Chapter 18: Acute Kidney Injury in the Elderly

Mitchell H. Rosner

Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia

Acute kidney injury (AKI), as defined by the precip-

itous decline in GFR, is frequently encountered in

the elderly. The effect of advancing age in decreas-

ing renal reserve and the associated comorbid con-

ditions of elderly patients increase the risk for the

development of AKI. Although studies describing

the incidence of AKI in this population are difficult

to compare because the definitions of AKI vary dra-

matically from study to study, it is clear that the

elderly are at the highest risk for the development of

AKI. Indeed, Feest et al.

showed that there is a

three- to eight-fold, progressive, age-dependent in-

crease in the frequency of development of commu-

nity-acquired AKI in patients older than 60 yr of

age. The mean age of patients with AKI has in-

creased by 5 to 15 yr over the past 25 yr.

Groen-

eveld et al.

showed that the age-related yearly inci-

dence of AKI rose from 17 per million in adults

under age 50 yr to 949 per million in the 80 to 89 yr

age group. Although all causes of AKI are encoun-

tered in this age group, the frequency of prerenal

and postrenal etiologies is especially prevalent in

the elderly.

Furthermore, elderly patients are more

frequently subjected to invasive procedures and ex-

posure to multiple (and possibly nephrotoxic)

medications and to radiocontrast agents, all of

which increase the risk for AKI.

STRUCTURAL AND FUNCTIONAL

ALTERATIONS IN THE AGED KIDNEY

In the absence of a specific disease, the kidney un-

dergoes age-dependent structural and functional

alterations leading to a significant decrease in renal

mass, functioning nephron numbers, and baseline

kidney function.

Under normal conditions, these

changes can be functionally compensated for by ad-

aptations in renal hemodynamics to maintain a suf-

ficient GFR. However, in the setting of pathophys-

iologic challenges, the older kidney lacks sufficient

functional reserve and is more likely to develop

clinically relevant damage.

Although it has been

proposed that parenchymal loss in the aging kidney

directly confers a higher susceptibility to acute

damage, this is not supported by experimental data

in which the reduction in renal mass surprisingly

protected against ischemia/reperfusion injury in a

5/6 nephrectomy model.

Thus, cellular and molec-

ular alterations that occur with aging may be more

important than simply a loss in nephron numbers.

Lameire et al.

showed that, in combination with

dehydration, a disturbance in autoregulatory de-

fense mechanisms that would normally preserve

GFR and renal blood flow can, in the elderly kidney,

lead to ischemia and AKI. One hypothesis links

blunted nitric oxide (NO) production in the elderly

kidney to an increased risk for AKI.

For example,

studies in a rat model of gentamicin-induced AKI

show that an increased glomerular NO production

seems to protect renal function through its vasodi-

latory effects.

When old and young animals are

treated with equivalent doses of gentamicin, older

animals show more severe AKI that correlates with

a blunted stimulation in NO production.

Miura et

al.

have also hypothesized that, in addition to al-

teration autoregulation, aging tubular cells may be

more vulnerable to ischemic damage because cellu-

lar antioxidant defenses decline with age as well as

the fact that tubular cells have alterations in metab-

olism that render them more susceptible to injury

(such as an accelerated rate of ATP depletion caused

by mitochondrial alterations).

CAUSES OF AKI IN THE ELDERLY

In the elderly, AKI is often iatrogenic and multifac-

torial. Elderly patients show the same spectrum for

the causes of AKI as the general population. How-

Correspondence: Mitchell H. Rosner, Division of Nephrology,

University of Virginia Health System, Box 800133, Charlottesville,

VA 22908. Phone: 434-924-2187; Fax: 434-924-5848; E-mail:

[email protected]

American Society of Nephrology Geriatric Nephrology Curriculum

ever, specific differences in the incidences and presentation

make this group unique. For example, elderly patients are

more likely to have received multiple concurrent insults that

result in AKI.

Prerenal AKI

Prerenal AKI is the second most common cause of AKI in the

elderly, accounting for nearly one third of cases.

The main

cause of prerenal AKI is decreased perfusion to the kidney.

Although many of the causes of renal hypoperfusion can be

reversed with adequate fluid replacement, others progress to

acute tubular necrosis (ATN). Interestingly, the evolution to

ATN occurs more frequently in the elderly than in younger

patients.

Decreased perfusion to the kidney can develop from

decrease in cardiac output or effective circulating volume (sep-

sis, cirrhosis, nephrotic syndrome) or hypovolemia (gastroin-

testinal losses, bleeding, diuretic use, poor oral intake).

Dehydration is a common occurrence in the elderly, affect-

ing nearly 1% of hospital admissions in the elderly.

