aged 40 to 82 (average age 62)
had diabetes for an average of 10 years
either already had diagnosed CVD or they
had at least two CVD risk factors.

Chronic kidney disease

Levey et al, Annals of Internal Medicine, 2003

Prevalence of Chronic Kidney Disease (CKD) Stages by Age Group in NHANES

1988-1994 and 1999-2004

Coresh, J. et al. JAMA 2007;298:2038-2047.

Copyright restrictions may apply.

CKD is common in the elderly.

Figure 1. Prevalence of low estimated GFR (eGFR) by age group

O'Hare, A. M. et al. J Am Soc Nephrol 2006;17:846-853

Copyright 2006 American Society of Nephrology

In VA 75-85 group is largest

Adapted from OHare et al JASN 2007

High prevalence of comorbidities

Practice guidelines

Framework

Can existing guidelines for the management of CKD be generalized

to these older patients?
What is the strength of evidence?
Does the evidence pertain specifically to older patients with CKD?
What are the characteristics of patients enrolled in clinical trails?

If not, can the available evidence reasonably be extrapolated to older

patients?
Is there any reason to expect that real and perceived benefits of an
intervention might differ by age?
Does CKD have similar features in older and younger patients?
Does CKD have similar clinical implications in older and younger patients?

Are the risks of the intervention comparable in older and younger patients?
Do the adverse effects of the intervention differ by age?
Do similar adverse effects have different implications for older and younger
patients?

What is the quality of the

evidence?
Figure 1. Number of randomized controlled trials (RCT) published in nephrology and 12 other specialties of
internal medicine from 1966 to 2002

Strippoli, G. F. M. et al. J Am Soc Nephrol 2004;15:411-419

Copyright 2004 American Society of Nephrology

Figure 2. Percentage of RCT versus total citations in nephrology and 12 other specialties of internal medicine
from 1966 to 2002

Strippoli, G. F. M. et al. J Am Soc Nephrol 2004;15:411-419

Copyright 2004 American Society of Nephrology

Early treatment can make a

difference
100
No Treatment
Current Treatment

GFR (mL/min/1.732)

Early Treatment

10

Kidney Failure
0

7
Time (years)

11

Strong evidence: the example

of ACE inhibitors
Patients with diabetic kidney disease, with or without
hypertension, should be treated with an ACE inhibitor or an ARB
ACE inhibitors and ARBs are effective in slowing the progression of
kidney disease with microalbuminuria due to type 1 and type 2
diabetes (Strong).
ACE inhibitors, ARBs, and nondihydropyridine calcium-channel
blockers have a greater antiproteinuric effect than other
antihypertensive classes in diabetic kidney disease (Strong).
Patients with nondiabetic kidney disease and spot urine total
protein to creatinine ratio 200 mg/g, with or without
hypertension, should be treated with an ACE inhibitor or ARB.
ACE inhibitors are more effective than other antihypertensive agents
in slowing the progression of most nondiabetic kidney diseases
(Strong). The beneficial effect is greater in patients with higher levels
of proteinuria (Strong).

Recommendations for clinical

performance measures
GUIDELINE 8
All patients with diabetic kidney disease should be
treated with either an ACE inhibitor or an ARB (Guideline
8.2), unless there is a documented contraindication in
the medical record (such as pregnancy or a history of
allergy; see Table 124).
GUIDELINE 9
All patients with nondiabetic kidney disease and spot
urine total protein-to-creatinine ratio 200 mg/g) should
be treated with either an ACE inhibitor or an ARB
(Guideline 9.2), unless there is a documented
contraindication in the medical record (such as
pregnancy or a history of allergy; see Table 124).

Adherence to treatment guidelines

room for improvement

Percent of patients

The percentage of diabetic CKD patients receiving ACE-Is/ARBs

has been slow to improve

USRDS ADR, 2007

Enrollment characteristics of trials of ACE

or ARB to slow progression of CKD
ACE DM
1

ACE DM 2

ARB DM
II

ACE or ARB
non-diabetic
CKD

All

Number of studies

11

31

Number of patients

775

4,941

4,267

6,451

16,434

Explicit upper age exclusion, %

3 (49-57)

5 (50-80)

3 (70-80)

7 (65-70)

18 (58%)

Maximum age of participants <70*

4 (67%)

3 (27%)

3 (60%)

7 (78%)

17 (55%)

Comorbidity exclusion, %

3 (50%)

9(82%)

4 (80%)

8 (89%)

24 (77%)

Weighted mean age, range

33.7
(28.9-39)

63.7 (4470.2)

