Calcium nephrolithiasis constitutes approximately 70% to 80% of all kidney

stones,

92 with calcium oxalate and calcium phosphate stones making up most of these.

Genetic factors appear to play an important role in the development of calcium

nephrolithiasis; the stereotypical patient is a man in his third to fifth decade of life.

Other risk factors for developing calcium nephrolithiasis are low urine output,

inadequate hydration (e.g., living in a hot climate and not drinking adequate fluids),

hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, and distal renal

tubular acidosis (Table 29-7). Generally, more than one of these conditions are

present simultaneously. The diagnosis and management of kidney stones are beyond

the scope of discussion in this chapter. However, pharmacists can be instrumental in

providing proper counseling on hydration and preventive measures.

CRYSTAL FORMATION

Crystal-induced AKI most commonly occurs as a result of acute uric acid

nephropathy and following the administration of drugs or toxins that are poorly

soluble or have metabolites that are poorly soluble in urine. Other drugs or toxins

(e.g., ascorbic acid, ethylene glycol) may be metabolized to insoluble products such

as oxalate, which are associated with precipitation of calcium oxalate crystals in the

urine within the tubular lumen resulting in kidney injury.

92,93

PRESENTATION AND TREATMENT

CASE 29-8

QUESTION 1: T.C., a 25-year-old male with a past medical history of schizophrenia, was seen in an

outpatient clinic 4 days prior to admission where he was started on oral acyclovir 800 mg 5 times a day for a

diagnosis of herpes zoster. He presents to the emergency department complaining of sharp flank pain, gross

hematuria, and dysuria. Serum chemistries are ordered and are significant only for a BUN of 34 mg/dL and a

SCr of 1.5 mg/dL, which are up from his baseline values of 7 and 0.9 mg/dL, respectively. A urine sample was

obtained and visualized with microscopy. Birefringent needle-shaped crystals were seen on polarizing light

microscopy. It was consistent with acyclovir-induced nephropathy. On questioning, he admits that he has not

been drinking much fluid during the past week owing to a busy work schedule, and his urine volume has been

markedly lower than usual. Which drugs can crystallize in the urine and cause AKI?

Table 29-8

Commonly Used Drugs that Cause Crystal-Induced Acute Kidney Injury

Acyclovir

Ciprofloxacin

Indinavir

Methotrexate

Sulfonamide antibiotics

Orlistat

Triamterene

Many commonly prescribed drugs are insoluble in urine and crystallize in the

distal tubule (Table 29-8). Risk factors that predispose patients to crystalluria

include severe volume contraction, underlying renal dysfunction, or acidotic or

alkalotic urinary pH. In conditions of renal hypoperfusion, high concentrations of

drug become stagnant in the tubule lumen. Drugs that are weak acids (e.g.,

methotrexate, sulfonamide antibiotics) precipitate in acidic urine; drugs that are weak

bases (e.g., ciprofloxacin, indinavir, and other protease inhibitors) precipitate in

alkaline urine. Patients with drug-related crystal-induced AKI are usually

asymptomatic, and kidney injury is detected by an increased SCr. Occasionally, like

T.C., patients present within 1 to 7 days after initiation of the offending drug with

renal colic symptoms such as flank or abdominal pain, nausea, or vomiting.

Urinalysis often reveals hematuria, pyuria, and crystalluria. The diagnosis is

suggested by the appearance of crystals in the urine, the morphology of which

depends upon the specific causative drug. Prevention of crystal-induced AKI is

targeted at dosage adjustment for patients with underlying renal dysfunction, volume

expansion to increase urinary output, and urine alkalization to enhance renal

elimination of drugs that are weak acids or urine acidification to enhance renal

elimination of drugs that are weak bases. Dialysis may be necessary in a small

percentage of patients. With appropriate pharmacotherapy, crystal-induced AKI is

usually reversible without long-term complications.

94

SUPPORTIVE MANAGEMENT OF ACUTE

KIDNEY INJURY

CASE 29-9

QUESTION 1: J.W. is a 75-year-old Native American man (height = 6 feet, 2 inches; weight = 200 pounds),

who presents to the emergency room with shortness of breath and progressive worsening edema in both lower

extremities. His medical history includes nephrotic syndrome secondary to diabetic nephrosclerosis, type 1

diabetes, hypertension, and chronic obstructive pulmonary disease. His surgical history includes a right-sided

nephrectomy many years ago. His chronic medications are furosemide 80 mg PO twice a day, metolazone 10

mg PO once a day, lisinopril 5 mg PO once a day, diltiazem extended-release 120 mg PO once a day, albuterol,

inhaler as needed, and subcutaneous 20 units insulin glargine at bedtime, and insulin aspart before meals. Vital

signs are temperature 36.3°C, pulse 77 beats/minute, respirations 16 breaths/minute, and BP 179/86 mm Hg.

