723

C HAP T E R

45 Acute Renal Failure

WILLIAM DAGER AND ANNE SPENCER

mating the clearance of medications associated with a high risk

KEY CONCEPTS of toxicity by the patient and the CRRT procedure.

 Acute renal failure (ARF) is a common complication in the hos-

pitalized patient and is associated with a high mortality rate.
The development of acute renal failure (ARF) presents a difficult
 ARF is predominantly categorized based on the anatomic area challenge to the clinician because there are many possible causes and
of injury or malfunction: (a) prerenal—decreased renal blood the onset is often asymptomatic. In the ambulatory setting, patients
flow, (b) intrinsic—a structure within the kidney is damaged, may not notice ARF symptoms for days to weeks. Changes in clinical
and (c) postrenal—an obstruction is present within the urine and laboratory markers of its presence can be subtle and are often
collection system. overlooked. Despite its often insidious presentation, the conse-
quences of ARF can be serious, especially in hospitalized patients,
 Risk factors for ARF include advanced age, acute infection, pre- among whom mortality rates of up to 60% have been reported.1,2
existing chronic respiratory or cardiovascular disease, dehydra- Supportive therapy is the focus of management for those with
tion, and chronic kidney disease. established ARF, as there is no therapy that directly reverses the injury
 ARF lacks a specific and sensitive sign to herald its onset. Hence, associated with the numerous causes of ARF. Management goals
a thorough patient history, including medications, recent proce- include maintenance of blood pressure, fluid, and electrolyte homeo-
dures and illnesses, physical examination, and laboratory assess- stasis, all of which may be dramatically altered in the presence of ARF.
ment of serum and urine are necessary components of an ARF Additional therapies designed to eliminate or minimize the insult that
evaluation after an elevated serum creatinine (Scr) is noted. precipitated ARF include discontinuation of the offending drug (i.e.,
the nephrotoxin), cardiac support of the failing heart, removal of the
 Prevention is key; there are very few therapeutic options for the obstruction from the urinary collection system, corticosteroids to
therapeutic management of established ARF. minimize any intrinsic inflammatory process, antibiotic therapy to
 Supportive management remains the primary approach to pre- treat any infection, or other specific maneuvers to limit or reverse the
vent or reduce the complications associated with ARF. Support- kidney injury. Because of the poor clinical outcomes and lack of
ive therapies include: renal replacement therapies (RRTs), specific therapies, the importance of preventing ARF cannot be
nutritional support, avoidance of nephrotoxins, and blood pres- overemphasized. Individuals at highest risk, such as those with
sure and fluid management. chronic kidney disease (CKD) and the elderly with chronic medical
conditions, need to be identified and their exposure to harmful
 For those patients with prolonged or severe ARF, RRTs are the diagnostic or therapeutic procedures or medications minimized.
cornerstone of support and facilitate an aggressive approach to Renal replacement therapies (RRTs) such as hemodialysis and
fluid, electrolyte and waste management. peritoneal dialysis have been available for decades, but have not
Diuretic resistance is a common phenomenon in the patient resulted in dramatic improvements in the outcomes of patients with
with ARF and can be addressed with aggressive sodium restric- ARF. However, newer RRT modalities including an array of continu-
tion, combination diuretic therapy, or a continuous infusion of ous renal replacement therapies (CRRTs) appear to offer some
a loop diuretic. benefits, although available resources may limit their use and drug
dosing is handicapped by a paucity of data. Careful patient monitor-
Drug-dosing regimens for ARF patients receiving intermittent ing for response to these therapies and attention to pharmacokinetic
hemodialysis (IHD) are predominantly extrapolated from data alterations make it possible to develop rational drug-dosing regimens
derived from patients with chronic kidney disease (CKD); how- for these complex patients. Despite the supportive care that CRRTs
ever, important pharmacokinetic differences exist in patients offer, development of ARF is frequently a catastrophic event. In this
with ARF that should be considered. chapter, the epidemiology and multiple etiologies of ARF, as well as
the clinical features associated with the most common types of ARF,
Drug dosing guidelines for ARF patients receiving continuous
are presented. Methods to recognize and identify the extent of
renal replacement therapies (CRRTs) are poorly characterized
functional loss are also discussed. Finally preventative strategies and
and individualized doses may need to be determined by esti-
management approaches for those with established ARF are reviewed.

Learning objectives, review questions, DEFINITION OF ACUTE RENAL FAILURE

and other resources can be found at
www.pharmacotherapyonline.com. ARF is broadly defined as a decrease in glomerular filtration rate
(GFR), generally occurring over hours to days, sometimes over weeks,
 724
that is associated with an accumulation of waste products, including (I), and failure of the kidney (F) are outlined. The clinical outcomes
urea and creatinine. This relatively abrupt decline in renal function is of loss of function (L), and end-stage renal disease (E) complete the
SECTION 5

in contrast to CKD, which is defined by the presence of proteinuria/ RIFLE acronym. Thus far, validation studies have confirmed the value
albuminuria for at least 3 months, in combination with a GFR of <90 of these criteria in predicting hospital mortality, although further
mL/min/1.73 m2.3 A decrease in urine output is often observed, but is assessment is still necessary.9,10
not required for ARF to be present.4 Compared to a normal urine
output of ≥1,200 mL/day, patients with ARF are often categorized as
being anuric (urine output <50 mL/day), oliguric (urine output <500 EPIDEMIOLOGY
mL/day), or nonoliguric (urine output >500 mL/day).
Currently, there is no universally accepted definition of ARF in ARF is an uncommon condition in the community-dwelling, gener-
Renal Disorders

clinical practice: in fact, more than 30 definitions for ARF are ally healthy population, with an annual incidence of approximately
reported in the medical literature.5 Many of these definitions incorpo- 0.02% (Table 45–1).11 In individuals with preexisting CKD, however,
rate selective aspects of ARF observed in different patient populations. the incidence may be as high as 13%. In nonhospitalized patients,
Comparisons between studies that describe incidences, treatment dehydration, exposure to selected pharmacologic agents such as
effects, and patient outcomes can thus be difficult, if not impossible contrast media, and the presence of heart failure are associated with
to interpret. Although a serum creatinine (Scr) or calculated creatinine an increased risk of ARF. Additionally, trauma, rhabdomyolysis,
clearance (Clcr) may not provide a reliable characterization of renal vessel thrombosis, and drugs are common culprits in the develop-
function in all ARF situations, clinicians frequently use some combi- ment of ARF.11 The pharmacologic agents commonly associated with
nation of the absolute Scr value, change in Scr value over time, and/or ARF, including contrast media, chemotherapeutic agents, nonster-
urine output as the primary criteria for diagnosing the presence of oidal antiinflammatory drugs (NSAIDs), angiotensin-converting
ARF.4,6 The commonly used and highly variable definitions for ARF enzyme inhibitors, angiotensin receptor blockers, and antiviral med-
are nonspecific and open to various interpretations. On a patient-by- ications are discussed in detail in Chap. 49. 11,12
patient basis, the semantics of the ARF definition are relatively  The hospitalized individual is at high risk of developing ARF;
meaningless. However, to move the prevention and treatment of ARF the reported incidence is 7%.13 The incidence of ARF is markedly
forward, consistent definitions must be employed. Without them, higher in critically ill patients, ranging from 6% to 23%.6 The high
clinicians will be unable to accurately use any data generated because mortality rate related to ARF, which is reported to range from 35% to
the nonspecific classification of ARF will be an insurmountable 80%, is a significant clinical concern that has been relatively unre-
barrier to the identification of who was studied, and hence, to whom sponsive to therapeutic intervention over the last four decades.
the data apply. A means to standardize the various aspects of the Although the relative contribution of ARF to mortality rates of the
clinical presentation is necessary to allow integration of the literature underlying disease states is unclear given that current illness and ARF
observations to bedside management. A new consensus-derived defi- cannot be reliably quantified, it is certain that the presence of ARF will
nition and classification system for ARF was recently proposed, and is independently contribute significantly to overall mortality.6 For sur-
currently being validated (Fig. 45–1).7,8 This three-tiered classification vivors of ARF, subsequent morbidity or development of some degree
uses both GFR and urine output, plus two clinical outcomes that may of CKD is also a consideration. Although 90% of individuals recover
occur subsequent to an episode of ARF as components of the enough renal function to live normal lives, approximately half of
paradigm. Definitions of risk of dysfunction (R), injury to the kidney these are left with subclinical deficits. Five percent will not regain

Risk

Injury

Failure

Loss
GFR/Scr Scr ↑ 50%, or Scr ↑ 100%,or Scr ↑ 200%, or
GFR ↓ 25% GFR ↓ 50% GFR ↓ 75%, or
Criteria Scr > 4 mg/dL
ESRD

Persistant ARF ESRD

(> 4 weeks) (> 3 months)
UOP < 0.5 UOP < 0.5 UOP > 0.3
Urine Output mL/kg/hr mL/kg/hr mL/kg/hr
(UOP) Criteria x 6 hr x 12 hr x 24 hr, or
Anuria x 12 hr

FIGURE 45-1. RIFLE classification for acute renal failure (ARF). (ESRD, end-stage renal disease; GFR, glomerular filtration rate; S cr, serum creatinine).
(Reprinted and adapted from Crit Care Clin, Vol. 21, Bellomo R. Defining, quantifying, and classifying acute renal failure, pages 223-237, Copyright
© 2005, with permission from Elsevier.)
 725

TABLE 45-1 Incidence and Outcomes of Acute Renal Failure Relative to Where It Occurs

CHAPTER 45
Community-Acquired Hospital-Acquired ICU-Acquired
Incidence Low (<1%) Moderate (2%–5%) High (6%–23%)
Cause Single Single or multiple Multifactorial
Overall survival rate 70%–95% 30%–50% 10%–30%
Worsened outcome if: RRT required RRT required Intrinsic renal disease
Poor preadmission health Poor preadmission health Ischemic ARF cause
Other failed organ systems Ischemic ARF cause Septic
Other failed organ systems RRT required
Poor preadmission health

Acute Renal Failure

Other failed organ systems
Better outcome if: Nonoliguric Nonoliguric Prerenal cause
Nephrotoxic cause Postrenal cause
Nonoliguric
Nephrotoxic cause
Hyperglycemia prevented
ARF, acute renal failure; RRT, renal replacement therapy.

sufficient renal function to live independently and thus require long- and efferent (vasodilation) arteriolar circumference. These clinical
term peritoneal or hemodialysis or transplantation. An additional 5% conditions are most commonly seen in individuals who have
will suffer from a progressive deterioration in kidney function after reduced effective blood volume (e.g., heart failure, cirrhosis, severe
initial recovery, likely as a consequence of hyperfiltration and sclerosis pulmonary disease, or hypoalbuminemia) or renovascular disease
of the remaining glomeruli.14 (e.g., renal artery stenosis) and who cannot compensate for changes
in afferent or efferent arteriolar tone. A decrease in efferent arteri-
olar resistance as the result of initiation of angiotensin-converting
ETIOLOGY enzyme inhibitor or angiotensin receptor blocker therapy is a
common cause of this syndrome. The hepatorenal syndrome is also
 The etiology of ARF can be divided into broad categories based included in this classification because the kidney itself may be
on the anatomic location of the injury associated with the precipi- damaged, and there is intense afferent arteriolar vasoconstriction
tating factor(s). The management of patients presenting with this leading to a decline in glomerular hydrostatic pressure. In all the
disorder is largely predicated on identification of the specific etiol- above conditions, the urinalysis is no different from its baseline state
ogy responsible for the patient’s current acute kidney injury (Table and the urinary indices suggest prerenal azotemia.
45–2). Traditionally, the causes of ARF have been categorized as Functional ARF is very common in individuals with heart failure
(a) prerenal, which results from decreased renal perfusion in the who receive an angiotensin converting enzyme inhibitor or an
setting of undamaged parenchymal tissue, (b) intrinsic, the result of angiotensin receptor blocker in an attempt to improve their left
structural damage to the kidney, most commonly the tubule from a ventricular function. Because the decline in efferent arteriolar resis-
ischemic or toxic insult, and (c) postrenal, caused by obstruction of tance resulting from the inhibition of angiotensin II occurs within
urine flow downstream from the kidney (Fig. 45–2). days, if the dose of the angiotensin-converting enzyme inhibitor is
 The most common cause of hospital-acquired ARF is prerenal increased too rapidly, a decline in GFR with a concomitant rise in
ischemia as the result of reduced renal perfusion secondary to the serum creatinine will be noticeable. If the increase in the serum
sepsis, reduced cardiac output, and/or surgery. Drug-induced ARF creatinine is mild to moderate (an increase of less than 30% from
may account for 18% to 33% of in-hospital occurrences. Other risk baseline) the medication can be continued.
factors for developing ARF while hospitalized include advanced age
(>60 years of age), male gender, acute infection, and preexisting
chronic diseases of the respiratory or cardiovascular systems.6 PRERENAL ACUTE RENAL FAILURE
Prerenal ARF results from hypoperfusion of the renal parenchyma,
PATHOPHYSIOLOGY with or without systemic arterial hypotension. Renal hypoperfusion
with systemic arterial hypotension may be caused by a decline in
PSEUDORENAL AND FUNCTIONAL ACUTE intravascular or effective blood volume that can occur in those with
RENAL FAILURE acute blood loss (hemorrhage), dehydration, hypoalbuminemia, or
diuretic therapy. Renal hypoperfusion without systemic hypotension
In selected situations their can be a rise in either the blood urea is most commonly associated with bilateral renal artery occlusion, or
nitrogen (BUN) or the Scr, suggesting presence of renal dysfunction unilateral occlusion in a patient with a single functioning kidney. The
when in fact GFR is not diminished. This could be the result of initial physiologic responses to a reduction in effective blood volume
cross-reactivity with the assay used to measure the BUN or Scr, or by the body includes activation of the sympathetic nervous and the
selective inhibition of the secretion of creatinine into the proximal renin–angiotensin–aldosterone systems, and release of antidiuretic
tubular lumen (see Chap. 44). The initiation or discontinuation of hormone if hypotension is present. These responses work together to
such agents should be considered in the assessment for acute directly maintain blood pressure via vasoconstriction and stimulation
changes in renal function, and should be looked for as part of the of thirst to increase fluid intake and the promotion of sodium and
work up in any patient who is suspected to have ARF. water retention. Additionally, GFR may be maintained by afferent
In functional ARF, a decline in GFR secondary to a reduced arteriole dilation and efferent arteriole constriction. In concert, these
glomerular hydrostatic pressure, which is the driving force for the homeostatic mechanisms are often able to maintain arterial pressure
formation of ultrafiltrate, can occur without damage to the kidney and renal perfusion, potentially averting the progression to ARF.15 If,
itself. The decline in glomerular hydrostatic pressure may be a direct however, the decreased renal perfusion is severe or prolonged, these
consequence of changes in glomerular afferent (vasoconstriction) compensatory mechanisms may be overwhelmed and ARF will then
 726