Risk fac-

tors for dehydration include acute febrile illnesses, polyphar-

macy (diuretics, laxatives, drugs that decrease appetite or level

of consciousness), and being bedridden. These patients often

present in AKI with significant hypernatremia and, if un-

treated, the condition has a very high mortality rate.

It may be difficult to make the diagnosis of hypovolemic

AKI in the elderly because the clinical signs and symptoms of

dehydration (such as tachycardia, skin tenting) are unreliable.

Furthermore, the traditional urinary parameters for differen-

tiating prerenal from intrinsic renal failure may simply reflect

age-related disturbances in tubular handling of sodium and

water as well as drug effects (diuretics). Thus, a high degree of

suspicion for prerenal etiologies must be entertained, and a

cautious trial of fluid therapy may be warranted. Because of the

high incidence of urinary incontinence, a foley catheter should

be placed to closely monitor urine output.

RENAL AKI

Numerous intrarenal causes of AKI can affect the elderly, of

which ATN is the most common. An exhaustive description of

these causes is beyond the scope of this chapter; however, those

causes that are more specifically relevant to the elderly popu-

lation are discussed below.

Renovascular Diseases

This group of etiologies includes any cause of acute obstruc-

tion of the renal vasculature. Thus, cholesterol embolization

after intravascular procedures or surgery or rarely acute renal

artery thrombosis may lead to this syndrome of AKI. Elderly

patients, by virtue for their increased burden of atherosclerotic

vascular disease and increased need for invasive procedures,

are at heightened risk.

Hemodynamically Mediated AKI

Direct interference with the protective autoregulatory mecha-

nisms of renal blood flow and GFR may precipitate AKI. Drugs

commonly prescribed to the elderly and known to impair renal

autoregulation or to interfere with the vasodilatory capacity

include nonsteroidal anti-inflammatory agents (NSAIDs), an-

giotensin-converting enzyme inhibitors (ACEi). and angioten-

sin receptor antagonists (ARB).

Well-known risk factors for NSAID-induced AKI include

age ⬎60 yr, atherosclerotic cardiovascular disease, pre-existing

chronic kidney disease (CKD), and renal hypoperfusion states

(sodium depletion, diuretic use, cirrhosis, congestive heart

failure, hypotension, volume depletion).

In one study,

NSAIDs accounted for 15.3% of all cases of drug-induced AKI

but accounted for ⬎25% of cases in those age ⬎65 yr.

should be recognized that there is little evidence of NSAIDs

impairing renal function in otherwise healthy elderly individ-

uals.

In the elderly, the frequency of AKI secondary to ACEi has

been estimated to vary between 6 to 38%.

In part, this may be

to the greater incidence of significant renovascular disease in

the elderly (either bilateral renal artery stenosis, or unilateral

stenosis in a solitary functioning kidney).

Acute Tubular Necrosis

Acute tubular necrosis is the most frequent cause of AKI in the

elderly, with an incidence ranging from 25 to 87%.

The in-

sults that lead to this condition include nephrotoxins (amino-

glycosides, radiocontrast agents), pigment-induced (rhabdo-

myolysis), and ischemia (sepsis, surgery). In older patients

with ATN, several chronic premorbid conditions such as con-

gestive heart failure, hypertension, and diabetes predispose to

the development of severe tubular injury. Elderly patients

more frequently undergo significant cardiovascular surgery

(aortic aneurysm repair, bypass surgery) that is associated with

a high risk for ATN. Elderly patients are more susceptible to

serious infections and the development of sepsis and multisys-

tem organ failure. In this setting, the development of AKI re-

quiring dialysis has an attendant mortality of ⬎80%.

Prevention of ATN requires careful attention to baseline

GFR. In the elderly, serum creatinine values may appear nor-

mal yet be associated with a significant decline in GFR. This

reliance on serum creatinine as a marker of renal function can

easily lead to inappropriate dosing of antibiotics and other

nephrotoxins. Thus, use of either the Cockroft-Gault or

Modification of Diet in Renal Disease (MDRD) equation to

estimate renal function is mandatory. When available, preven-

tative strategies such as intravenous hydration before radio-

contrast administration should be undertaken.

Acute Interstitial Nephritis

Elderly patients are at increased risk secondary to the large

number of medications that they may be taking. This may in-

clude herbal supplements and other over-the-counter medica-

tions. Given the complex comorbidities of elderly patients, it

2 Geriatric Nephrology Curriculum American Society of Nephrology

may be difficult to make the diagnosis of acute interstitial ne-

phritis (AIN) as the cause of AKI, and renal biopsy may be

required.

Glomerulonephritis

Elderly patients have a higher incidence of p-anti-neutrophil

cytoplasmic antibody (ANCA) and anti-glomerular basement

membrane (GBM) associated with rapidly progressive glomer-

ulonephritis (RPGN).

