Given the history and laboratory data, what is the likely source of T.G.’s AKI?

The source of AKI in this situation is likely multifactorial (Table 29-2). Low renal

perfusion secondary to low ejection fraction can result in prolonged renal ischemia.

Second, T.G. has received 1 week of gentamicin, a well-known nephrotoxic

antibiotic. The risk factors for developing aminoglycoside nephrotoxicity are listed

in Table 29-6. The latest gentamicin trough concentration of 6 mg/L is far higher than

the target value of less than 1 mg/L for a traditional 3-times-daily dosing regimen

used for synergy for bacterial endocarditis.

80 Given the laboratory data (Table 29-3)

and the clinical course of prolonged hypotension, vasopressor, and aminoglycoside

administration, nonoliguric ATN is the most likely diagnosis.

PRESENTATION

CASE 29-6, QUESTION 2: How does aminoglycoside-induced ATN present, and what are the mechanisms

of toxicity?

Table 29-6

Risk Factors for Developing Aminoglycoside Nephrotoxicity

Patient Factors

Elderly

Underlying renal disease

Dehydration

Hypotension and shock syndromes

Hepatorenalsyndrome

Aminoglycoside Factors

Aminoglycoside choice: gentamicin > tobramycin > amikacin

Therapy >3 days

Multiple daily dosing

Serum trough >2 mg/L

Recent aminoglycoside therapy

Concomitant Drug Therapy

Amphotericin B

Cisplatin

Cyclosporine

Foscarnet

Furosemide

Radiocontrast media

Vancomycin

T.G. illustrates the typical presentation of aminoglycoside-induced nephrotoxicity.

Generally, the onset occurs after 5 to 7 days of treatment and presents as a hypoosmolar, nonoliguric renal failure with a slow rise in SCr.

81 Because of the tubular

necrosis that occurs, the urinalysis is often positive for low-molecular-weight

proteins, tubular cellular casts, epithelial cells, WBCs, and brush-border cells.

82

T.G.’s plasma and urinary laboratory indices are consistent with those listed for

ATN in Table 29-3.

The mechanism of aminoglycoside-induced ATN is complex. Approximately 5%

of filtered aminoglycoside is actively reabsorbed by the proximal tubule cells. These

agents are polycationic and bind to the negatively charged brush-border cells within

the tubule lumen. Once attached, these agents undergo pinocytosis and enter the

intracellular space, setting off complex biochemical events that result in the

formation of myeloid bodies. With continued formation of myeloid bodies, the brushborder cells swell and burst, releasing large concentrations of aminoglycoside and

lysosomal enzymes into the tubule lumen, thereby beginning a cascade of further

tubular destruction.

81,83 The following rank order of nephrotoxicity has been collated

from human and animal data: neomycin > gentamicin > tobramycin > amikacin >

netilmicin > streptomycin.

82

EXTENDED-INTERVAL DOSING

CASE 29-6, QUESTION 3: Is “extended-interval” aminoglycoside dosing less nephrotoxic than multiple daily

dosing regimens?

Extended-interval aminoglycoside dosing entails the administration of one large

daily aminoglycoside dose instead of multiple daily dosing. This dosing scheme

takes advantage of the concentration-dependent killing activity and post-antibiotic

effect observed with aminoglycosides while minimizing time-dependent toxicity.

p. 644

p. 645

The net effect of this dosing scheme, purportedly, is greater efficacy with reduced

toxicity. Aminoglycoside nephrotoxicity is a function of drug exposure, and it might

be minimized with extended-interval dosing because of saturable uptake kinetics in

the proximal tubule. That is, only a maximal amount of aminoglycoside is transported

into the tubule cell, no matter how much aminoglycoside is present in the tubule.

Consequently, once saturation occurs, the remaining aminoglycoside concentration

passes through the proximal tubule without being absorbed, and is excreted in the

urine. Accumulation is therefore averted.

84 This concept is supported by studies

demonstrating that continuous-rate gentamicin infusions, which produce sustained

low plasma concentrations, result in greater proximal tubule uptake and

nephrotoxicity than extended-interval regimens. This is probably because the

achieved drug concentrations are well below those required to saturate the uptake

mechanism. Extended-interval dosing results in very high peak concentrations to

improve efficacy and generally undetectable trough concentrations before the next

dose, thus minimizing accumulation. Numerous clinical trials and meta-analyses have

compared the efficacy and toxicity of extended-interval aminoglycoside dosing with

conventional multiple daily dosing regimens. For endocarditis, aminoglycosides,

such as gentamicin 1 mg/kg q8 hours or 3 mg/kg once daily, adjusted for renal

function are recommended by the American Heart Association for the management of

selected cases of bacterial endocarditis for their synergistical activity with the βlactams. The extended interval dosing is less well studied for endocarditis.

80

In

summary, extended-interval aminoglycoside dosing appears to result in similar or

greater efficacy, with similar or reduced toxicity. This dosing schedule is also less

costly when considering therapeutic drug monitoring, preparation, and administration

costs. Although the typical extended interval in patients with normal renal function is

dosing every 24 hours, the interval may have to be prolonged to several days in

patients with renal failure.

Drug-Induced Acute Interstitial Nephritis

Drug-induced AIN accounts for approximately 1% to 3% of all AKI cases.