TABLE 45-2 Classification of Acute Renal Failure

SECTION 5

Abnormality Causing Abnormality Causing

Category Acute Renal Failure Possible Causes Category Acute Renal Failure Possible Causes
Prerenal Intravascular volume deple- Dehydration Intrinsic Vascular damage Vasculitis
tion resulting in arterial Inadequate fluid intake Polyarteritis nodosa
hypotension Excessive vomiting, diarrhea or Hemolytic uremic syndrome-throm-
gastric suctioning botic thrombocytopenic purpura
Increased insensible losses (e.g., Emboli
fever, burns) Atherosclerotic
Diabetes insipidus Thrombotic
Renal Disorders

High serum glucose (glucosuria) Accelerated hypertension

Overdiuresis Glomerular damage Systemic lupus erythematosus
Hemorrhage Poststreptococcal glomerulonephritis
Decreased cardiac output Antiglomerular basement membrane
Hypoalbuminemia disease
Liver disease Acute tubular necrosis Ischemic
Nephrotic syndrome Hypotension
Arterial hypotension (regard Anaphylaxis Vasoconstriction
less of volume status) Sepsis Exogenous toxins
Excessive antihypertensive use Contrast dye
Decreased cardiac output Heart failure Heavy metals
Sepsis Drugs (amphotericin B, aminogly-
Pulmonary hypertension cosides, etc.)
Aortic stenosis (and other valvular Endogenous toxins
abnormalities) Myoglobin
Anesthetics Hemoglobin
Isolated renal hypoperfusion Bilateral renal artery stenosis (unilat- Acute interstitial nephritis Drugs
eral renal artery stenosis in solitary Penicillins
kidney) Ciprofloxacin
Emboli Sulfonamides
Cholesterol Infection
Thrombotic Viral
Medications Bacterial
Cyclosporine Postrenal Bladder outlet obstruction Prostatic hypertrophy, infection, cancer
Angiotensin-converting enzyme Improperly placed bladder catheter
inhibitors Anticholinergic medication
Nonsteroidal antiinflammatory drugs Ureteral Cancer with abdominal mass
Radiocontrast media Retroperitoneal fibrosis
Hypercalcemia Nephrolithiasis
Hepatorenal syndrome Renal pelvis or tubules Nephrolithiasis
Oxalate
Indinavir
Sulfonamides
Acyclovir
Uric acid

be clinically evident. If renal artery stenosis is present, narrowing kidney. Atheroemboli most commonly develop during vascular pro-
bilaterally (both kidneys) or unilaterally (one functional kidney) of cedures that cause atheroma dislodgement, such as angioplasty or
the artery responsible for blood flow to the kidney can lead to reduced aortic manipulations. Thromboemboli may arise from dislodgement
renal function. The most common cause is atherosclerosis, with of a mural thrombus in the left ventricle of a patient with severe heart
severe abrupt occlusion sometimes occurring as the result of an failure, or from the atria of a patient with atrial fibrillation. Renal
embolism.16 artery thrombosis may occur in a similar fashion to coronary throm-
bosis, in which a thrombus forms in conjunction with an atheroscle-
rotic plaque.
INTRINSIC ACUTE RENAL FAILURE Although smaller vessels can also be obstructed by atheroemboli or
Acute intrinsic renal failure results from damage to the kidney itself. thromboemboli, the damage is limited to the vessels involved, and the
Conceptually, acute intrinsic renal failure can be categorized on the development of significant ARF is unlikely. However, these small
basis of the structures within the kidney that are injured: the renal vessels are susceptible to inflammatory processes that lead to
vasculature, glomeruli, tubules, and the interstitium. Many diverse microvascular damage and vessel dysfunction when the renal capillar-
mechanisms have been associated with the development of intrinsic ies are affected. Neutrophils invade the vessel wall, causing damage
ARF, many of which are categorized in Table 45–2. that can include thrombus formation, tissue infarction, and collagen
deposition within the vessel structure. Diffuse renal vasculitis can be
mild or severe, with severe forms promoting concomitant ischemic
Renal Vasculature Damage
acute tubular necrosis (ATN). The Scr is usually elevated as the lesions
Occlusion of the larger renal vessels resulting in ARF is not common, are diffuse, and thus the area of damage is large. Accelerated hyper-
but can occur if large atheroemboli or thromboemboli occlude the tension that is not treated may also compromise renal microvascular
bilateral renal arteries, or one vessel of the patient with a single blood flow, and thus cause diffuse renal capillary damage.
 727

Intrinsic Renal Impairment

CHAPTER 45
Pre-Renal Impairment • Glomerular Injury
• Tubulointerstitial
• Tubular obstruction

Afferent Proximal Tubule FIGURE 45-2. Physiologic classification

Renal Kidney Arteriole Distal Tubule of ARF. Blood flows through the afferent
Artery arteriole, to the glomerulus and exits
through the efferent arteriole. The forma-

Acute Renal Failure

Renal tion of glomerular ultrafiltrate is depen-
Pelvis dent on the surface area of the capillaries
within the glomerular region, their perme-
Collecting Duct
ability, and the net hydrostatic pressure
Ureter
across the capillary wall. A decrease in
blood flow and renal perfusion can lead
Bladder to a prerenal reduction in renal function.
Under conditions in which renal blood
flow is diminished, the kidney maintains
glomerular ultrafiltration by vasodilating
the afferent and vasoconstricting the
Urethra efferent arterioles. Medications that may
Glomerulus interfere with these processes might
result in an abrupt decline in glomerular
Efferent Arteriole
filtration. Damage to the glomerular or
tubular regions leads to intrinsic ARF.
Obstruction of urine flow once in the
collecting tubule, ureter, bladder, or ure-
Post-Renal Impairment thra is termed postrenal failure.

Glomerular Damage less of the etiology, tubular injury leads to a loss in the ability to
concentrate urine, to defective distal sodium reabsorption, and, ulti-
Only 5% of the cases of intrinsic ARF are of glomerular origin. The
mately, to a reduction in the GFR.20 Continued kidney hypoxia or toxin
glomerulus is one of two capillary beds in the kidney, and serves to
exposure after the original insult kills more cells, and propagates the
filter fluid and solute into the tubules while retaining proteins and
inflammatory response and can extend the injury and delay the recov-
other large blood components in the intravascular space. Because it’s
ery process. With prolonged ischemia, the tubular epithelial cells in the
a capillary system, glomerular damage can occur by the same
corticomedullary junction are damaged and die. When the toxin or
mechanisms described for the renal vasculature, and one additional
ischemia is removed, a maintenance phase ensues (typically 2 to 3
mechanism, that is, severe inflammatory processes specific to the
weeks), followed by a recovery phase (2 to 3 weeks) during which new
glomerulus. The pathophysiology and specific therapeutic approaches
tubule cells are regenerated. The recovery phase is associated with a
used to combat the inflammatory processes are described in detail in
notable diuresis, which requires attention to fluid balance to ensure that
Chap. 50.
a secondary prerenal injury does not occur. However, if the ischemia or
injury is extremely severe or prolonged, cortical necrosis may occur,
Tubule Damage preventing any tubule cell regrowth in the affected areas.
Approximately 85% of all cases of intrinsic ARF are caused by ATN, of
which 50% are a result of renal ischemia, often arising from an Interstitial Damage
extended prerenal state. The remaining 35% are the result of exposure
The interstitium of the kidney is rarely the primary cause of end-stage
to direct tubule toxins, which can be endogenous (myoglobin, hemo-
renal disease (ESRD), but it can become severely inflamed and lead to
globin, or uric acid) or exogenous (contrast agents, heavy metals, or
ARF. Acute interstitial nephritis is most commonly caused by medica-
aminoglycoside antibiotics). The tubules located within the medulla of
tions (see Chap. 49), or bacterial or viral infections.21 Up to 30% of
the kidney are particularly at risk from ischemic injury, as this portion
cases have no identifiable cause.22 Whatever the inciting event, inter-
of the kidney is metabolically active and thus has high oxygen require-
stitial nephritis is characterized by lesions comprised of monocytes,
ments, yet even in the best of situations, receives relatively low oxygen
macrophages, B cells, or T cells, clearly identifying an immunologic
delivery (as compared to the cortex). Thus, ischemic conditions caused
response as the injurious process affecting the interstitium.23 Because
by severe hypotension or exposure to vasoconstrictive drugs preferen-
of the interwoven nature of the interstitium and the tubules, the
tially affect the tubules more than any other portion of the kidney.
widespread inflammation and edema affect the function of the
The clinical evolution of ATN is characterized by the initial injury
tubules, and may cause fibrosis if the administration of the nephro-
causing tubule epithelial cell necrosis or apoptosis, followed by an
toxin is not discontinued and inflammation quickly controlled.24
extension phase with continued hypoxia and an inflammatory response
involving the nearby interstitium.17 The onset of ATN can occur over
days to weeks, and rarely longer than that depending on the factors POSTRENAL ACUTE RENAL FAILURE
responsible for the damage to the tubular epithelial cells.18 Once tubular
cells die, they slough off into the tubular lumen. The debris causes Postrenal ARF may develop as the result of obstruction at any level
increased tubular pressure and reduces glomerular filtration.19 Addi- within the urinary collection system from the renal tubule to urethra
tionally, the loss of epithelial cells leaves only the basement membrane (see Table 45–2). However, if the obstructing process is above the
between the filtrate and the interstitium, which results in dysregulation bladder, it must involve both kidneys (one kidney in a patient with a
of fluid and electrolyte transfer across the tubular epithelium. Regard- single functioning kidney) to cause significant ARF. Bladder outlet
 728
obstruction, the most common cause of obstructive uropathy, is often increase in the patient’s weight or complaints of tight-fitting rings
caused by a prostatic process (hypertrophy, cancer or infection) causing secondary to salt and water retention also may be helpful in defining
SECTION 5

a physical impingement on the urethra and thereby preventing the the time of onset of renal failure.
passage of urine. It may also be the result of an improperly placed Patients who develop renal insufficiency while hospitalized usually
urinary catheter. Neurogenic bladder or anticholinergic medications have an acute initiating event that can be identified from a review of the
may also prevent bladder emptying and cause ARF. The blockage may laboratory data, urine output record, and the medication administra-
occur at the ureter level, secondary to nephrolithiasis, blood clots, a tion and procedure records. In addition to its prognostic significance,
sloughed renal papillae, or physical compression by an abdominal changes in urine output may be helpful in characterizing the cause of
process such as retroperitoneal fibrosis, cancer, or an abscess. Crystal the patient’s ARF. Acute anuria is typically caused by either complete
deposition within the tubules from oxalate and some medications urinary obstruction or a catastrophic event (e.g., shock or acute cortical
Renal Disorders