Although the same principles apply to

treatment of older adults with RPGN as with younger individ-

uals, caution in the use of immunosuppressant medications

such as corticosteroids, cytotoxic drugs, and plasmapheresis is

warranted given a much higher risk of opportunistic infections

and complications. The relative risk of death is 5.3 times higher

in patients ⬎60 yr compared with younger patients after ag-

gressive immunosuppression in the treatment of RPGN.

However, because of the potential for reversing AKI in some

forms of glomerulonephritis, one should not hesitate to per-

form a renal biopsy if indicated. The procedure does not carry

a higher risk in the elderly.

However, the presence of signifi-

cant glomerulosclerosis and arteriosclerosis in biopsy tissue

may render the interpretation of histologic findings more dif-

ficult.

POSTRENAL AKI

In two major series, the incidence of postrenal obstructive AKI

was 7.9 and 9% in patients over 65 and 70 yr, respectively.

1,4

The obstruction may be either intrinsic or extrinsic and can

occur at any level of the urinary tract. Among the causes of

lower urinary tract obstruction, the most common in males is

prostatic enlargement caused by benign prostatic hypertrophy

or carcinoma. The second most common cause in males is

urethral stricture disease often secondary to trauma. In fe-

males, the most common cause of postrenal failure is ureteral

obstruction caused by pelvic malignancy (invasive carcinoma

of the cervix). An uncommon cause of obstruction seen in the

elderly is caused by an inflammatory aortic aneurysm and can

be identified through proper imaging studies.

All elderly patients presenting with AKI require urethral

catheterization and ultrasonography to identify possible ob-

structive etiologies. False-negative ultrasonography is usually

only seen in those with very early obstruction or in those pa-

tients with significant retroperitoneal fibrosis that encases the

ureters and renal pelvis preventing dilation.

LABORATORY EVALUATION OF AKI IN THE

ELDERLY

The laboratory evaluation of AKI in the elderly patient is no

different than for other patients. Attention to the history and

physical examination is critical in narrowing the differential

diagnosis to potential etiologies and to specific laboratory or

imaging tests. As stated above, given the high prevalence of

obstructive causes for AKI in this group, ultrasonography is

mandatory. Microscopic examination of the urine for cellular

elements, casts, and crystals is also mandatory and can lead to a

proper diagnosis in a rapid, efficient manner. The finding of

pigmented granular casts in the urine is indicative of tubular

damage and supports the diagnosis of ATN. The appearance of

red blood cell casts in the urine indicates active glomerular

damage (glomerulonephritis) and warrants consideration of

whether a renal biopsy should be performed. Urine electro-

lytes, urine eosinophils, and serologic testing for glomerulone-

phritis should be used when appropriate. There are no specific

caveats for the elderly patient in this regard.

TREATMENT OF THE ELDERLY WITH AKI

In general, the treatment of AKI in the elderly follows the same

principles as for the general population. However, the decision

to initiate dialytic support in the very elderly with multiple

comorbidities and a very poor prognosis may be difficult. This

is especially true for those individuals with significant baseline

renal impairment where the likelihood of renal recovery may

be low. The decision to initiate dialysis in these patients re-

quires a coordinated discussion with family members, consult-

ing physicians and other care providers.

PREVENTION OF AKI IN THE ELDERLY

Given the morbidity and mortality associated with AKI, pre-

ventative strategies are clearly important. Tables 1 and 2 list

both general preventative strategies and exposure-specific

strategies that can be used in patients at risk for AKI.

Table 1. General approaches for the prevention of AKI

Avoidance of nephrotoxins

Recognition of potential nephrotoxic agents

Recognition of high risk patients and clinical settings

Avoidance of concomitant use of multiple nephrotoxins

Use of lowest dose and for shortest time possible

If applicable, monitoring of drug dose

Frequent monitoring of renal function

Maintain euvolemia

Minimization of nosocomial infection

Extracellular fluid expansion

(maintain good urine output, stable hemodynamics)

Avoid agents that impair renal blood flow autoregulation

(NSAIDS, ACE inhibitors, ARBs)

Pharmacologic interventions if applicable

Use of computer surveillance systems

Identify high risk patients and medications

Determine correct dose for GFR

American Society of Nephrology Geriatric Nephrology Curriculum 3

RECOVERY OF RENAL FUNCTION AND PROGNOSIS

OF AKI IN THE ELDERLY

A recent systematic review and meta-analysis of recovery of

kidney function after AKI in the elderly has shown that recov-

ery after AKI is approximately 28% less likely to occur when

the patient is older than 65 yr.