85–89 A

variety of antibiotics, such as penicillins, cephalosporins, quinolones, particularly

ciprofloxacin, sulfonamides, and rifampin, as well as NSAIDs, loop diuretics,

thiazide-like diuretics, and proton pump inhibitors, have been implicated as common

drug causes of AIN. The pathophysiology of this reaction is not well understood; it is

suspected that either humoral or cell-mediated immune mechanisms or both are

involved.

90 Humoral immune reactions occur within minutes to hours of drug

exposure and involve the drug or its metabolite acting as a hapten that binds to host

proteins, making them antigenic. The drug–protein antigens become lodged in the

renal tubules, which initiate the inflammatory cascade. Cell-mediated injury can

occur days to weeks after drug exposure and is identified by the presence of

mononuclear inflammation and the lack of detectable immune complexes. This

suggests a delayed hypersensitivity rather than a direct cytotoxic effect from a given

drug. Both immune mechanisms probably contribute to the development of druginduced AIN.

PENICILLIN-INDUCED ACUTE INTERSTITIAL NEPHRITIS

CASE 29-7

QUESTION 1: J.S. is a 50-year-old Hispanic woman (height = 5 feet, 3 inches; weight = 160 pounds), who

exhibited cellulitis 3 days after a car door was closed on her right hand. She was admitted to the hospital, where

blood and wound cultures were found to be positive for methicillin-sensitive Staphylococcus aureus. She

received 2 full days of nafcillin 2 g IV every 4 hours before being discharged to complete a 14-day course with

dicloxacillin 500 mg PO 4 times daily (QID). Ten days after discharge, J.S. returned to the emergency

department complaining of malaise, fever, diffuse rash, hematuria, and reduced urine output. The following

laboratory values were significant:

BUN, 39 mg/dL

SCr, 2.3 mg/dL

WBC count, 18,500 cells/μL with 18% eosinophils

The urinalysis was positive for elevated specific gravity, WBC, RBC, eosinophiluria, and a FENa of 3%.

What objective data suggest drug-induced AIN?

J.S.’s onset of symptoms suggests antibiotic-induced AIN. As illustrated by this

case, the median onset of penicillin-induced AIN generally occurs 6 to 10 days after

drug exposure. Hallmark symptoms of antibiotic-associated AIN include fever,

macular rash, and malaise. Fever is present in nearly all patients with antibioticinduced AIN, and rash occurs in 25% to 50% of patients. In contrast, NSAIDs,

proton pump inhibitors, and rifampin are less commonly associated with rash, fever,

eosinophilia, and the onset of AIN may occur several weeks to months or longer

following drug exposure.

89,90 J.S.’s objective laboratory data that suggest AIN

include azotemia, elevated SCr, proteinuria, cellular urinary sediment, eosinophilia,

and eosinophiluria. Her FENa of 3% suggests intrinsic renal disease, and her

eosinophiluria and eosinophilia indicate an immune-mediated allergic reaction.

Drug-induced AIN is generally nonoliguric, but oliguria can develop in severe cases

of AIN.

CASE 29-7, QUESTION 2: How should J.S.’s penicillin-induced AIN be treated?

The dicloxacillin should be stopped immediately because most patients recover

normal kidney function once the offending agent is discontinued. Clindamycin or

doxycycline may be chosen to finish the course of treatment for cellulitis. However,

J.S. has completed 12 out of 14 days of antibiotic therapy and alternate agents would

be optional. General supportive measures that maintain fluid and electrolyte balance

are necessary. Renal recovery may take weeks to months. Corticosteroids have been

used with variable results to shorten the duration of AKI, but no clinical guidelines

have been developed to delineate when to administer them and for how long. Some

clinicians prefer to administer prednisone 1 mg/kg for 7 days and then gradually

taper the dose during the next several weeks. The response to corticosteroids may be

delayed or absent in some patients. Dialysis may be needed in patients who are

oliguric, but it is usually not required for those who are nonoliguric. The clinician

should document J.S.’s allergic reaction to penicillins in her medical record, and not

rechallenge the patient to antibiotics with similar chemical structures because

repeated exposure is likely to result in similar reactions.

POSTRENAL ACUTE KIDNEY INJURY

Any condition that results in the obstruction of urine flow at any level of the urinary

tract is termed postrenal AKI. Common causes of postrenal AKI are nephrolithiasis

(stone formation), crystal formation, underlying malignancies of the prostate or

cervix, prostatic hypertrophy, or bilateral ureter strictures. Conditions that result in

bladder outlet obstruction (e.g., prostatic hypertrophy) are the most common causes

of postrenal AKI. The onset of signs and symptoms is generally gradual; it often

presents as decreased force of urine stream, dribbling, or polyuria. Drugs can also

result in insoluble crystal formation in the urine and should be included in the

differential diagnosis.

p. 645

p. 646

Table 29-7

Risk Factors for Nephrolithiasis

Low urine volume

Hypercalciuria

Hyperoxaluria

Hyperuricosuria

Hypercitruria

Chronically low or high urinary pH

Nephrolithiasis

Kidney stones generally consist of uric acid, cystine, struvite (also called magnesium

ammonium phosphate or triple phosphate nephrolithiasis), and calcium salts. Of

these, calcium stones are by far the most prevalent.

91