severe enough to cause ARF is uncommon, but is possible in patients necrosis). Oliguria (<500 mL/day of urine output), which often devel-
with severe volume contraction and in those receiving large doses of a ops over several days, suggests prerenal azotemia, whereas nonoliguric
drug with relatively low urine solubility (see Chap. 49). In these cases, (>500 mL/day of urine output) renal failure usually results from acute
patients have insufficient urine volume to prevent crystal precipitation intrinsic renal failure or incomplete urinary obstruction.
in the urine.25 Extremely elevated uric acid concentrations from che-
motherapy-induced tumor lysis syndrome should be minimized by the
CLINICAL PRESENTATION OF ACUTE
initiation of an aggressive fluid regimen and pharmacologic preventa-
RENAL FAILURE
tive therapies in at-risk patients. Wherever the location of the obstruc-
tion, urine will accumulate in the renal structures above the obstruction General
and cause increased pressure upstream. The ureters, renal pelvis, and ■ Community-dwelling patients often are not in acute distress.
calyces all expand, and the net result is a decline in GFR. If renal
■ Hospitalized patients may develop ARF after either a notable
vasoconstriction ensues, a further decrement in GFR will be observed.
reduction in blood pressure or intravascular volume, signifi-
cant insult to the kidney, or sudden obstruction after cathe-
CLINICAL PRESENTATION terization. Generally, an acute reduction in urine output
coinciding with a rise in BUN and Scr is observed.
 The initiating sign or symptom prompting the eventual diagnosis Symptoms
of ARF is highly variable, depending on the etiology. It may be an
■ Outpatient: Change in urinary habits, sudden weight gain, or
elevated Scr, decreased urine output, blood in the urine, pain during
flank pain.
voiding, or severe abdominal or flank pain. The first step is to
determine if the renal complication is acute, chronic, or the result of ■ Inpatient: Typically, ARF is recognized by clinicians before the
an acute change in a patient with known CKD. BUN, potassium, patient, who may not experience any obvious symptoms.
phosphorous, and, potentially, magnesium concentrations in serum Signs
will likely become elevated and should be promptly evaluated. For ■ Patient may have edema; urine may be colored or foamy;
those presenting in the outpatient environment it may be difficult orthostatic hypotension in volume-depleted patients, hyper-
to determine when the onset was as the initial presentation of ARF tension in the fluid-overloaded patient or in the presence of
may have been asymptomatic. The onset of ARF may, in fact, trigger acute or chronic hypertensive kidney disease.
independently symptoms of a concurrent medical condition or
excessive drug response from a renally eliminated agent. Laboratory Tests
■ Elevations in the serum potassium, BUN, creatinine, and phos-
PATIENT ASSESSMENT phorous, or a reduction in calcium and the pH (acidosis), may be
present. The clinical findings are different based on the cause of
A past medical history for renal disease-related chronic conditions, the ARF.
such as poorly controlled hypertension or diabetes mellitus, previous ■ An increased serum white blood cell count may be present in
laboratory data documenting the presence of proteinuria or an ele- those with sepsis-associated ARF, and eosinophilia suggests
vated Scr, and the finding of bilateral small kidneys on renal ultra- acute interstitial nephritis.
sonography suggests the presence of CKD. A thorough medical history
and a review of past medical records, if available, that includes recent ■ Urine microscopy can reveal cells, casts, or crystals that help
procedures and illnesses, should be done as soon as possible. The distinguish among the possible etiologies and/or severities of ARF.
medication and recent procedure history may suggest causes for acute ■ An elevated urine specific gravity suggests prerenal ARF, as
interstitial nephritis or other nephrotoxic effects. An exhaustive review the tubules are concentrating the urine. Urine chemistry also
of their recent prescription, as well as nonprescription, complemen- indicates the presence of protein, which suggests glomerular
tary, and alternative medications, should be completed. Special atten- injury, and blood, which can result from damage to virtually
tion should be focused on diuretics, NSAIDs, antihypertensives, recent any kidney structure.
contrast dye exposure and any other recent additions or changes in the Other Diagnostic Tests
patient’s medications. Patients may have noticed an acute change in
■ Renal ultrasonography or cystoscopy may be needed to rule
their voiding habits with an increase in urinary frequency or nocturia,
out obstruction; renal biopsy is rarely used, and is reserved for
both suggesting a urinary concentrating defect. A decrease in the force
difficult diagnoses.
of the urinary stream may suggest an obstruction. The presence of
cola-colored urine also often stimulates people to seek medical care
and its presence is indicative of blood in the urine, a finding com- A physical examination, including assessment of the patient’s
monly associated with acute glomerulonephritis. The onset of flank volume and hemodynamic status, is an important step in evaluating
pain is suggestive of a urinary stone; however, if bilateral, it may individuals with ARF. Table 45–3 lists common physical findings in
suggest swelling of the kidneys secondary to acute glomerulonephritis patients with ARF. The physical exam should be thorough, as clues
or acute interstitial nephritis. Complaints of severe headaches may regarding the etiology of the patient’s ARF can be evident from the
suggest the presence of severe hypertension as a result of ARF. A recent patient’s head (eye exam) to toe (evidence of dependent edema).
 729

TABLE 45-3 Physical Examination Findings in Acute Renal Failure TABLE 45-4 Diagnostic Parameters for Differentiating Causes of

CHAPTER 45
Acute Renal Failure
Physical
Examination Category of Acute Prerenal Acute Intrinsic Postrenal
Finding Possible Diagnosis Renal Failure Laboratory Test Azotemia Renal Failure Obstruction
Vital signs Urine sediment Normal Casts, cellular debris Cellular debris
Orthostatic Volume depletion Prerenal Urinary RBC None 2–4+ Variable
hypotension Urinary WBC None 2–4+ 1+
Febrile Sepsis Intrinsic—tubule necrosis Urine sodium <20 >40 >40
Skin FENa (%) <1 >2 Variable
Tenting Volume depletion Prerenal Urine/serum osmolality >1.5 <1.3 <1.5

Acute Renal Failure

Rash Hypersensitivity reaction Intrinsic—interstitial nephritis Urine/Scr >40:1 <20:1 <20:1
Petechiae Thrombotic thrombocy- Intrinsic—vasculitis BUN/Scr >20 ~15 ~15
topenic purpura
ARF, acute renal failure; BUN, blood urea nitrogen; FENa, fractional excretion of sodium; Scr, serum
Hemolytic uremic
creatinine; RBC, red blood cell; WBC, white blood cell.
syndrome Common laboratory tests are used to classify the cause of ARF. Functional ARF, which is not included
Sepsis Intrinsic—tubule necrosis in this table, would have laboratory values similar to those seen in prerenal azotemia. However, the
Splinter hemor- Endocarditis Intrinsic—glomerulonephritis urine osmolality-to-plasma osmolality ratios may not exceed 1.5, depending on the circulating levels
rhages of antidiuretic hormone. The laboratory results listed under acute intrinsic renal failure are those seen
Janeway lesions in acute tubular necrosis, the most common cause of acute intrinsic renal failure.
Osler nodes
Edema Total-body volume Intrinsic or prerenal because
overload of heart failure possible postrenal obstruction, such as the presence of a urinary
Other types of prerenal unlikely catheter, an enlarged prostate in males or cervical/uterine abnormal-
HEENT ities in females. Renal artery stenosis can be identified via Doppler
Hollenhorst plaque Cholesterol emboli Intrinsic—vascular ultrasound by measuring changes in flow distal to the narrowing if
Roth spots Endocarditis Intrinsic—glomerulonephritis visible, or by computed tomography (CT) angiography, which can
Elevated jugular Heart failure Prerenal describe the anatomy of the renal vessels.
venous pressure Pulmonary hypertension
Heart
S3 heart sound Heart failure Prerenal LABORATORY TESTS AND INTERPRETATION
New or increased Endocarditis Intrinsic—glomerulonephritis
murmur The commonly available laboratory tests used to evaluate the patient
Lung with renal insufficiency are described in Chap. 44, and those of
Rales Heart failure Prerenal particular value in the assessment of renal function in patients with
Abdomen
ARF are highlighted in Table 45–4. There is currently no consensus on
Renal artery bruit Renal artery stenosis Prerenal
the degree and time frame of changes in Scr values that clearly defines
Ascites Liver failure or right- Prerenal
heart failure Hepatorenal syndrome
the presence of ARF. The difficulty of using Scr as a diagnostic
Bladder distension Bladder outlet obstruction Postrenal laboratory test for patients with ARF is its lack of sensitivity to rapid
Genitourinary changes in GFR. An abrupt cessation in glomerular filtration will not
Prostatic Prostatic hypertrophy or Postrenal yield an immediate measurable change in Scr. The reasons for this are:
enlargement cancer creatinine generation and accumulation is relatively slow, there is a lag
Gynecologic time between test and clinical event, lab tests may not be very sensitive
Abnormal biman- Possible bilateral ure- Postrenal to small changes in GFR, and fluid retention that commonly accompa-
ual examination teral obstruction or nies ARF dilutes the retained creatinine.26 Additionally, when decreased
cervical cancer filtration of creatinine occurs, functional tubules can increase the
HEENT, head, eyes, ears, nose, and throat. secretion of creatinine into the urine, further complicating the
interpretation of Scr.
Observations will either support or refute the cause as prerenal, An example of this phenomenon is illustrated by an acute renal
intrinsic or postrenal. In those with prerenal ARF, low effective artery thrombus that results in abrupt cessation of GFR in one kidney
arterial blood volume may be evidenced by the presence of postural as a consequence of the complete obstruction of blood flow to that
hypotension and decreased jugular venous pressure (JVP). Fluid kidney (Fig. 45–3). Although 5 minutes following the event GFR is
overload as a consequence of ATN on the other hand is often reflected decreased 50% (assuming the other kidney is functioning and unaf-
by rales in the lower lung fields and/or the presence of peripheral fected), the serum creatinine remains unchanged. Assuming a standard
edema. If ascites or pulmonary edema is present, the effective arterial daily creatinine production of approximately 20 mg/kg of lean body
blood volume perceived by the kidneys may be low and thus suggest weight, one can expect approximately 1.4 g of creatinine production in
the diagnosis of functional ARF. a 24-hour period in a 70-kg individual. In pharmacokinetic terms, daily
When the interstitium of the kidney is damaged (e.g., acute allergic creatinine production is analogous to a continuous infusion, and GFR
interstitial nephritis), the concentrating gradient within the kidney determines the elimination rate of creatinine. In the patient with
may be attenuated and ammonia handling disrupted, resulting in a normal renal function (GFR of 120 mL/min), the half-life of creatinine
very dilute-appearing urine. Consequently, patients presenting with is 3.5 hours with 95% of steady state achieved in approximately 14
acute interstitial nephritis frequently are unable to concentrate the hours. If GFR declines to 60, 30, or 12 mL/min, the half-life of
urinary solutes. Blood pressure should be evaluated for elevations that creatinine increases, resulting in prolongation of the time to reach 95%
may accompany intrinsic renal damage. Any recent history of an of steady state, specifically taking 1, 2, and 4 days, respectively.27
infection may suggest postinfective glomerulonephritis. Although Other biomarkers for acute renal injury and failure are being
uncommon, thromboembolism occurring in the renal artery or vein explored. One such marker, serum cystatin C (see Chap. 44) has been
can potentially result in ischemic damage, and should be a compo- explored as a more sensitive and rapid means to detect renal dysfunc-
nent of the physical assessment. Physical examination may detect tion and injury.28 Although an elevation in serum creatinine or
 730
SECTION 5

Renal artery thrombus

120
GFR
mL/min
60

Serum
Renal Disorders

FIGURE 45-3. Glomerular filtration rate (GFR; mL/min) and 2.0

Creatinine
serum creatinine (Scr; g/dL) versus time following acute renal (mg/dL) 1.5
injury. Prior to time 0, a GFR of 120 mL/min and a Scr of 1.0 g/dL
exist. At time 0, an abrupt renal artery thrombus forms, depriving 1.0
one kidney of renal blood flow. Composite GFR immediately
declines by 50% to approximately 60 mL/min. However, Scr does
–4 0 4 8 12 18 24 30
not increase immediately, as it is dependent on creatinine produc-
tion and attainment of steady-state serum concentrations. Time (hours)

