노년기 약물 처방시 고려사항; 신기능의 변화

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노년기 약물 처방시 고려사항; 신기능의 변화

가톨릭대학교 의과대학 내과학교실

김 석 영

N ational Inst it ut e on A ging, 2007

(2)

St ages of Chronic Kidney Disease (CKD)

N KF/K-DOQI. Am J Kidney Dis 39 (Suppl 2), 2002

St age Descr ipt ion GFR

1 Kidney dam age w it h norm al or ↑ GFR

≥ 90

2 M ild ↓ GFR 60-89

3 M oderat e ↓ GFR 30-59

4 Sever e ↓ GFR 15-29

5 Kidney failure ≤ 15 or dialysis

Prevalence of CKD in the U.S.

Coresh J, et al. JAM A 298:2038, 2007

• At least 10% of the adult U.S. population has CKD ? often not diagnosed

• Only 20% of CKD patients are aware of the diagnosis

0 2 4 6 8 1 0

1 2 3 4

CKD Stage

Prevalence(%)

Prevalence of CKD in the U.S.

Coresh J, et al. JAM A 298:2038, 2007

0 10 20 30 40

20-39 40-59 60-69 70+

A g e(Y ears)

Percent

Stag e 1 Stag e 2 Stag e 3 Stag e 4

1994 -2004: Prevalence of CKD in those > 70 yrs of age ↑ 38% → 47%

The A xis of Evil: CKD & CV D

2.1 3.7

11.3 21.8

36.6

0 5 10 15 20 25 30 35 40

> 60 45-59 30-44 15-29 < 15 Estimated GFR(ml/ min/ 1.73²) Rate of CV Events Per 100 pt*yr

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A cute Kidney Injury in t he Elderly

• AKI is more comm on in older patients

• AKI is a risk factor for CV event including mortality

• CV risk factors →↑ risk of AKI in the elderly

• AKI is a risk factor for subsequent CKD

M any predisposing fact ors of A KI in t he Elderly

• Reduced renal blood flow

• Reduced GFR

• Volume contraction

• M edications:

– N SAID. ACEI/ARB, Diuretics

• Surgery

• Arrhythm ias

• Sepsis

• Toxins, including drugs

• Thromboembolic disease

• Obstruction

(4)

Effect of A CEI on A ge-Related CKD

Anderson S, et al. Am J Physiol 267:F35, 1994

0 5 10 15 20 25 30 35 40

6 10 16 18 24 26 32

M onth of Age

Ualb(mg/day) A C EI

N o R x

M echanism s of Prot ect ion w it h A CEI/A RB in A ging

• ↓ Glomerular hypertension

• ↓ TGF b

• ↓ PAI-1

• ↑ Peritubular capillary density

• ↑ N O synthesis

• ↓ Endothelial dysfunction

• ↓ ECM proteins

• ↓ M itochondria dysfunction

• ↓ Oxidative stress

• ↓ Apoptosis

Det erm inant s of Decreased GFR in A ging H um ans

Hoang K, et al. Kidney Int 64:1417, 2003

• Studies in healthy renal transplant donors, aged 23 to 69 years

• M easurements of GFR, determ inants of GFR, and morphometry

• Results: Age-associated decrease in GFR was due to reduction in renal plasma flow, and in Kf (ultrafiltration coefficient)

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M echanism s of V ascular and Renal A ging

Barton M . N ephrol Dial Transpl 20:485, 2005

Com plicat ions of CKD

• The patient with CKD is less able to:

– Excrete water, sodium , potassium , phosphate

– Retain water or sodium

– Defend against m etabolic acidosis – Excrete phosphate, form Vitamin D, limit

PTH

– M ake erythropoeitin

– Excrete drugs and/or their m etabolites

Other Consequences in Older A dults

Campbell KH, et al. Curr Opin N ephrol HTN 17:298, 2008

• ↑ risk of non-cardiovascular m ortality

• Greater loss of lean m uscle m ass (men)

• Greater loss of bone m ineral density (m en)

• ↑ risk of hip fracture (wom en)

• Independent risk factor for falls and fractures in patients with osteoporosis

• ↑ risk of developing functional lim itations

Quant ificat ion of Kidney Function

• Serum creatinine : insensitive

– does not ↑ until > 50% of GFR is lost

• Creatinine clearance (Ccr)

– expensive & rarely done correctly

• Estim ation of Ccr(eGFR) from the serum creatinine

– Cockcroft-Gault formula:

(140-age)(wt in kg)

GFR = --- [x 0.85 for female]

Cr x 72 – M DRD form ula

eGFR = 186.3 x (Cr^)-1.154x (age)^-0.203x 1.212 (if AA) x 0.74 (if female)