Whether these results are

caused by the effects of advanced age on the kidney itself or the

increased number of comorbidities (including baseline CKD)

in the elderly is not certain. Long-term recovery is also less

likely and it is believed that AKI in elderly more often results in

CKD.

The lower likelihood of renal recovery in the elderly

may be due to the effects of aging to impair the capacity for

kidney repair.

The capacity for renal epithelial cell prolifera-

tion declines with aging as does the function of progenitor and

stem cells that are critical for tubular repair.

Several other individual studies have not been able to show

that age is specifically associated with impaired renal recov-

ery.

Thus, in the individual patient, it may not be clear if age

is an independent predictor of a poor prognosis and other

comorbid conditions may play a more important role in driv-

ing the risk for poor outcomes.

CONCLUSIONS

For numerous reasons, elderly patients are at higher risk for the

development of AKI, and certain causes of AKI are more com-

monly seen in this group. In fact, there are more often multiple

etiologies of AKI in this age group. Diagnostic approaches to

AKI should focus on the most likely etiologies. Because of mul-

tiple factors, the likelihood of complete renal recovery is im-

paired in this group.

TAKE HOME POINTS

• Elderly patients are at higher risk for the development of AKI

• Specific hemodynamic, metabolic, and molecular changes lead to in-

creased susceptibility to injury in the aged kidney

• Certain causes of AKI are more common in the elderly: postrenal

obstructive disease, ischemic ATN, and hemodynamically mediated

AKI

• Multiple etiologies are often operative in the development of AKI

• Diagnostic and therapeutic issues in AKI are no different for the elderly

patient as for the general population

• The outlook for renal recovery is likely impaired in the elderly patient

DISCLOSURES

None.

REFERENCES

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Table 2. Examples of specific renal protective strategies

Exposure Strategy

Radiocontrast agents Intravenous hydration (normal saline)

Intravenous sodium bicarbonate (?)

N-acetylcysteine

Vitamin C

Iso-osmolar contrast

Aminoglycoside

antibiotics

Once-daily dosing

Monitoring of drug levels

Tumor lysis (uric acid) Allopurinol/rasburicase

Intravenous hydration/urine alkalinization

Ethylene glycol

ingestion

Ethanol/fomepizole

Hemodialysis

Rhabdomyolysis Intravenous hydration/urine alkalinization⫾

mannitol

Methotrexate Intravenous hydration/urine alkalinization

Acyclovir Intravenous hydration

Calcineurin inhibitors Monitor drug levels ⫾ calcium-channel

blockers

Amphotericin B Use of lipid formulation

4 Geriatric Nephrology Curriculum American Society of Nephrology

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American Society of Nephrology Geriatric Nephrology Curriculum 5

REVIEW QUESTIONS: ACUTE KIDNEY INJURY IN

THE ELDERLY

1. Which one of the following statements is true?

a. Serum creatinine in the elderly patient (age ⬎65 yr) is an

accurate reflection of GFR and can be used to predict the

risk for acute kidney injury

b. Aggressive immunosuppression for elderly patients with

glomerulonephritis is associated with a five-fold higher

risk of death than in younger patients

c. Acute interstitial nephritis is less commonly seen in elderly

patients than in younger cohorts.

d. The likelihood of complete renal recovery after acute kid-

ney injury in the elderly is similar to that in the general

population

e. The diagnostic ability of granular, pigmented casts for

acute tubular necrosis is poor in the elderly patient

2. A 76-yr-old male presents to the emergency department with

complaints of lethargy and fatigue. Laboratory work reveals a

serum creatinine of 6.5 mg/dl, blood urea nitrogen of 104 mg/

dl, and serum electrolytes are within normal limits. Recent

history reveals that he just began furosemide 40 mg daily for

complaints of dyspnea on exertion. Prior laboratory work 1 wk

ago was notable for a serum creatinine of 1.9 mg/dl (baseline

value). Which one of the following steps is indicated in the

further evaluation of acute kidney injury in this patient?

a. Renal biopsy

b. Urine electrolytes and calculation of fractional excretion

of sodium

c. Urgent initiation of hemodialysis

d. Intravenous hydration with normal saline at a rate of 500

ml/h

e. Placement of a foley catheter and urgent renal ultrasound

3. Which statement regarding recovery of renal function after

acute kidney injury in the elderly is correct?

a. The prognosis for renal recovery in the elderly is similar to

that of the general population

b. Renal function never recovers to baseline after an episode

of acute kidney injury in the elderly

c. The capacity for renal epithelial cell proliferation declines

with aging as does the function of progenitor and stem

cells that are critical for tubular repair

d. Elderly patients with acute kidney injury have a 60%

higher rate than the general population of requiring long-

term dialysis

6 Geriatric Nephrology Curriculum American Society of Nephrology