22

URINALYSIS

The urinalysis is an important diagnostic tool for differentiating AKI into prerenal

azotemia, intrinsic AKI, or obstructive AKI (Table 29-3). The presence of highly

concentrated urine, as determined by elevated urine osmolality and specific gravity,

suggests prerenal azotemia. During dehydrated states, vasopressin (antidiuretic

hormone) is secreted, and the renin–angiotensin–aldosterone system (RAAS) is

activated. These mechanisms promote the reabsorption of water and sodium at the

collecting duct of the nephron, which serves to expand the effective circulating

volume in an attempt to restore renal perfusion. As a result of diminished urine

volume, the urine osmolality and specific gravity increase dramatically. Patients with

prerenal azotemia and oliguria often have a urine osmolality greater than 500

mOsm/kg. The maximal urine osmolality can exceed 1,200 mOsm/kg.

Table 29-3

Urinary Indices in Acute Kidney Injury

Component Prerenal Azotemia

Acute Tubular

Necrosis Postrenal Obstruction

Urine Na+ (mEq/L) <20 >40 >40

FENa

(%) <1 >2 >1

Urine/plasma creatinine >40 <20 <20

Specific gravity >1.010 <1.010 Variable

Urine osmolality

(mOsm/kg)

Up to 1,200 <300 <300

The presence of proteinuria or hematuria can indicate glomerular damage.

Nephrotic syndrome is characterized by urinary protein losses greater than 3.5 g/1.73

m2

/day. Proteinuria can also result from tubular damage; that protein loss is rarely

over 2 g/day, however. The protein content can be used to differentiate glomerular

versus tubular damage. The low-molecular-weight protein, β2

-microglobulin, is

freely filtered at the glomerulus and reabsorbed at the proximal tubule. Therefore, the

presence of excessive β2

-microglobulin in the urine suggests a tubular source of AKI,

such as ATN. Conversely, albumin is not readily filtered at the glomerulus; hence, the

presence of heavy albuminuria suggests a glomerular source of AKI.

Microscopic examination of the urine provides helpful clues for determining the

source of AKI (Table 29-4). Pigmented granular casts are generally seen with

ischemic or nephrotoxin-induced AKI. White blood cells (WBCs) and WBC casts

can indicate an inflammatory process in the glomerulus, such as acute interstitial

nephritis (AIN) or pyelonephritis. Red blood cells (RBCs) and RBC casts can result

from strenuous exercise or can indicate glomerulonephritis. Allergic interstitial

nephritis can be detected by the presence of urinary eosinophils. Obstructive AKI

causes, such as nephrolithiasis, can be identified by the presence of crystals in the

urine. Cystine, leucine, and tyrosine crystals are considered pathologic. The presence

of calcium oxalate crystals may suggest toxic ingestion of ethylene glycol.

Table 29-4

Clinical Significance of Urinary Sediment in Acute Kidney Injury

Cellular Debris Clinical Significance

Red blood cells Glomerulonephritis

IgA nephropathy

Lupus nephritis

White blood cells Infection (pyelonephritis)

Interstitial nephritis

Glomerulonephritis

Acute tubular necrosis

Eosinophils Drug-induced acute interstitial nephritis

Pyelonephritis

Renal transplant rejection

Hyaline casts Glomerulonephritis

Pyelonephritis

Heart failure

Red blood cell casts Acute tubular necrosis

Glomerulonephritis

Interstitial nephritis

White blood cell casts Pyelonephritis

Interstitial nephritis

Granular casts Dehydration

Interstitial nephritis

Glomerulonephritis

Acute tubular necrosis

Tubular cell casts Acute tubular necrosis

Fatty casts Nephrotic syndrome

Myoglobin Rhabdomyolysis

Crystals Nonspecific

Note: Hyaline casts may also be detected in normal renal function.