cystatin C may be clearly indicative of a reduction in renal function, drawn prior to removal of a postrenal obstruction, such as a nonfunc-
these are not quantitative indices that allow one to ascertain the degree tional Foley catheter, with liters of urine now being voided over a
of remaining function the patient has. Although several methods, such relatively short period of time (hours). Scr and BUN are extensively
as the Cockcroft-Gault or one of the Modification of Diet in Renal removed during acute hemodialysis treatments, so when assessing any
Disease equations (see Table 44–4), have been extensively used to change in these parameters in the ARF patient, one must pay close
estimate GFR in patients with CKD, they are not applicable for ARF attention to when the lab specimens were collected relative to the
patients with changing Scr values because by the nature of the condi- dialysis procedure.
tion, renal function is unstable. In ARF, these equations can overesti- Several mathematical approaches to estimate GFR in patients with
mate GFR when the ARF is worsening, and underestimate it when the unstable Scr that incorporate the principles of creatinine accumula-
ARF is resolving. To avoid missing changes in renal function when tion and elimination have been proposed29–31 and are discussed in
relying on equations to predict renal function, consider looking at the detail in Chap. 44. These methods have not been extensively validated
sequence of Scr values to determine if renal function is potentially in the setting of acute alterations in renal function and their value for
improving (values declining) or worsening (values rising). The most adjusting medication dosing is questionable. Additionally, these
recent Scr value reflects the time-averaged kidney function over the equations are complex, rendering bedside implementation difficult
preceding time period. Assessment of urine output can assist in and highly likely to be complicated by calculation errors.
verifying observed serum laboratory values, as well as providing an up- Another approach to measuring renal function when Scr values alone
to-the-moment means of identifying any changes in the kidney func- are not reflective of function is to directly measure urine Clcr over a
tion. While dependent on several factors such as hydration status and short period of time, such as 4 to 12 hours.32 Although potentially
medications, urine output measured over a finite period of time (e.g., precise and fairly simple to do, accuracy is questionable because the
4 hours) is a useful short-term assessment of kidney function. An urine output is generally low and if the collection is incomplete, the lost
abrupt decline or increase compared to previous values is highly urine can have a dramatic impact on the clearance determination.
suggestive of a change in functional status. Because of the shortcom- To facilitate its diagnosis and management, ARF can be classified
ings associated with serum creatinine, urine output is an extremely into several broad categories based on precipitating factors (see Table
useful parameter in the assessment of the patient with ARF. Anuria, 45–2). Traditionally this includes prerenal (resulting from decreased
defined as <50 mL/day of urine, suggests complete kidney failure. renal perfusion), acute intrinsic (resulting from structural damage to
Conversely, oliguria (<17 mL/h urine output) certainly indicates the kidney), and postrenal failure (obstruction of urine from removal).
kidney damage; however, some function is present. In the setting of A fourth category, functional acute renal failure, is characterized by
ARF, any urine production >17 mL/h indicates the presence of hemodynamic changes at the glomerulus independent of decreased
nonoliguric ARF. Despite reasonable urine output, the quality of the perfusion or structural damage. Identifying the cause of ARF, which
urine being produced is not reliably composed of the expected waste strongly influences potential outcomes and therapies, is of paramount
products and solutes. Damaged tubules may allow substantial urine to importance.
be produced; however, the electrolyte, protein, and acid–base func- Selected blood tests in addition to BUN and Scr can be quite
tions of the kidney may be severely compromised. For these reasons, valuable in differentiating the cause of ARF and also contribute to
urine output alone is an unreliable marker of kidney function. optimal patient management. For example, infectious causes of ARF
Instead of using fixed numbers to determine renal function, can be assessed using a complete blood cell count with differential.
changes in the value, even if it remains within the normal range, may Serum electrolyte values are likely to be abnormal because of the acute
indicate marked impairment of renal function. For example, patients decline of the kidney’s ability to regulate electrolyte excretion, and
with reduced creatinine production, such as those with low muscle particular attention should be paid to serum potassium and phospho-
mass either because of being bedridden for long periods of time or a rus values, which can be markedly elevated and cause life-threatening
concurrent emaciated state, may have very low baseline Scr values complications.
(<0.6 mg/dL) and thus the presence of a gradual Scr rise to normal In individuals with normal renal function, the ratio between the
values (0.8 to 1.2 mg/dL) may actually indicate reduced GFR. When BUN and Scr is usually less than 15:1. In the presence of prerenal ARF,
coupled with a decline in urine output, this might suggest the presence reabsorption of BUN exceeds that of creatinine and thus one often sees
of ARF. However, in the presence of improved nutrition and an a ratio greater than 20:1. Given the limited usefulness of solely using Scr
expanding muscle mass, it may be a true representation of the person’s or BUN concentrations to differentiate the etiology of ARF, urinary
current renal status. In contrast, a high Scr value may be present if electrolytes and osmolality should be determined, and both a micro-
 731

TABLE 45-5 Urine Analysis Findings as a Guide to the Etiology of TABLE 45-6 Differential Diagnosis of Acute Renal Failure on the

CHAPTER 45
Acute Renal Failure Basis of Urine Microscopic Examination Findings
Presence of Suggestive of Urine Sediment Suggestive of
Leukocyte esterase Pyelonephritis Cells
Nitrite Pyelonephritis Microorganisms Pyelonephritis
Protein Red blood cells Glomerulonephritis, pyelonephritis, renal infarction,
Mild Tubular damage papillary necrosis, renal tumors, kidney stones
Moderate Glomerulonephritis, pyelonephritis, tubular damage White blood cells Pyelonephritis, interstitial nephritis
Large Lupus nephritis Eosinophils Drug-induced allergic interstitial nephritis, renal trans-
Hemoglobin Glomerulonephritis, pyelonephritis, renal infarction, papil- plant rejection

Acute Renal Failure

lary necrosis, renal tumors, kidney stones, tubular necro- Epithelial cells Tubular necrosis
sis from rhabdomyolysis Casts
Specific gravity Granular casts Tubular necrosis
Low Tubular necrosis White blood cell casts Pyelonephritis, interstitial nephritis
High Prerenal Red blood cell casts Glomerulonephritis, renal infarct, lupus nephritis,
Myoglobin Rhabdomyolysis-associated tubular necrosis vasculitis
Urobilinogen Hemolysis-associated tubular necrosis Crystals
Urate Postrenal obstruction
scopic and chemical analysis of the urine should be performed (Table Phosphate Alkaline urine, possibly secondary to Proteus sp.
infection, postrenal obstruction
45–5). The finding of a high urinary specific gravity, in the absence of
glucosuria or mannitol administration, suggests an intact urinary con-
centrating mechanism, and that the cause of the patient’s ARF is likely is intact. These findings are most characteristic of prerenal azotemia.
prerenal azotemia. The presence of urinary protein is often difficult to Unfortunately, diuretic use in the preceding days limits the usefulness
interpret, especially in the setting of acute on chronic renal failure. A of the fractional excretion of sodium calculation by increasing natri-
patient with CKD may have a baseline proteinuria, thus clouding the uresis, even in hypovolemic patients. The fractional excretion of urea
clinical presentation, unless this is known at the time of ARF assess- (FeUrea), which can be calculated similarly to the FeNa, is sometimes
ment. Classically, proteinuria is a hallmark of glomerular damage. used as an alternative means to assess tubule function.
However, tubular damage can also result in proteinuria, as the tubules The inability to concentrate urine results in a high fractional
are responsible for reabsorbing small proteins that are normally filtered excretion of sodium (>2%), suggesting tubular damage is the
by all glomeruli. The presence of blood also results in a positive urine primary cause of the intrinsic ARF. Diagnosing the type of ARF
protein test, so this confounder must always be assessed for when a using fractional excretion of sodium is not absolute, as there are
positive urine protein is obtained. Hematuria suggests acute intrinsic some intrinsic causes that can be associated with a low fractional
ARF secondary to glomerular or injury to other kidney tissue. On excretion of sodium (e.g., contrast nephropathy, myoglobinuria,
microscopic examination, the key findings are cells, casts, and crystals, and interstitial nephritis). Highly concentrated urine (>500 mOsm/
and the presence of one or more of these suggests specific etiologies of L) suggests stimulation of antidiuretic hormone and intact tubular
the ARF (Table 45–6). The presence of crystals may suggest nephroli- function. These findings are consistent with prerenal azotemia.
thiasis and a postrenal obstruction. If red blood cells or red blood cell
casts are present, one should consider the presence of a physical injury
to the glomerulus, renal parenchyma or vascular beds. The finding of DIAGNOSTIC PROCEDURES
white blood cells or white blood cell casts suggests interstitial inflamma-
When the source of renal failure is unclear after a history, physical
tion (i.e., interstitial nephritis), which can be secondary to an allergic,
examination, and assessment of laboratory values, then imaging
granulomatous, or infectious process.
techniques such as abdominal radiography (kidneys, ureters, and
Simultaneous measurement of urine and serum electrolytes is also
bladder), CT, or ultrasonography may be helpful. These may reveal
helpful in the setting of ARF (see Table 45–4). From these values a
small, shrunken kidneys indicative of CKD, and postrenal obstruc-
fractional excretion of sodium can be calculated. The equation for the
tion can often be identified with a renal ultrasonogram and/or CT
calculation of the fractional excretion of sodium (FeNa) is:
scan. Renal ultrasonography is a useful means to detect obstruction
FeNa = (excreted Na/filtered Na) · 100 = (Uvol · UNa)/(GFR · SNa) · or hydronephrosis. Nephrolithiases as small as 5 nm, or narrowing
100 of the ureteral tract can be detected by ultrasonography. No contrast
dye is required, and it is noninvasive, simple, portable, and rapid to
where accomplish. In selected conditions under the guidance of a nephrol-
GFR = (Uvol · Ucr)/(Scr · t) ogist, more invasive procedures, such as cystoscopy or biopsy, may
be considered to detect the presence of malignancy, prostate hyper-
Thus trophy, uterine fibroids, nephrolithiases or ureterolithiases.
FeNa = (UNa · Scr · 100)/(Ucr · SNa) If insertion of a urinary catheter into the patient’s bladder after the
patient has voided or attempted to void does not yield a large volume
where Uvol is urine volume; Ucr is urine creatinine concentration; of urine (>500 mL), then one can usually exclude postrenal obstruction
UNa is urine sodium; Scr is serum creatinine concentration; SNa is distal to the bladder as the cause of ARF. Cystoscopy with retrograde
serum sodium concentration, which usually does not vary much; pyelography may be helpful if the possibility of obstruction exists, and
GFR is the glomerular filtration rate; and t is the time period over the insertion of a catheter did not result in a significant volume of urine.
which the urine is collected. In cases in which the cause of ARF is not evident, renal biopsies
The fractional excretion of sodium is one of the better diagnostic are useful in determining the cause in the majority of patients.33
parameters to differentiate the cause of ARF. A low urinary sodium Because of the associated risk of bleeding, a renal biopsy is rarely
concentration (<20 mEq/L) and low fractional excretion of sodium undertaken and should only be performed in those rare circum-
(<1%) in a patient with oliguria suggest that there is stimulation of the stances when a definitive diagnosis is needed to guide therapy, such
sodium-retentive mechanisms in the kidney and that tubular function as the precise etiology of glomerulonephritis (see Chap. 50).
 732
toxic agent, causing ARF in approcimately 30% of patients who
PREVENTION AND TREATMENT receive it.37 However, there are many infections for which no good
SECTION 5

alternative treatment exists. The nephrotoxic potential of amphoter-

Acute Renal Failure icin B deoxycholate can be reduced significantly simply by slowing
the infusion rate from a standard 4-hour infusion to a slower 24-
■ DESIRED OUTCOME hour infusion of the same dose.38 In a patient with risk factors for the
 Given the dismal outcome of established ARF, prevention is critical. development of ARF, liposomal forms of amphotericin B can be
In some cases, the risk of developing ARF may be predictable, such as used. These liposomal formulations are more expensive, but have
decreased perfusion secondary to abdominal surgery, coronary bypass been associated with a lower incidence of kidney damage.39
surgery, acute blood loss in trauma, and uric acid nephropathy, where
Renal Disorders

preventative strategies can be effective. When patients with risk factors Preventive Dialysis
for developing ARF are scheduled for surgery, the clinician should be
A novel approach to reducing the incidence of nephrotoxicity
aware that the likelihood of the patient developing ARF is high and
associated with radiocontrast dye administration is to provide RRT
consider preventative measures, including discontinuation of medica-
prophylactically to patients who are at high risk of ARF. Hemofiltra-
tions that may enhance the likelihood of renal damage (e.g., NSAIDs,
tion initiated prior to and continued for 24 hours after dye adminis-
angiotensin-converting enzyme inhibitors). Consequently the goals
tration has resulted in a significant reduction in mortality and a
are (a) to prevent ARF, (b) avoid or minimize further renal insults that
reduced need for dialysis.40 In contrast, the use of hemodialysis
would worsen the existing injury or delay recovery, and (c) provide
within 1 hour of contrast dye infusion did not yield an improvement
supportive measures until kidney function returns.
in nephrotoxicity rates, possibly because the toxicity caused by dye
occurs within minutes of its administration.41 Overall, evidence to
■ GENERAL APPROACH TO PREVENTION date does not support any consistent significant benefit with the
The general approach to the prevention of ARF is dependent on the routine use of extracorporeal blood purification to prevent radio-
setting the patient is in. To prevent the development of ARF, contrast dye–induced nephropathy over standard medical therapy.42
healthcare professionals should educate the patient on preventative
measures. The patient should receive guidance regarding their opti- ■ PHARMACOLOGIC THERAPIES
mal daily fluid intake (approximately 2 L/day) to avoid dehydration,
and if they are to receive any treatment that can pose a risk for insult Dopamine and Diuretics
to the kidney (e.g., chemotherapy or uric acid nephropathy). The Given the dismal outcome of established ARF, many drugs have been
patient’s fluid balance can be evaluated by measuring acute changes investigated for its prevention. Almost all of these approaches have
in weight, as other typical sources for weight changes in an adult been shown to be of little to no value. Low doses of dopamine (≤2
occur over more prolonged periods, and blood pressure changes. If mcg/kg/min) increase renal blood flow and might be expected to
the patient has a history of nephrolithiasis, they may benefit from increase GFR. Theoretically, this could be considered beneficial, as
dietary restrictions, depending on the type of stones that were an enhanced GFR might flush nephrotoxins from the tubules,
present in the past. If a patient has a Foley catheter in place, proper minimizing their toxicity. Furthermore, loop diuretics may decrease
care and monitoring needs to be performed to ensure that postob- tubular oxygen consumption by reducing solute reabsorption.43
structive ARF does not develop. Selected strategies to prevent drug- Despite these theoretical suggestions, controlled studies have not
related ARF are discussed briefly below and in detail in Chap. 49. supported these theories. Dopamine (2 mcg/kg/min) worsened renal
perfusion indices compared to saline in a crossover study in patients
■ NONPHARMACOLOGIC THERAPIES with ARF.44 A blinded and randomized trial conducted in patients
who were undergoing cardiac surgery compared dopamine at 2 mcg/
There are many situations in which administration of a nephrotoxin
kg/min, furosemide at 0.5 mcg/kg/min, and a 0.9% NaCl given at
cannot be avoided, such as when radiocontrast dye is to be adminis-
initiation of surgery to determine whether any of the these interven-
tered. In these settings, one of several nonpharmacologic therapies
tions is beneficial.45 Postoperative increases in Scr occurred signifi-
can be employed in an attempt to prevent the development of ARF.
cantly more often in the furosemide-treated patients than in the
Adequate hydration and sodium loading prior to radiocontrast dye
other two groups. Dopamine afforded no benefit compared to the
administration have been shown to be beneficial therapies. A trial
0.9% NaCl infusion, and thus also should not be used routinely in
comparing infusions of 0.9% NaCl or 5% dextrose with 0.45% NaCl
this manner.
administered prior to radiocontrast dye infusion conclusively dem-
onstrated that normal saline was superior in preventing ARF.34 The
intravenous solution infusion rate used in this study was 1 mL/kg per
hour beginning the morning that the radiocontrast dye was going to
CLINICAL CONTROVERSIES
be given, and all subjects were encouraged to drink fluids liberally as Despite most studies not showing improved patient outcomes
well. The benefits of 0.9% NaCl infusions have been found in similar with its use, low-dose dopamine continues to be commonly
studies,35 suggesting this regimen should be used in all at-risk used. The risks associated with dopamine use (extravasation and
patients who can tolerate the sodium and fluid load. In addition to the potential for significant dosing errors) suggest that its use
the correction of dehydration, saline administration may result in should be avoided whenever possible.
dilution of contrast media, prevention of renal vasoconstriction
leading to ischemia, and avoidance of tubular obstruction. The Giving low-dose dopamine infusions (≤2 mcg/kg/min) for the
results of one recent study suggest that hydration with sodium prevention of ARF is a surprisingly common practice given the
bicarbonate provides more protection than saline, perhaps by reduc- paucity of data to support its use. Although most studies do report
ing the formation of pH-dependent oxygen free radicals.36 an increase in urine output when low-dose dopamine is adminis-
In some cases, when nephrotoxic agent use cannot be avoided, tered, almost none report that this practice yields a benefit to the
there may be ways to administer them in a manner that reduces their patient. A meta-analysis of all low-dose dopamine studies con-
nephrotoxic potential. A good example of this is the use of ampho- ducted from 1966 to 2000 concluded that low-dose dopamine does
tericin B to treat fungal infections. Amphotericin is a highly nephro- not prevent ARF and its use cannot be justified.46
 733
The use of diuretics to prevent nephrotoxicity may actually result development of ARF. While it appears that blood glucose control
in intravascular volume depletion and thereby increase the risk of was the key factor associated with the mortality benefit, the reduc-