59.4
(58.6-60)

63.3 (45.370.2)

60.8

2004 KDOQI guidelines on Hypertension and Anti-hypertensive agents in CKD; 2007 KDOQI guideline on Diabetes
and Chronic Kidney Disease

Scatter plot of mean age by

number of participants

Mean weighted age 60.8 yr

ALLHAT

ALLHAT differs in some important ways from other studies of

antihypertensive agents in CKD.
First, the ACE inhibitor and dihydropyridine calcium-channel
blocker were prescribed without a diuretic. By contrast, other studies
in CKD have compared classes of antihypertensive agents usually
prescribed in combination with a diuretic.
Second, the risk of kidney failure was lower than observed in other
studies in CKD.
Third, proteinuria was not measured in ALLHAT, either in baseline
or in follow-up. By contrast, most studies in CKD have included
patients with proteinuria.
Thus, differences between ALLHAT and other studies in CKD may
be due to the study design and the type of patient enrolled, rather
than true differences in efficacy of combinations of
antihypertensive agents used in CKD in slowing progression of
kidney disease.

Risk for end-stage renal disease (ESRD) (A), combined outcome of doubling of
serum creatinine or ESRD (B), or relative risk for these outcomes (CandD) in
patients taking angiotensin-converting enzyme inhibitors (squares) and controls
(circles), according to baseline urinary protein excretion

Jafar, T. H. et. al. Ann Intern Med 2001;135:73-87

 It is the opinion of the Work Group that the

ALLHAT results do not rule out a beneficial
effect of ACE inhibitors in nondiabetic
kidney disease, particularly in patients with
proteinuria. Instead, the Work Group
concluded that ACE inhibitors should be
used to delay the progression of most
nondiabetic kidney diseases.

Prevalence of Chronic Kidney Disease (CKD) Stages by Age Group in NHANES

1988-1994 and 1999-2004

Coresh, J. et al. JAMA 2007;298:2038-2047.

Copyright restrictions may apply.

CKD phenotype in older

patients
NHANES 99-04: inclusive of patients 20
and older with a measured serum
creatinine and single spot urine albumin
and creatinine measurement (n=13,011)
CKD (n=1,525):
eGFR<60
eGFR>=60 with ACR>=200 mg/g

OHare et al, unpublished work

70.2 yr
59.7 yr
52.4 yr

OHare et al, unpublished work

Burden of co-morbidity

OHare et al, unpublished work

162,277 veterans with an

eGFR<60 or ACR>=200mg/g

Summary patients
The vast majority of older individuals with CKD
do not have proteinuria and do not have
diabetes.
More than half of all non-proteinuric diabetic and
non-diabetic CKD occurs in those 70 or older.
Older patients with CKD have a higher
prevalence of co-existing cardiovascular disease
compared with their younger counterparts.

Summary trials
Most trials of ACE/ARB conducted among
populations with diabetes
Most have an upper age exclusion
Most have not enrolled participants older than 70
ALLHAT included the largest number of
participants (with and without diabetes) and had
the highest mean age and was a negative trial
ALLHAT participants accounted for 58% of all
participants in trials of non-diabetic CKD

Background considerations in evaluating

benefits of ACE/ARB in elderly
We know very little about how the course of CKD varies
with age. CKD progression may be slower in the elderly
though this may reflect the higher prevalence of nonproteinuric CKD.
It is unclear that the same proxy outcomes are
appropriate in elders (e.g. development of albuminuria in
patients with diabetes).
Limited life expectancy. Competing risk of death is much
higher in older compared with younger adults with CKD.
Higher prevalence of competing co-morbid conditions
and polypharmacy in older patients with CKD may
modify the benefits of ACE or ARB.

Rate of change in eGFR

Hemmelgarn et al, Kidney International Kidney Int. 2006 Jun;69(12):2155-61.

Absolute risk of ESRD decreases with

age among patients with similar level of
eGFR
Figure 2. Baseline eGFR threshold below which risk for ESRD exceeded risk for death for each age group

O'Hare, A. M. et al. J Am Soc Nephrol 2007;18:2758-2765

Copyright 2007 American Society of Nephrology

Do the real and perceived risks

of treatment differ by age?
Side effect profile of ace inhibitors in older
patients is largely unstudied.
Burden of a given side-effect may differ by
age (e.g. hyperkalemia may prompt
hospital admission vs. outpatient
treatment in a frail older patient).
Multiple comorbidities and polypharmacy
so common in the elderly may complicate
the burden and risks of any intervention.

What can primary care

providers do?