p. 636

p. 637

URINARY CHEMISTRIES

Analyzing urine electrolyte concentrations and simultaneously comparing them with

serum sodium and creatinine concentrations is useful for differentiating between

prerenal azotemia and ATN ( Table 29-3). The fractional excretion of sodium (FENa

)

is a measurement of how actively the kidney is reabsorbing sodium, and it is

calculated as the fraction of filtered sodium excreted in the urine using creatinine as a

measure of GFR. In normal conditions, the proximal tubule reabsorbs 99% of filtered

sodium. The FENa

formula is listed as follows:

where UNa

is the urine sodium concentration (mEq/L), SCr is the serum creatinine

concentration (mg/dL), UCr

is the urine creatinine concentration (mg/dL), and SNa

is

the serum sodium concentration (mEq/L).

35

In prerenal azotemia, the functional

ability of the proximal renal tubule remains intact. In fact, its sodium-reabsorbing

abilities are markedly enhanced because of the effects of circulating vasopressin and

activation of the RAAS. Both the FENa and urine sodium concentration become

markedly low (<1% and <20 mEq/L, respectively) in prerenal conditions. In

contrast, these indices are elevated in ATN because the renal tubules lose their

ability to reabsorb sodium; the FENa

is greater than 2%, and the urine sodium is

greater than 40 mEq/L. FENa values between 1% and 2% are generally inconclusive.

The clinician should ensure that the patient is not receiving scheduled thiazide or

loop diuretic therapy when the FENa

is calculated. These diuretics increase

natriuresis, thereby making the results difficult to interpret. Urea excretion is not

affected by diuretics. The FEUrea appears more accurate in detecting prerenal

azotemia, particularly in patients taking diuretics. Serum and urine creatinine

concentrations are replaced by blood and urine urea concentrations in the FENa

formula. A FEurea of <35% and >50% are used to distinguish prerenal azotemia and

ATN, respectively.

36

PRERENAL AND FUNCTIONAL ACUTE KIDNEY

INJURY

Chronic Heart Failure and Nonsteroidal AntiInflammatory Drug Use

CASE 29-1

QUESTION 1: A.W. is a 71-year-old white male (height = 6 feet; weight = 194 pounds), who had an STsegment elevation myocardial infarction (STEMI) 2 months ago. His ejection fraction is currently 15% (normal,

50%–60%). He presents today for his 2-month follow-up clinic appointment complaining of shortness of breath,

dyspnea on exertion, and inability to produce much urine. His medical history is significant for long-standing

hypertension, coronary artery disease, osteoarthritis, and recent-onset HF after his MI. His home medications

include furosemide 40 mg daily, lisinopril 20 mg daily, metoprolol succinate 100 mg daily, digoxin 0.125 mg daily,

atorvastatin 40 mg daily, and naproxen sodium 550 mg twice daily (BID), all of which are taken orally (PO).

With the exception of naproxen, A.W. often forgets to take his medications. Physical examination reveals lower

leg 3+ pitting edema, pulmonary crackles and wheezes, positive jugular venous distension, and an S3

heart

sound. His vital signs are significant for a blood pressure (BP) of 198/97 mm Hg and a weight gain of 4 kg

since his last visit 2 months ago. Last week, his BUN and SCr were 23 and 1.2 mg/dL, respectively. What are

A.W.’s risk factors for AKI?

A.W.’s risk factors for AKI are heart failure (HF) with poor cardiac output

(ejection fraction, 15%) that resulted from his STEMI and his medication, naproxen

sodium. HF is a major cause of functional AKI.

37 A.W.’s diminished cardiac output

has resulted in decreased effective circulating volume and activation of the RAAS,

which are impairing his renal perfusion. In states of decreased renal perfusion,

prostaglandins E2 and I2 compensate for the afferent arteriole vasoconstriction by

stimulating afferent arteriole vasodilation, thereby enhancing renal blood flow.