CHAPTER 45
ARF. A trial of forced diuresis, in which mannitol, furosemide, and/ tion in ARF may have been a consequence of the total dose of
or dopamine were given, and the resultant urinary losses were insulin used to treat the patient, suggesting a direct protective effect
replaced with intravenous solutions, found that diuretic use resulted of insulin.60 Strict glycemic control is recognized as an important
in little benefit compared to the administration of IV solutions goal for outpatient diabetics 61; however, intensive insulin therapy
alone.47 Interestingly, these investigators noted that patients who may now also become the standard of care for all critically ill
were unable to increase their urine output after diuretic administra- patients to prevent ARF and improve mortality.
tion were more likely to develop ARF than were patients who did
respond to diuretics. While this unresponsiveness to diuretics might
MANAGEMENT

Acute Renal Failure

simply be an indication of preexisting kidney damage, similar
reports have linked diuretic unresponsiveness to increased mortality
rates in critically ill patients with ARF.48 Established Acute Renal Failure
Fenoldopam ■ DESIRED OUTCOMES
Fenoldopam mesylate is a selective dopamine A-1 receptor agonist Short-term goals include minimizing the degree of insult to the kidney,
that increases blood flow to the renal cortex that has been investigated reducing extrarenal complications, and expediting the patient’s recov-
for its ability to prevent the development of ARF in many settings ery of renal function. The ultimate goal is to have the patient’s renal
including contrast dye induced nephropathy (CIN). Originally function restored to their pre-ARF baseline.
approved for use as an intravenous antihypertensive agent, several
small studies suggested that fenoldopam had salutary properties for ■ GENERAL APPROACH TO TREATMENT
the prevention of drug-induced nephrotoxicity. The largest, multi- Prerenal sources of ARF should be managed with hemodynamic
center, randomized, placebo-controlled trial of fenoldopam con- support and volume replacement. If the cause is immune related, as
ducted to date in patients with CKD found that fenoldopam use did may be the case with interstitial nephritis or glomerulonephritis,
not reduce the risk of CIN.49 Indeed, the CIN Consensus Working appropriate immunosuppressive therapy must be promptly initiated.
Panel stated that, fenoldopam along with dopamine, calcium channel Postrenal therapy focuses on removing the cause of the obstruction.
blockers, atrial natriuretic peptide, and 1-arginine, were not effective It is important to approach the treatment of established ARF with an
preventative therapeies to reduce the incidence of CIN.50 However, a understanding of the patient’s comorbidities and baseline renal func-
recent systematic review of randomized controlled trials of critically tion. Loss of kidney function combined with other clinical conditions,
ill patients or those undergoing major surgery, revealed that such as cardiac and liver failure, are associated with higher mortality
fenoldopam significantly reduced the risk of acute kidney injury and than that associated with the development of ARF alone.62 At times,
the need for renal replacement therapy. This analysis suggests that the most efficacious remedy for ARF is management of the comorbid
fenoldopam may be a viable entity to prevent the development of precipitating event. Appreciation of the baseline renal function is also
ARF in some clinical settings.51 A prospective, appropriately powered important at the outset of ARF management, because the presence of
trial will need to be performed to validate this observation. CKD indicates the highest degree of renal function that can be
attained after ARF resolution. Finally, the presence of CKD indicates
Acetylcysteine that the kidneys have less reserve, and thus there is a greater likelihood
N-acetylcysteine is a thiol-containing antioxidant that may effectively that the individual may not fully recover from the current insult.
reduce the risk of developing CIN in patients with pre-existing kidney  Once acute renal failure is established, the cause is known, and
disease, although a therapeutic benefit has not been consistently any specific therapy implemented, supportive care is the mainstay
demonstrated.52,53 The mechanism for N-acetylcysteine’s ability to of ARF management regardless of etiology. RRT may be necessary
reduce the incidence of contrast dye induced nephrotoxicity is not to maintain fluid and electrolyte balance while removing accumu-
clear, but likely is due to its antioxidant effects. Given the consistent lating waste products. The slow process of renal recovery cannot
findings of its efficacy and its relatively low cost, N-acetylcysteine begin until there are no further insults to the kidney. In the case of
should be given to all patients at risk for CIN.52,54–57 The recom- ATN, the recovery process typically occurs within 10 to 14 days after
mended N-acetylcysteine dosing regimen for prevention of CIN is 600 resolution of the last insult. The recovery period will be prolonged
mg orally every 12 hours for 4 doses with the first dose administered if the kidney is exposed to repeated insults.
prior to contrast exposure. Several other drugs have been investigated
for the prevention of ARF with varying degrees of success.42,52,53 ■ NONPHARMACOLOGIC
Theophylline may reduce the incidence of CIN with an efficacy
Initial modalities to reverse or minimize prerenal ARF include
that is perhaps comparable to that reported in studies of N-
removal of medications associated with diminished renal blood flow
acetylcysteine. However, findings are inconsistent across studies.58
or the physical removal of a prerenal obstruction. If dehydration is
A large, well-designed trial that incorporates the evaluation of
evident, then appropriate fluid replacement therapy, as described
clinically relevant outcomes is required to more adequately assess
below, should be initiated. Moderately volume-depleted patients can
the role of theophylline in CIN prevention.
be given oral rehydration fluids; however, if intravenous fluid is
required, isotonic normal saline is the replacement fluid of choice,
Glycemic Control and large volumes may be necessary to provide adequate fluid
Perhaps the most promising agent for the prevention of hospital- resuscitation. Typically, IV fluid challenges are initiated with 250 to
acquired ARF is a very old drug, but its use in the prevention of ARF 500 mL of normal saline over 15 to 30 minutes with an assessment
is new. Van den Berghe et al. randomized patients in a surgical after each challenge of the patient’s volume status. Unless profound
intensive care unit to receive either standard control (<200 mg/dL) dehydration is present, as may be seen in diabetic ketoacidosis or
or intensive glucose control measures (goal blood glucose concen- hyperosmolar hyperglycemic states, 1 to 2 L is usually adequate.
trations of 80 to 110 mg/dL).59 Tight blood glucose resulted in Patients with diabetic ketoacidosis or a hyperosmolar hyperglycemic
significant improvements in mortality and a 41% reduction in the state often have a 10% to 15% total-body water deficit, and more
 734
aggressive fluid replacement is necessary. The patient should be TABLE 45-7 The AEIOUs That Describe the Indications for Renal
monitored for pulmonary edema, peripheral edema, adequate blood Replacement Therapy
SECTION 5

pressure (diastolic blood pressure >60 mm Hg), normoglycemia and

Indication for Renal
electrolyte balance. Urine output may not be promptly observed, as
Replacement Therapy Clinical Setting
the kidney continues to retain sodium and water until rehydration is
achieved. Up to 10 L may be required in the septic patient during the A Acid–base abnormalities Metabolic acidosis resulting from the accumula-
first 24 hours, because of the profound increase in vascular capaci- tion of organic and inorganic acids
E Electrolyte imbalance Hyperkalemia, hypermagnesemia
tance and fluid leakage into the extravascular, interstitial space. 63
I Intoxications Salicylates, lithium, methanol, ethylene glycol,
Patients with ARF on top of preexisting CKD should not be
theophylline, phenobarbital
expected to produce urine beyond their preexisting baseline. In O fluid Overload Postoperative fluid gain
Renal Disorders

patients with anuria or oliguria, slower rehydration, such as 250-mL U Uremia High catabolism of acute renal failure
boluses or 100 mL/h infusions of normal saline, should be considered
to reduce the risk for pulmonary edema, especially if heart failure or
situations if dialysis can improve survival in ARF. Some recent data
pulmonary insufficiency exists. Other replacement fluids may be
suggest that more aggressive approaches using RRTs in a more
considered if the dehydration is accompanied by a severe electrolyte
liberal fashion may improve survival in critically ill ARF patients.65
imbalance amenable to large and relatively rapid infusions. For exam-
The choice of whether continuous therapies or intermittent RRTs
ple, dehydration resulting from severe diarrhea is often accompanied
are used is a matter of debate and is usually determined by physician
by metabolic acidosis caused by bicarbonate losses. A reasonable IV
preference and the resources available at the hospital.
rehydration fluid in this situation is 5% dextrose with 0.45% NaCl plus
50 mEq of sodium bicarbonate per liter, administered as boluses as
described above, followed by a brisk continuous infusion (200 mL/h) Intermittent Hemodialysis
until rehydration is complete, acidosis corrected, and diarrhea Intermittent hemodialysis (IHD) is the most frequently used RRT and
resolved. This fluid will remain mostly in the intravascular space, has several advantages. IHD machines are readily available in most
providing the necessary perfusion pressure to the kidneys, and also acute care facilities and healthcare workers are familiar with their use.
provide a substantial amount of bicarbonate to correct the acidosis. Hemodialysis treatments usually last 3 to 4 hours with blood flow rates
If the prerenal ARF is a result of blood loss, or complicated by to the dialyzer typically ranging from 200 to 400 mL/min. Advantages
symptomatic anemia, red blood cell transfusion to a hematocrit no of IHD include rapid removal of volume and solute, and rapid
higher than 30% is the treatment of choice.64 Although albumin is correction of most of the electrolyte abnormalities associated with
sometimes used as a resuscitative agent, its use should be limited to ARF. IHD can be scheduled at times to maximize staffing availability
individuals with severe hypoalbuminemia (e.g., liver disease, nephritic and treatments per day per machine, while minimizing inconvenience
syndrome) who are resistant to crystalloid therapy. These patients have to the patient. The primary disadvantage is hypotension, typically
severe hypoalbuminemia-associated third spacing that complicates caused by rapid removal of intravascular volume over a short period of
fluid management, and albumin may be useful in this setting. time. Venous access for dialysis can be difficult in hypotensive patients
The most common interventions that must be made when treating and can limit the effectiveness of IHD, leading to ineffective solute
patients with intrinsic or postobstructive ARF involve fluid and elec- clearance, lack of acidosis correction, continued volume overload, and
trolyte management. Most patients with these types of ARF, as well as delayed recovery because of further renal ischemia insults. If hemodi-
those with a prerenal cause who are excessively fluid resuscitated alysis is carefully monitored and hypotension avoided, better patient
ultimately become fluid overloaded. This means drug infusions and outcomes can be achieved.66 Patients with stage 5 CKD generally
nutrition solutions must be maximally concentrated. So-called keep achieve adequate solute and volume control with thrice-weekly dialy-
vein open or maintenance intravenous infusions should be minimized sis, but hypercatabolic, fluid-overloaded patients with ARF may
unless the patient is euvolemic or is receiving RRT to maintain fluid require daily hemodialysis treatments.67 The use of daily versus thrice-
balance. Supportive care goals for the hospitalized patient with any weekly IHD in the setting of ARF patients is associated with a
type of ARF include maintenance of adequate cardiac output and reduction in dialysis-related hypotension and a shorter period of time
blood pressure to allow adequate tissue perfusion. However, a fine to full recovery of kidney function.68 Chapter 48 provides a more
balance must be maintained in anuric and oliguric patients unless the detailed explanation of the principles and processes of hemodialysis.
patient is hypovolemic or is able to achieve fluid balance via RRT. If
fluid intake is not minimized, edema may rapidly develop, especially in Continuous Renal Replacement Therapies
hypoalbuminemic patients. In contrast, vasopressors, like dopamine at
In contrast to IHD, CRRTs that were developed over the past 15 years
doses of ≥2 mcg/kg/min or norepinephrine when used to maintain
have proven to be a viable management approach for hemodynami-
adequate tissue perfusion, may also induce kidney hypoxia as the result
cally unstable patients with ARF.69 Several CRRT variants have been
of a reduction in renal blood flow. Consequently, Swan-Ganz moni-
developed, including continuous venovenous hemofiltration (CVVH),
toring may be necessary for critically ill patients (see Chap. 25).
continuous venovenous hemodialysis (CVVHD), and continuous ven-
 Because there is no current definitive therapy for ARF, support-
ovenous hemodiafiltration (CVVHDF). They differ in the degree of
ive management remains the primary approach to prevent or reduce
solute and fluid clearance that can be clinically achieved as a result of
associated complications or death. In the presence of severe ARF,
the use of diffusion, convection, or a combination of both. Although
RRTs are commonly prescribed to manage uremia, metabolic acido-
solute removal is slower, a greater amount can be removed over a 24-
sis, hyperkalemia and complications of excess fluid retention, such as
hour period compared to IHD, which is associated with improved
pulmonary edema or accumulation of renally cleared medications.
outcomes in critically ill patients with ARF.70
Although precise indications for starting RRT are unclear, some
In CVVH, solute and fluid clearance is primarily a result of
general guidelines for therapy have been proposed (Table 45–7).
convection where passive diffusion of fluids containing solutes is
removed while volume absent of the solutes is replaced to the patient
Renal Replacement Therapies (Fig. 45–4). Continuous venovenous hemodialysis (CVVHD) provides
RRTs can be administered either intermittently or continuously. extensive solute removal primarily by diffusion, where solute molecules
The optimal mode for hemodialysis is unclear, and varies depending at a higher concentration (plasma) pass through the dialysis membrane
on the clinical presentation of the patient. It is unclear in many to a lower concentration (dialysate) and some fluid is removed as a
 735