Caveats to eGFR

• An estimate based on population data

– not the patient’s

actual GFR

• N either C-G nor M DRD has been validated in adults > age 70

• M DRD is not reliable when used in patients:

– GFR > 60 m l/ min/1.73 m2

– rapidly changing creatinine levels (e.g., AKI in ICU) – extremes in muscle m ass

• e.g. cachexia, paraplegia – Under age 18

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Cyst at in C

Stevens et al, N EJM 354:2473, 2006; and others

• N ew indicator of kidney function

– better predictor of GFR than creatinine

• Freely filtered

/ not reabsorbed / no tubule secretion

• Useful in the elderly

– not influenced by age, gender, or muscle mass

• N ot yet clear whether useful for estim ating eGFR

Cyst at in C and M ort alit y Risk in t he Elderly

Shlipak M G, et al. JASN 17:254, 2006

• Longitudinal cohort study of healthy elderly

• 3075 subjects, ages 70-79, without disability

• Assessed mortality risk by quintile of serum cystatin C level

• Cystatin C = strong, independent risk fact or for m ortality

0 1 2 3 4 5 6

Cystatin C Quintile

Mortality Risk, % per Year

The A ging Kidney

• Risk Factors for Age-Associated CKD

– M ale gender

– Hypertension

– Dietary and pharmacologic factors

– Sm oking and atherosclerosis

Increase in M icroalbum inuria w it h A ge

Jones CA, et al. Am J Kidney Dis 39:445, 2002

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The A ging Kidney

• Risk Factors for Age-Associated CKD

– M ale gender

– Hypertension

Baltimore Longitudinal Study on Aging

? Significant negative correlation (p < 0.0001) between m ean blood pressure and decline in CCr with age

Lindeman RD, et al. Kidney Int 26:861, 1984

Renovascular Disease

• Primarily a disease of the older population

• Presentation, diagnosis, and treatment are, in principle, no different in older than in younger population

• Risk factors increase with increasing age:

– Smoking – Atherosclerosis

– Thromboembolic disease – Dissecting aneurysm – Vasculitis

– N eurofibromatosis

Risk Fact ors for Elevat ed SCr in A ging

Fox CS, et al. JAM A 291:2819, 2004

Framingham Study

2.36 2.6

1.57 1.42

0.8

0 0.5 1 1.5 2 2.5 3

A g e D iab etes H TN Sm o kin g H D L

Odds Ratio

Electrolyte Disorders in the Elderly

• In general there are no specific changes in serum electrolyte levels in healthy elderly individuals

• However, because of decreasing ability of the aging kidney to adapt to various stimuli, elderly patients are more

susceptible to development of electrolyte disorder

Electrolyte Disorders in the Elderly

• Im paired N a excretion - Volume overload

• Im paired N a retention - hypovolem ia

• Im paired concentrating capacity - hypernatremia

• Im paired diluting ability - hyponatremia

• Decreased K stores, diuretics - hypokalemia

• Decreased aldo response - hyperkalemia

• Predisposition to Vitamin D deficiency - Calcium. Phosphate

CKD: Baseline Evaluat ion

• Assess eGFR (formula).

• Clinical evaluation

– presence of primary disorders, volume status, blood pressure, nephrotoxic drugs (N SAIDs)

• Adjust drug doses for lower GFR

• “Start low and go slow”

– Start drugs at lowest possible dose (higher risk of adverse effects)

• ? Screening for microalbuminuria

– ↑ incidence in the elderly

– ↑ incidence in diseases of the elderly (hypertension, CHF) – N o clear data or guidelines as to how this would change outcome

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Int erventions

• Progression of age-related nephropathy m ay be slowed experimentally by:

– Restriction of intake of total calories, protein, or sodium

– Renin-angiotensin system inhibition – Antioxidant therapy (e.g. taurine) – AGE inhibition

• Clinically - ?

Slow ing t he Progression of CKD

• Educate patient and family about CKD

• Remove/avoid nephrotoxins

– including N SAIDs, contrast, gadolinium…

• Aggressive BP control (< 130/80 mmHg)

• ACEI or ARB as first line therapy, unless contraindicated,

– esp. if diabetic or proteinuric

• Possibly helpful:

– Lipid control (LDL < 100) – Smoking cessation

Unansw ered Quest ions

• Is the age-related decline in GFR truly CKD?

– M any with low GFR will never progress, especially in the absence of diabetes or proteinuria

– M ost will die with low GFR, not because of it

Sum m ary

• N ormal aging is accompanied by a various but often substantial loss of renal function

• Rate of decline is hastened by smoking and vascular disease

• In itself, this decline poses little danger however it renders the aging kidney more vulnerable to acquired insults (volume depletion, nephrotoxins, contrast dye)