Prostaglandin synthesis is mediated predominantly by cyclo-oxygenase-1 (COX-1)

and perhaps cyclo-oxygenase-2 (COX-2). Nonsteroidal anti-inflammatory drugs

(NSAIDs), such as naproxen, are often overlooked as causes of AKI. NSAIDs exert

their pharmacologic effect by inhibiting prostaglandin synthesis, thereby negating

compensatory vasodilation. NSAIDs induce abrupt decreases in GFR in at-risk

patient populations, specifically those with HF, liver disease, the elderly, or

dehydrated patients. Figure 29-2 illustrates common medications that alter renal

hemodynamics by causing either afferent arteriole vasoconstriction or efferent

arteriole vasodilation. The term “triple whammy” refers to the risk of AKI when an

ACE inhibitor or ARB is combined with a diuretic and NSAID. This combination

might be seen in a patient with hypertension, congestive heart failure, or renal

disease who has arthritis or other mild-to-moderate pain.

38,39

COX-2 inhibitors also inhibit prostaglandin synthesis. A study comparing the

effects of rofecoxib (voluntarily withdrawn from the market in 2004) and celecoxib

to nonselective NSAIDs demonstrated similar renovascular effects.

40

In a large

cohort of more than 1.4 million new NSAID users receiving care in the US

Department of Veterans Affairs health care system, a greater risk of AKI (based on

AKIN criteria) was found in nonselective versus COX-2 selective agents.

41 Highdose aspirin (defined as doses of at least 400 mg) was associated with the highest

AKI risk. Naproxen, piroxicam, ketorolac, etodolac, indomethacin, sulindac,

ibuprofen, and salsalate were also associated with a higher risk of AKI, whereas

celecoxib, meloxicam, diclofenac, and other NSAIDs were not associated

significantly with AKI. The highest risk was found in those using more than one

NSAID, and in those switching from one agent to another. The lowest risk was found

in those using the same agent continuously.

41,42 AKI risk was highest in the first 45

days of treatment initiation.

40 Sulindac may offer a “renal-sparing” effect. Sulindac is

a prodrug that is converted to its active sulfide metabolite by the liver and then

becomes reversibly oxidized back to its parent compound in the kidney; renal

prostaglandin synthesis is essentially unaltered by sulindac. Cases of sulindacinduced renal dysfunction have been reported when the drug was administered to

patients with cirrhosis and ascites.

CASE 29-1, QUESTION 2: A.W.’s cardiologist obtains a stat digoxin level, serum and urine electrolyte

panels, and urinalysis. The digoxin level is reported as “not detectable” (target, 0.5–0.8 ng/mL). Other

significant serum laboratory values include:

Na

+

, 140 mEq/L

BUN, 56 mg/dL

SCr, 1.8 mg/dL

p. 637

p. 638

The urinalysis is significant for a urinary osmolality of 622 mOsm/kg, and specific gravity of 1.092. The urine

electrolytes are significant for Na

+ of 12 mEq/L and creatinine of 102 mg/dL. What laboratory findings suggest

functional AKI? Define the criteria used for the detection of AKI and staging of AKI in this patient.

A.W. has classic laboratory findings associated with poor renal perfusion (Table

29-3). It is important to compare the current and previous laboratory data to assess

acute changes in renal function. Compared with last week, A.W.’s renal function has

deteriorated based on substantial increases in BUN and SCr concentrations; BUN has

increased nearly twofold and creatinine by 50% (SCr increased × 1.5-fold within 7

days). According to the AKIN/KDIGO criteria, the patient has stage 1 AKI. Renal

demise is most likely due to functional AKI because the BUN:SCr ratio is greater

than 20:1, suggesting poor renal blood flow, which is corroborated by other urinary

indices such as the urinary Na

+ 12 mEq/L; specific gravity, 1.090 (elevated); urine

osmolality, 622 mOsm/kg; and the calculated FENa, 0.1%. These values reflect the

ability of the renal tubules to respond to vasopressin and aldosterone in an attempt to

expand effective circulating volume and restore renal perfusion.