CVVH CVVHD

CHAPTER 45
Blood Flow Out IV Replacement Fluid Blood Flow Out
190 mL/min 30 mL/min 190 mL/min
Dialysate Flow Rate
IV Fluids
IV Fluids 30 mL/min
Medications
Medications

Acute Renal Failure

UF Out: 32–45 mL/min Dialysate/Ultrafiltrate Out: 35 mL/min
Blood Flow In
Blood Flow In Net fluid removal: 10 mL/min Net fluid removal: 5 mL/min
200 mL/min 200 mL/min

CVVHDF SLEDD
Blood Flow Out Blood Flow Out
150–200 mL/min
190 mL/min
Dialysate Flow Rate Dialysate Flow Rate
15 mL/min 300–400 mL/min
IV Replacement Fluids IV Fluids
IV Fluids Medications
Medications

Dialysate Out: 300–400 mL/min

Dialysate/Ultrafiltrate Out: Blood Flow In UF Out: Variable
Blood Flow In
25–50 mL/min 150–200 mL/min
200 mL/min

FIGURE 45-4. Several RRTs are commonly utilized in ARF patients including one of the three primary CRRT variants: (a) continuous veno-venous
hemofiltration (CVVH), (b) continuous veno-venous hemodialysis (CV VHD), (c) continuous veno-venous hemodiafiltration (CV VHDF), and the hybrid
intermittent hemodialysis therapy (d ) slow extended daily dialysis (SLEDD). The blood circuit in each diagram is represented in red, while the hemofilter/
dialyzer membrane is yellow and the ultrafiltration/dialysate compartment is depicted in brown. Excess body water and accumulated endogenous waste
products are removed solely by convection when CV VH is employed. With CV VHD, waste products are predominantly removed as the result of passive
diffusion from the blood where they are in high concentration to the dialysate. The degree of fluid removal which is accomplished by convection is
usually minimal. CVVHDF utilizes convection to a degree similar to that employed during CV VH as well as diffusion, and thus is often associated with
the highest clearance of drugs and waste products. Finally, SLEDD employs lower blood and dialysate flow rates that IHD, but due to its extended
duration it is a gentler means of achieving adequate waste product and fluid removal.

function of the ultrafiltration coefficient of the dialyzer. Because the Because of the reduced blood flow rates relative to IHD, thrombosis
dialysate flows in a countercurrent direction to the plasma flow on the is a significant concern with CRRT, and thus some form of anticoagula-
other side of the membrane, the concentration gradient is maximized. tion is generally necessary for almost all patients. Typical anticoagulation
This procedure is associated with a lower incidence of clotting than is achieved by the administration of unfractionated heparin, or in some
CVVH because of reduced hemoconcentration as there is less fluid cases, a low-molecular-weight heparin, a direct thrombin inhibitor, or
removal during the process. CVVHDF combines both hemofiltration citrate solution.71 Replacement fluids can be infused either just before or
and hemodialysis, achieving even higher solute and fluid removal rates after the dialyzer/hemofilter. Infusing fluids after the hemofilter can
(Fig. 45–4). The ultrafiltration rate is an important determinant of the result in hemoconcentration within the filter, a factor associated with an
effectiveness of all three forms of CRRT: achievement of a removal rate increased risk of thrombosis of the dialyzer. Replacing fluids before the
of 35 mL/kg/h is associated with improved survival.70 filter reduces thrombosis risk, but also reduces solute clearance.
 736
Disadvantages of CRRT are that not all hospitals have the special found ineffective in human trials. Numerous agents have been investi-
equipment necessary to provide these treatments, they require inten- gated and shown no benefit in the treatment of established ARF.77 In
SECTION 5

sive nursing care around the clock, and they are more expensive than recent years thyroxine,78 dopamine,79,80 and loop diuretics47,81,82 have
IHD because of the need to individualize the intravenous replacement all been documented to either be of no help or to worsen patient
and dialysate fluids. There is also very little known about drug-dosing outcomes. For example, a 77% increase in mortality or nonrecovery of
requirements for those who are receiving these therapies. CRRT use is renal function was reported in patients with ARF who received a loop
most commonly considered for those patients with higher acuity diuretic compared to patients who did not receive loop diuretics.47
because of their intolerance of IHD-associated hypotension. In one These findings may be explained by the fact that sicker, fluid-over-
meta-analysis, no difference in clinical outcomes between the two loaded patients may be more likely to receive diuretics, nonetheless no
approaches was seen until there was an adjustment for severity of benefit to loop diuretic use could be found in any subanalysis. Conse-
Renal Disorders

illness. CRRT was then found to be associated with a lower mortality quently, loop diuretic use should be reserved for fluid-overloaded
rate.72 Because patients treated with continuous therapies are almost patients who make adequate urine in response to diuretics to merit
always more critically ill than those treated by IHD, comparisons of their use.81 Prevention of pulmonary edema is an important goal, and
outcome must control for illness severity. it is preferable that it be accomplished with diuretics instead of more
invasive RRTs, despite the previously mentioned finding that diuretic
use may be associated with diminished outcomes.47 The most effective
drugs in producing diuresis in the patient with ARF, mannitol and the
CLINICAL CONTROVERSY loop diuretics, have distinct advantages and disadvantages. Mannitol,
Some clinicians believe that CRRTs are preferable to IHD because which works as an osmotic diuretic, can only be given parenterally. A
they provide more consistent fluid and waste product removal. typical starting dose is mannitol (20%) 12.5 to 25 g infused intrave-
Others suggest that IHD is preferable because the nursing and nously over 3 to 5 minutes. It has little nonrenal clearance, so when
medical staff is more familiar with its use and round-the-clock given to anuric or oliguric patients, mannitol will remain in the patient,
nursing is not needed. New hybrid approaches with slower removal potentially causing a hyperosmolar state. Additionally, mannitol may
over a prolonged time period may potentially appeal to both groups. cause ARF itself, so its use in ARF must be monitored carefully by
measuring urine output and serum electrolytes and osmolality.83
CRRT and hybrid extended-duration intermittent hemodialysis are Because of these limitations of mannitol, some clinicians recommend
now being commonly used for critically ill patients with ARF. With that it be reserved for the management of cerebral edema.84
CRRT, more solute and water removal can be achieved than with the Furosemide, bumetanide, and torsemide are the most frequently
thrice-weekly hemodialysis treatments used for patients with ESRD. used loop diuretics in patients with ARF. Ethacrynic acid is typically
This has influenced how dialysis is prescribed in the intensive care unit reserved for patients who are allergic to sulfa compounds. Furo-
for hypercatabolic patients with ARF. Daily IHD is associated with semide is the most commonly used loop diuretic because of its lower
improved survival and faster resolution of ARF compared to dialysis cost, availability in oral and parenteral forms, and reasonable safety
given every other day.62 Daily delivery of IHD presents challenges to and efficacy profiles. A disadvantage with furosemide is its variable
clinicians prescribing drug and nutrition therapy, as most of these oral bioavailability in many patients and potential for ototoxicity with
dosing guidelines are based on thrice-weekly dialysis, and application high serum concentrations that may be attained with rapid, high-dose
of these guidelines may yield inappropriate outcomes. bolus infusions. Consequently, initial furosemide doses, which should
Hybrid IHD therapies have a variety of names, with the two most not exceed 40 to 80 mg, are usually administered intravenously to
common being sustained low-efficiency dialysis73 and slow, extended, assess whether the patient will respond. Torsemide and bumetanide
daily dialysis (see Fig. 45–4).74 These therapies use slower blood (150 have better oral bioavailability than furosemide. Torsemide has a
to 200 mL/min) and dialysate flow rates (300 mL/min) with extended longer duration of activity than the other loop diuretics, which allows
treatment periods of 6 to 12 hours. Unlike CRRT, these therapies do for less-frequent administration but which also may make it more
not require any new equipment.74 Anticoagulation is still required, difficult to titrate the dose. Loop diuretics all work equally well
but the amount necessary compared to CRRT is lower.74 Although provided that they are administered in equipotent doses. In a patient
the use of hybrid hemodialysis therapies is increasing, our knowledge who is unresponsive to aggressive intravenous loop diuretic therapy,
of the impact of these therapies on drug removal is very limited.75,76 switching to another loop diuretic is unlikely to be beneficial.

■ PHARMACOLOGIC Diuretic Resistance

Once the kidney has been damaged by an acute insult (e.g., reduced Inability to respond to administered diuretics is common in ARF
perfusion or exposure to exogenous or endogenous nephrotoxins), and is associated with a poor patient outcome (Table 45–8).47 An
initial therapies should be directed to prevent further insults to the effective technique to overcome diuretic resistance is to administer loop
kidney, thereby minimizing extension of the injury.20 If sepsis is diuretics via continuous infusions instead of intermittent boluses. Less
present, antibiotic therapy regimens should be adjusted for decreased natriuresis occurs when equal doses of loop diuretics are given as a
renal elimination, the potential for increased elimination if the agent is bolus instead of as a continuous infusion. Furthermore, adverse reac-
removed by hemodialysis, and the ability to treat the infection to tions from loop diuretics (myalgia and hearing loss) occur less fre-
prevent further damage to the kidney. The time to recovery from ARF quently in patients receiving continuous infusion compared to those
is determined from the most recent insult to the kidney, not the first receiving intermittent boluses, ostensibly because higher serum con-
insult. Hospitalized patients with ARF are at high risk for repeated centrations are avoided. However, these adverse effects still may occur
episodes of kidney injury as the result of repeated exposures to with continuous infusion of loop diuretics and should be monitored.85
nephrotoxic agents and hypotensive episodes, among other problems. The finding that the continuous infusions of loop diuretics have
These increased risks, coupled with the fact that no drugs have been efficacy that is at least as good as intermittent bolus dosing, with fewer
found to accelerate ARF recovery, dictate the way clinicians approach adverse effects, appears to be consistent for all agents, including furo-
the ARF patient. semide,86 bumetanide,87 and torsemide.88 When a continuous loop
To date, no pharmacologic approach to reverse the decline or diuretic infusion is used, an initial loading dose is given (equivalent to
accelerate the recovery of renal function has been proven to be clinically furosemide 40 to 80 mg) prior to the initiation of a continuous infusion
useful. Many agents have looked promising in animal trials, only to be at 10 to 20 mg/h of furosemide or its equivalent. Patients with low
 737

TABLE 45-8 Common Causes of Diuretic Resistance in Patients dose of 5 mg is commonly administered 30 minutes prior to an
intravenous loop diuretic to allow time for absorption. Additionally,

CHAPTER 45
with Acute Renal Failure
this combination has been found to be efficacious in pediatric patients
Causes of Diuretic Resistance Potential Therapeutic Solutions
in addition to adults.90 The combination of mannitol plus intravenous
Excessive sodium intake (sources may Remove sodium from nutritional loop diuretics is used by some practitioners,51 but no convincing
be dietary, IV fluids, and drugs) sources and medications evidence of the superiority of this combination regimen to conven-
Inadequate diuretic dose or inappropri- Increase dose, use continuous infusion tional dosing of either diuretic alone exists.
ate regimen or combination therapy
Reduced oral bioavailability (usually Use parenteral therapy; switch to oral
furosemide) torsemide or bumetanide ■ ELECTROLYTE MANAGEMENT
Nephrotic syndrome (loop diuretic pro- Increase dose, switch diuretics, use Hypernatremia and fluid retention are frequent complications of ARF,

Acute Renal Failure

tein binding in tubule lumen) combination therapy and thus sodium restriction is a necessary intervention. In general,
Reduced renal blood flow
patients should receive no more than 3 g of sodium per day from all
Drugs (NSAIDs ACEIs, vasodilators) Discontinue these drugs if possible
sources, including intravenous fluids, drugs, and enteral intake. Clini-
Hypotension Intravascular volume expansion and/or
vasopressors cians should be vigilant about sources of sodium. Excessive sodium
Intravascular depletion Intravascular volume expansion intake is a common reason diuretic therapy fails. Commonly adminis-
Increased sodium resorption tered intravenous antibiotics, as well as other medications, may con-
Nephron adaptation to chronic Combination diuretic therapy, sodium tain significant amounts of sodium; for example, 1 L of 0.9% NaCl
diuretic therapy restriction yields 154 mEq (3.5 g) of sodium. At usual doses, intravenous metro-
NSAID use Discontinue NSAID nidazole provides 1.3 g of sodium per day, ampicillin up to 800 mg,
Heart failure Treat the heart failure, increase diuretic piperacillin approximately 700 mg, and fluconazole 500 mg. The
dose, switch to better-absorbed loop cumulative effect of a few sodium-containing medications and fluids
diuretic can be significant.
Cirrhosis High-volume paracentesis
In continuous and intermittent RRTs there usually is less concern
Acute tubular necrosis Higher dose of diuretic, diuretic combina-
tion therapy, add low-dose dopamine
about hyponatremia developing because these therapies often
incorporate isonatremic (135 to 140 mEq/L of sodium) solutions as
ACEIs, angiotensin-converting enzyme inhibitors; NSAIDs, nonsteroidal antiinflammatory drugs. the dialysate or ultrafiltrate replacement solutions. Serum sodium
concentrations should be monitored daily. Hyperkalemia, hyper-
creatinine clearances may have much lower rates of diuretic secretion phosphatemia, and, to a lesser extent, hypermagnesemia are electro-
into the tubular fluid; consequently, higher doses are generally used in lyte disorders that are frequently seen in patients with ARF. This is
patients with renal insufficiency.84 Diuretic resistance may occur simply generally not a serious concern in those who are receiving RRT, but
because excessive sodium intake overrides the ability of the diuretics to electrolytes should be monitored closely in all patients with ARF.
eliminate sodium. However, other reasons for diuretic resistance often The most common electrolyte disorder encountered in ARF
exist in this population. Patients with ATN have a reduced number of patients is hyperkalemia, as more than 90% of potassium is renally
functioning nephrons on which the diuretic may exert its action. Other eliminated. Life-threatening cardiac arrhythmias may occur when the
clinical states, like glomerulonephritis, are associated with heavy pro- serum potassium is over 6 mmol/L, so potassium restriction is essen-
teinuria. Intraluminal loop diuretics cannot exert their effect in the loop tial. All patients with ARF should have serum potassium monitored at
of Henle because they are extensively bound to proteins present in the least daily, and twice daily for those who are seriously ill. This
urine. Still other patients may have greatly reduced bioavailability of frequency is a consequence of the seriousness of the potential arrhyth-
oral furosemide because of intestinal edema, often associated with high mias, the dynamic nature of potassium serum concentrations in the
preload states, which further reduces oral furosemide absorption. Table acutely ill patient, the potential for metabolic acidosis leading to
45–8 includes possible therapeutic options to counteract each form of increased extracellular potassium concentrations, and potassium’s
diuretic resistance. Combination therapy of loop diuretics plus a diuretic ubiquitous presence in foods and some medications. Commonly
from a different pharmacologic class may be an alternative approach in encountered medications that contain substantial amounts of potas-
the setting of ARF.89 Loop diuretics increase the delivery of sodium sium include oral phosphorous replacement powders (e.g., Neutra-
chloride to the distal convoluted tubule and collecting duct. With time, Phos and Neutra-Phos-K) and alkalinizers (Polycitra). Many foods are
these areas of the nephron compensate for the activity of the loop high in potassium, including potatoes, beans, and various fruits. Some
diuretic and increase sodium and chloride resorption. Diuretics that medications may promote potassium retention by the kidneys, and
work at the distal convoluted tubule (chlorothiazide and metolazone) or should also be avoided or closely monitored (see Chap. 54 ). Typically
the collecting duct (amiloride, triamterene, and spironolactone) may no potassium should be added to parenteral solutions unless hypoka-
have a synergistic effect when administered with loop diuretics by lemia is documented. Patients receiving enteral nutrition should be
blocking the compensatory increase in sodium and chloride resorption. limited to a 3-g potassium diet. Patients receiving RRT should also
The combination of loop diuretics and usual doses of thiazide diuretics have their serum potassium concentration measured at least daily.
may be effective in renal disease despite the accumulation of endogenous Some centers add no potassium to their CRRT solutions and hypoka-
organic acids in renal disease that blocks the transport of loop diuretics lemia can result unless one is prospectively monitoring for its develop-
into the lumen. If oral thiazides cannot be given to the patient, chlo- ment. Chapter 54 discusses the treatment of hyperkalemia in detail.
rothiazide 500 mg can be administered parenterally. Other electrolytes that require monitoring include phosphorous
Several drug combinations with loop diuretics have been investi- and magnesium. Both are eliminated by the kidneys and are not
gated, including the addition of one or more of the following: theophyl- removed efficiently by dialysis. In the early stages of ARF, hyperphos-
line, acetazolamide, spironolactone, thiazides, or metolazone.83 Of phatemia might be more common than hypophosphatemia. Patients
these combinations, oral metolazone is used most frequently with who have significant tissue destruction (e.g., trauma, rhabdomyolysis,
furosemide. Metolazone, unlike other thiazides, produces effective tumor lysis syndrome) may have significant phosphorus released from
diuresis at a GFR below 20 mL/min. This combination of metolazone the destroyed tissue. Treatment of the hyperphosphatemic state can
and a loop diuretic has been used successfully in the management of include CRRT. Calcium-containing antacids should be avoided to
fluid overload in patients with heart failure, cirrhosis, and nephrotic prevent precipitation of calcium phosphate in the soft tissues. Typi-
syndrome. Despite a lack of supporting evidence, oral metolazone at a cally, the dietary intake of phosphorous and magnesium is restricted,
 738
but in patients receiving prolonged renal replacement, deficiency states cian’s projection of the optimal dosage regime. For renally eliminated
can occur, particularly in pediatric patients because of their reduced drugs (>30% excreted unchanged in the urine), particularly for agents
SECTION 5

body stores. In contrast to the patient with CKD, calcium balance is with a narrow therapeutic range, serum drug concentration measure-
usually not an important issue for the ARF patient because of the ments and assessment of pharmacodynamic responses are likely to be
limited duration of the illness. One exception to this is in patients who necessary. If hepatic function is intact, choosing an agent eliminated
are receiving CRRT with citrate as the anticoagulant. Citrate binds to primarily by the liver may be preferred. However, any renally elimi-
serum calcium and without an adequate concentration of calcium, nated active metabolites may accumulate to a point where they can
blood cannot form a clot. Citrate is thus typically infused before the elicit an undesired pharmacologic effect. Renal failure can also inde-
dialyzer/hemofilter to maintain the dialyzer circuit calcium levels pendently impair drug metabolism.99 Clinical experiences and phar-
between 0.35 and 0.50 mmol/L. Calcium chloride (10 g of CaCl diluted macokinetic studies in patients with established ARF are fairly limited.
Renal Disorders

in 500 mL normal saline), or gluconate (20 g of calcium gluconate to The use of dosing guidelines based on data derived from patients with
500 mL normal saline) is then administered prior to returning the stable CKD, however, may not reflect the clearance and volume of
blood to the patient to maintain systemic ionized calcium levels distribution in critically ill ARF patients (see Chap. 51).100
between 1.11 to 1.31 mmol/L.92 The citrate that reaches the systemic Edema, which is common in ARF, can significantly increase the
circulation is subsequently metabolized by the liver. Severe hypocalce- volume of distribution of many drugs, particularly water-soluble
mia can result in arrhythmias, and even death, so frequent monitoring ones with relatively small volumes of distribution. Increased fluid
of unbound serum calcium concentrations is essential. distribution into the tissues (i.e., sepsis, anasarca in heart failure) can
also contribute to a larger volume of distribution for many drugs and
■ NUTRITIONAL INTERVENTIONS thereby reduce the proportion of drug in the plasma that is available
to be removed by CRRT or IHD. ARF frequently occurs in critically
Baseline nutritional status is a strong predictor of outcomes in ill patients and thus multisystem organ failure must often be con-
patients with ARF.93 The provision of enteral nutrition to patients tended with. Reductions in cardiac output or liver function in
with ARF in intensive care units is associated with an improvement in addition to volume overload can significantly alter the pharmacoki-
outcomes.94 Parenteral nutrition, however, has not demonstrated the netic profile of many drugs such as vancomycin, aminoglycosides,
same benefit and some have questioned whether it should be used in and low-molecular-weight heparins.101,102
this population.95 (see Chapter 147 for a detailed discussion.) In almost all cases where rapid onset of activity is desired, a
Because fluid intake often must be restricted in severely volume- loading dose may be necessary to promptly achieve desired serum
overloaded ARF patients, the design and provision of adequate concentrations because the expanded volume of distribution and
parenteral or enteral nutrition are problematic (see Chap. 147). the prolonged elimination half-life result in an extended time (3.5
Septic patients with ARF usually are hypercatabolic and normalized times the half-life) until steady-state concentrations are achieved.
protein catabolic rates of up to 1.75 g/kg/day have been reported, Maintenance dosing regimens should be reassessed frequently and
but this value varies widely among patients.96 Most patients with be based on the patient’s current renal function. A dose that
ARF have difficulty tolerating the amount of intravenous fluid provides the desired serum concentration on one day may be
required to replace catabolized protein unless they are receiving inappropriate only a few days later if the patient’s fluid status or
CRRT or daily hemodialysis. renal function has changed dramatically.
Although patients with ARF typically experience elevated levels of
potassium, magnesium, and phosphorus, which often necessitate
restriction of these from nutrition formulas, it is not uncommon for
CLINICAL CONTROVERSY
deficiency states to occur in patients receiving CRRT, despite incorpo-
ration of these electrolytes into the replacement fluid solutions. The In the volume-depleted patient requiring a renally eliminated med-
effect of CRRT on the delivery and removal of macro- and micronutri- ication, dosing regimens based on the initial Scr prior to fluid
ents must also be taken into account. The dextrose contained in CRRT therapy have the potential to underestimate renal function and drug
replacement solutions may contribute a significant amount of calories elimination, resulting in subtherapeutic serum concentrations.
to the patient’s regimen. The removal of protein during dialysis, Although not accepted as a standard practice, an initial 24-hour
especially during peritoneal dialysis, may necessitate an increase of the dosing regimen with a bolus might be optimal for many patients.
protein intake up to 2.5 g/kg/day in some patients (see Chap. 147).
Another nutritional consideration for patients receiving CRRT is Drug therapy individualization for the ARF patient who is receiv-
the heat losses as a consequence of the cooling of the patient’s blood ing any form of renal replacement therapy is complicated by the fact
as it traverses the extracorporeal circuit and as a result of the use of that patients with ARF may have a higher residual nonrenal clearance
room-temperature intravenous ultrafiltrate replacement solutions.97 than CKD patients who have a similar CLcr. This has been reported with
The energy loss for patients who are receiving continuous hemofil- some drugs, such as ceftriaxone, imipenem, and vancomycin.103–106
tration is estimated to be as high as 800 kcal/day.98 Most of this heat Alterations in the activity of some, but not all, cytochrome P450
loss can be attenuated by warming the intravenous ultrafiltrate enzymes have been demonstrated in patients with CKD.99 The nonre-
replacement solution.98 However, many hospitals are unable to heat nal clearance of imipenem in patients with ARF (91 mL/min) is
intravenous solutions as they are infused, so recognition of this large between the values observed in stage 5 CKD patients (50 mL/min)
source of energy loss is necessary so that the clinician can design an and those with normal renal function (130 mL/min).106 This may be
adequate nutritional prescription. the result of less accumulation of uremic waste products that may
alter hepatic function. A nonrenal clearance value in a patient with
ARF that is higher than anticipated based on data from individuals
■ DRUG-DOSING CONSIDERATIONS with CKD would result in lower-than-expected, possibly subthera-
Optimization of drug therapy for patients with ARF is often quite peutic, serum concentrations. For example, to maintain comparable
challenging. The multiple variables influencing responses to the drug serum concentrations, the imipenem dose requirement in patients
regimen include the patient’s residual drug clearance, the accumula- with ARF would be 2,000 mg/24 hours as compared to the recom-
tion of fluids, which can markedly alter a drug’s volume of distribu- mended dosage for patients with ESRD of 1,000 mg/24 hours.106 As
tion, and delivery of CRRT or IHD, which can increase drug clearance ARF persists, the nonrenal clearance values appear to approach those
and impact the patient’s fluid status to further complicate the clini- observed in patients with CKD.107,108 Finally, the clearance of ami-
 739
noglycosides has been reported to be higher and the elimination half- 50
life shorter in those with severe ARF compared to ESRD patients