Another consideration is furosemide-induced volume depletion; however, the

nondetectable serum digoxin level indicates likely noncompliance with his

medications. A more likely explanation is poor renal perfusion because of his heart

failure (i.e., low cardiac output).

CASE 29-1, QUESTION 3: How should A.W.’s prerenal azotemia be treated?

The presence of volume overload in the face of prerenal azotemia suggests a

decreased effective circulating volume, most likely from poorly controlled HF.

Restoring and improving A.W.’s cardiac output and renal perfusion will rapidly

correct the prerenal azotemia. This can be achieved by (a) optimizing doses and

assuring adherence to his heart failure medications (furosemide, lisinopril,

metoprolol succinate, and digoxin); (b) controlling BP to a goal of lower than 140/90

mm Hg by decreasing both preload and afterload; and (c) modifying any drug therapy

that has deleterious effects on the renal hemodynamics (e.g., NSAID). The specific

therapies for controlling hypertension and improving cardiac output are presented in

Chapter 9, Essential Hypertension, and Chapter 14, Heart Failure. Naproxen should

be discontinued and substituted with acetaminophen to treat his osteoarthritis.

Normal renal function should return in a few days after correction of the underlying

causes.

Angiotensin-Converting Enzyme Inhibitor and

Angiotensin Receptor Blocker–Induced Acute Kidney

Injury

CASE 29-2

QUESTION 1: G.B. is a 53-year-old white woman (height = 5 feet, 3 inches; weight = 170 pounds) with

hypertension, coronary artery disease, peripheral vascular disease, and diabetes, for which she had been taking

hydrochlorothiazide 25 mg PO daily, atorvastatin 10 mg PO daily, aspirin 81 mg PO daily, and insulin glargine 30

units subcutaneously once daily every morning. At last week’s clinic visit, she had two consecutive BP readings

of 187/96 and 193/95 mm Hg, respectively, measured 20 minutes apart. At that time, G.B.’s primary-care

physician started her on lisinopril 5 mg PO daily. Other notable laboratory values at the time included HgA1c

7.5% and urine albumin to creatinine ratio (ACR) 50 mg/g. The region was in the midst of a protracted heat

wave with temperatures above 95°F and she claims not drinking much liquids. She returns to the clinic today for

her 1-week follow-up appointment complaining of dizziness, dry mouth, and very little urine production during

the past week. Laboratory values and vitalsigns obtained at this visit include the following:

BP, 98/43 mm Hg

Hg, 15 g/dL

Hct, 45%

Na, 145 mEq/L

K, 5.2 mEq/L

BUN, 62 mg/dL

SCr, 2.7 mg/dL (baseline SCr, 1.0 mg/dL)

Why is G.B. experiencing AKI?

According to AKIN/KDIGO criteria, G.B. is diagnosed with stage 2 AKI most

likely because of prerenal azotemia. Inhibition of the RAAS in patients with

compromised renal blood flow is a common cause of functional AKI. A basic

understanding of the effects of the RAAS on renal hemodynamics is necessary in this

situation (Fig. 29-3). When renal perfusion is impaired, the juxtaglomerular cells of

the kidney secrete renin into the plasma and lymph. Renin cleaves circulating

angiotensinogen to form angiotensin I (AT I), which is further cleaved by

angiotensin-converting enzyme (ACE) to form angiotensin II (AT II). AT II induces

two physiologic events to improve renal perfusion. First, it directly causes systemic

vasoconstriction, which shunts blood to the major organs, and indirectly increases

intravascular volume through aldosterone- and vasopressin-mediated activity.

Second, it preferentially vasoconstricts the efferent renal arteriole to maintain

adequate intraglomerular hydrostatic pressure. Under conditions of decreased

arterial pressure or effective circulating volume, the RAAS is activated and plasma

renin and AT II activity are increased.

43,44