CHAPTER 45
requiring hemodialysis.100 Thus, application of dosing regimens
derived from studies in patients with CKD and ESRD may result in 40

Ceftazidime clearance, mL/min

underdosing of these agents and thereby contribute to less than
optimal clinical outcomes.
30

IHD Compared to CRRT

In addition to patient-specific differences, there are marked differ- 20
ences between IHD and the three primary types of CRRT—CVVH,

Acute Renal Failure

CVVHD, and CVVHDF—with regard to drug removal.109–111
10
CRRT During CVVH, drug removal primarily occurs via convec-
tion/ultrafiltration (the passive transport of drug molecules at the
concentration at which they exist in plasma water into the ultrafil- 0
5.0 45.0 8.3 16.7 25.0 33.3
trate). Convective removal is most efficient for smaller agents,
UFR DFR
typically less than 15,000 daltons in size, and those that are primarily
unbound in the plasma. The clearance of a drug by either of these FIGURE 45-5. The effect of increasing ultrafiltration rate (UFR in millili-
methods is thus a function of the membrane permeability for the ters per minute) and dialysate flow rate (DFR in milliliters per minute) on
drug, which is called the sieving coefficient (SC) and the rate of the clearance of ceftazidime. (Adapted from reference 116.)
ultrafiltrate formation (UFR). Alteration in the pore size of the filter
and surface charge relative to the molecule being removed may vary agents such as ceftazidime during CVVH and CVVHD, respectively
between different dialyzers. If diffusion of the drug is not dependent (Fig. 45–5).116
on the filter pore size, then the SC can be calculated as follows: Another readily apparent factor that changes drug dosing is the
type of RRT used in the patient. CRRT can rapidly remove excess
SC = (2 × CUF)/[(Ca) + (Cv)]
fluid from edematous patients, thereby changing the volume of
where Ca and Cv are the concentrations of the drug in the plasma distribution (VD) of drugs with limited distribution (low VD suggest-
going into and returning from the dialyzer/hemofilter, respectively, ing a greater proportion in the plasma or extracellular fluid) fairly
and CUF is the concentration in the ultrafiltrate. The SC is often rapidly. Drug clearances attained by IHD, CRRTs, and hybrid RRTs
approximated by the fraction unbound (fu) because this informa- all differ from each other and must be added to any endogenous drug
tion may be more readily available. Thus the clearance by CVVH clearance that the patient generates.105 An algorithmic approach for
can be calculated as: drug dosage adjustment in patients undergoing CRRT has been
proposed.110 In CRRT, the clearance of a given agent may be ascer-
ClCVVH = UFR × SC tained from published reports.110,117,118 Table 45–9 summarizes the
or approximated as:
ClCVVH = UFR × fu TABLE 45-9 Predicted and Measured Sieving Coefficients of
Selected Drugs
In CVVHDF, clearance is a combination of both diffusion and
Drug Predicted Measured
convection. The ClCVVHDF can be mathematically approximated
providing the blood flow rate is greater than 100 mL/min and the Amikacin 0.95 0.88
dialysate flow rate (DFR) is between 8 and 33 mL/min as: Amphotericin 0.01 0.32–0.4
Ampicillin 0.80 0.6–0.69
ClCVVHDF = (UFR × fu) + Cldiffusion Cefepime 0.97 0.47-0.97
Cefoperazone 0.10 0.27–0.69
where Cldiffusion is the clearance via diffusion from plasma water to Cefotaxime 0.62 0.55–1.1
the dialysate. In the clinical setting, it is not possible to separate Cefoxitin 0.30 0.32
these two components (UFR and DFR) of ClCVVHDF. In essence the Ceftazidime 0.90 0.38–0.78
ClCVVHDF is calculated as the product of the combined ultrafiltrate Ceftriaxone 0.10 0.71–0.82
and dialysate volume (Vdf) and the concentration of the drug in this Clindamycin 0.25 0.49–0.98
fluid (Cdf) divided by the plasma concentration (Cpmid) at the Digoxin 0.75 0.96
midpoint of the Vdf collection period. Erythromycin 0.25 0.37
Individualization of therapy for a patient receiving CRRT therapy 5-Fluorocytosine 0.96 0.98
is dependent on the patient’s residual renal function and the clearance Gentamicin 0.95 0.81–0.75
Imipenem 0.80 0.78
of the drug by the mode of CRRT the patient is receiving. There are
Metronidazole 0.80 0.80
differences in the rate of drug removal, not only between the three
Mezlocillin 0.68 0.68
primary modes of CRRT, but also within each mode.105,109–112 This is a N-acetylprocainamide 0.80 0.92
result of differences in the filter membrane composition, variable Nafcillin 0.20 0.47
degrees of drug binding to the membrane, and the permeability charac- Netilmicin — 0.85
teristics of the membrane.113–116 The primary factors that influence Oxacillin 0.05 0.02
drug clearance during CRRT are thus ultrafiltration rate, blood flow Phenobarbital 0.60 0.86
rate, and dialysate flow rate. For example, clearance in CVVH is directly Phenytoin 0.10 0.45
proportional to the ultrafiltration rate, whereas clearance during Procainamide 0.80 0.86
CVVHDF, which depends on both the ultrafiltration rate and the Theophylline 0.47 0.85
dialysate flow rate, increases as either flow rate increases. An increase in Tobramycin 0.95 0.78–0.86
Vancomycin 0.90 0.5–0.8
ultrafiltration flow rate (5 to 45 mL/min) and dialysate flow rate (8.3 to
33.3 mL/min), however, can have dramatic effects on clearance of Adapted from references 109–112, 117 and 118.
 740
sieving coefficients of frequently used drugs. These data can be used dosing regimen may require daily assessment of the clinical status of
to design initial dosage regimens for patients receiving CVVH.109,112 the patient and any planned or recently administered hemodialysis.
SECTION 5

For example, IM is a 48-year-old, 60-kg male with a Scr that has

increased from 2.3 mg/dL to 7.2 mg/dL over 3 days. The residual
Clcr value in this patient, calculated using the Jeliffe and Jeliffe CLINICAL CONTROVERSY
equation (see Chap. 44) is 4.8 mL/min. The consulting nephrologist
Some clinicians use a standard ESRD dosage regimen despite the
recommends that CVVHDF be initiated using a Fresenius F-80 filter
fact that renal function can fluctuate such that the patient may
at blood, ultrafiltrate, and dialysate flow rates of 150, 15, and 33.3
be in one dosing range one day and in another the next. Others
mL/min, respectively. The patient is to receive cefepime while on
believe, however, that the patient’s clinical need for the drug and
CVVHDF. The patient’s residual cefepime clearance (ClRES) can be
any change in the volume of distribution or the RRT therapy
Renal Disorders

estimated using the following regression equation relating Clcr and should be considered if one has any chance of achieving the
cefepime clearance: target serum concentrations.
ClRES (mL/min) = [0.96 × (Clcr)] + 10.9
Overall, there are a tremendously large number of potential
ClRES = [0.96 × (4.8)] + 10.9 = 15.5 mL/min pharmacokinetic and pharmacodynamic alterations to be aware of
The total clearance while on CVVHDF would be the sum of the in the patient with ARF. Unfortunately, there is a dearth of data to
patient’s residual clearance and the cefepime clearance associated quantify these changes, and even less evidence to prove that if one
with CVVHDF (which can be approximated as described above) as incorporates these considerations into patient care that the associ-
follows: ated outcomes will be improved.

ClCVVHDF = [(UFR + DFR) × fu)]

EVALUATION OF THERAPEUTIC OUTCOMES
ClCVVHDF = [(15 + 33) × 0.97]
Vigilant monitoring of patients with ARF is essential, particularly in
ClT = CLRES + CLCVVHDF
those who are critically ill (Table 45–10). Once the laboratory-based
ClT = 15.5 mL/min + 47 mL/min = 62.1 mL/min tests (e.g., urinalysis, fractional excretion of sodium calculations) have
been conducted to diagnose the cause of ARF, they usually do not have
This patient’s clearance value can be used to adjust the cefepime to be repeated. In established ARF, daily measurements of urine output,
dose as described below. The cefepime clearance in a patient with fluid intake, and weight should be performed. Vital signs should be
normal renal function would be calculated as: monitored at least daily, more often if patient acuity of illness is high.
Clnorm (mL/min) = [0.96 × (Clcr)] + 10.9 Daily blood tests for electrolytes, BUN, and a complete blood cell count
should be considered routine for hospitalized patients.
Clnorm = [0.96 × 120] + 10.9 Therapeutic drug monitoring should be performed for drugs that
have a narrow therapeutic window that can be measured by the
Clnorm = 126.1
hospital laboratory. If results from these serum drug concentrations
The dosage adjustment factor would then be: cannot be obtained in a timely fashion (<24 hours) to the patient’s
care team, then their value is limited. When considering approaches to
Q = ClT/Clnorm
measuring serum concentrations, consensus is limited. Measuring a
Q = 62.1 ÷ 126 = 0.49 serum drug concentration prior to hemodialysis has the advantage of
allowing time for the result to be reported and redosing done shortly
For this patient’s situation, the normal regimen of cefepime
would be 2,000 mg (Dn) every 12 hours (τn). If one wanted to
TABLE 45-10 Key Monitoring Parameters for Patients with
maintain Dn and extend the dosing interval, then τf would be
Established Acute Renal Failure
calculated as:
Parameter Frequency
τf = τn/Q
Fluid ins/outs Every shift
τf = 12 hours/0.49 Patient weight Daily
Hemodynamics (blood pressure, heart Every shift
τf ≈ 24 hours rate, mean arterial pressure, etc.)
Blood chemistries
This approach suggests the patient should receive cefepime 2,000 Sodium, potassium, chloride, bicarbon- Daily
mg every 24 hours. If the additional clearance associated with ate, calcium, phosphate, magnesium
CVVHDF (40.2 mL/min) was not considered, the calculated dosing Blood urea nitrogen/serum creatinine Daily
interval would have been considerably longer. Several variables can Drugs and their dosing regimens Daily
impact the outcome of these calculations, including the multiple Nutritional regimen Daily
variables within the dialysis therapy—for example, UFR, blood flow Blood glucose Daily (minimum)
rate, and DFR—and interpatient variability in nonrenal and renal Serum concentration data for drugs After regimen changes and after renal
drug clearance, to name just two. replacement therapy has been instituted
Times of administered doses Daily
Intermittent Hemodialysis Limitations of IHD-based dosing Doses relative to administration of renal Daily
charts include variability in the patients’ individual pharmacokinetic replacement therapy
parameters, differences in the dialysis prescription, such as dialyzer Urinalysis
blood flow or duration, and the use of new IHD dialyzers. The Calculate measured creatinine Every time measured urine collection
approach to hemodialysis may also change on a daily basis, especially clearance performed
in unstable individuals with ARF. This could include, for example, the Calculate fractional excretion of Every time measured urine collection
sodium performed
dialyzer/filter used, the duration, the degree of hemofiltration com-
Plans for renal replacement Daily
pared to convection, and blood flow rate. Individualization of a
 741
after dialysis with minimal delay. This is especially important if the ATN: acute tubular necrosis
desired pharmacologic effects are lost during or after hemodialysis is

CHAPTER 45
BUN: blood urea nitrogen
complete because the serum concentrations have become subthera-
CKD: chronic kidney disease
peutic. Knowledge based on previous observations of how a particular
agent is removed for a given dialysis approach and any prehemodialy- CLcr: creatinine clearance
sis serum concentration of the agent can assist in estimating the CRRT: continuous renal replacement therapy
amount removed and predicting any necessary postdialysis dose.
CT: computed tomography
Serum concentrations drawn after hemodialysis may reflect plasma
concentrations that are transiently depressed until the drug can CVVH: continuous venovenous hemofiltration
reequilibrate from the tissues (plasma rebound effect). The advantage CVVHD: continuous venovenous hemodialysis

Acute Renal Failure

with an after-dialysis level is the greater accuracy in determining how CVVHDF: continuous venovenous hemodiafiltration
much drug was cleared during hemodialysis, but may delay reestab-
FENa: fractional excretion of sodium
lishing target effects. Greater therapeutic drug monitoring may be
necessary in patients with ARF than what is done routinely for other GFR: glomerular filtration rate
patients because of the potential changes in dynamic status (changing IHD: intermittent hemodialysis
volume status, changing renal function, and RRTs) of ARF patients.
NSAID: nonsteroidal antiinflammatory drug
QALY: quality-adjusted life-year
PHARMACOECONOMIC CONSIDERATIONS RRT: renal replacement therapy
ARF is a large financial burden on the healthcare system. Much of this Scr: serum creatinine
cost is because many of these patients are in intensive care units where
daily costs are high. It is estimated that the average total hospital cost
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