Physical examination reveals periorbital edema, jugular venous distension at a 45-degree angle to the jaw,

dullness to percussion halfway up the lungs bilaterally, and 4+ pitting edema in the extremities. Admitting

laboratory tests reveal the following:

Sodium, 140 mEq/L

Potassium, 5.5 mEq/L

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Chloride, 103 mEq/L

Bicarbonate, 19 mEq/L

Glucose, 249 mg/dL

BUN, 67 mg/dL

SCr, 5.2 mg/dL

Serum albumin, 2.0 g/dL

Spot urine albumin:creatinine ratio, 350 mg/g

Baseline renal function tests 1 month ago are BUN 45 mg/dL and SCr 3.0 mg/dL. J.W. is oliguric with a

urine output of 10 mL/hour. The nephrologist wants to use supportive management of AKI by first optimizing

diuretic therapy. If no increase in urine output occurs during the next several hours, then the patient will undergo

RRT. What is the supportive management of AKI?

Despite years of study, no pharmacologic “cure” for AKI exists. Supportive

management is therefore directed at preventing its morbidity and mortality. This is

achieved by close patient monitoring; strict fluid, electrolyte, and nutritional

management; treatment of life-threatening conditions such as pulmonary edema,

hyperkalemia, and metabolic acidosis; avoidance of nephrotoxic drugs; and the

initiation of dialysis or CRRT.

An assessment of volume status should be performed in all patients who present

with AKI, since correction of volume depletion or volume overload may reverse or

ameliorate AKI. The underlying cause dictates management of AKI. Treating the

underlying cause is of extremely important. For example, prerenal AKI because of

volume-depleted states, such as septic shock, requires administration of fluids and

vasopressors to restore renal perfusion and increase urine output. On the other hand,

diuretic administration for preload reduction to increase cardiac output would be

required for prerenal AKI because of volume-overload states as in congestive heart

failure.

As discussed earlier, diuretics currently have no role in preventing AKI

progression or reducing mortality, but they can prevent complications, such as

pulmonary edema. For edema, intravenous furosemide (e.g., 80–120 mg) is preferred

because of its potency and pulmonary vasodilation properties. Oral furosemide

therapy should be avoided because gut edema may limit its bioavailability.

Torsemide and bumetanide are two other loop diuretics that have excellent oral

bioavailability and are unaffected by gut edema. The dosage of diuretic needed is

highly patient specific, especially in those with frank proteinuria, glomerulonephritis,

or the nephrotic syndrome. Low serum albumin limits drug transport to the kidneys

and thus limits diuretic effectiveness. In addition, furosemide is highly protein bound,

and thus binds to filtered protein, which negates its pharmacologic effect on the

kidneys. Combinations of loop and thiazide diuretics may be needed in patients with

AKI if they become diuretic resistant. This combination acts synergistically to block

sodium and water reabsorption in both Henle’s loop and the distal convoluted tubule.

Other alternatives include continuous loop diuretic infusions, such as furosemide 1

mg/kg/hour. The infusion rate should not exceed 4 mg/minute because these rates are

associated with ototoxicity, especially when given in combination with

aminoglycoside antibiotics. Close monitoring of serum bicarbonate, potassium,

magnesium, and calcium is necessary when giving large doses of loop diuretics.

Diuresis should aim for a weight loss of 0.5 to 1.0 kg/day. If diuretics fail to achieve

the desired fluid overload reduction, dialysis or CRRT can be considered.

Hyperkalemia commonly occurs in patients with AKI because the kidneys regulate

potassium homeostasis. It can be life threatening. It is prevalent in oliguric patients

who are catabolic or have evidence of active cellular breakdown, such as

rhabdomyolysis and tumor lysis syndrome. J.W. is mildly hyperkalemic, but his

serum potassium may decrease after furosemide therapy. Management of

hyperkalemia is discussed in Chapter 27, Fluid and Electrolyte Disorders. In cases of

severe hyperkalemia in which conventional pharmacologic treatment is not feasible,

or not working, emergency hemodialysis should be performed. Medications that can

cause hyperkalemia such ACE-inhibitors, ARBs, or trimethoprim should be avoided.

Metabolic acidosis is a common manifestation of AKI because the kidneys are

responsible for excreting organic acids. Other factors also contribute to severe

acidosis among patients with AKI, who are often critically ill. For example, patients

with AKI because of septic shock, trauma, and multi-organ failure often have

increased production of lactic acid or ketoacids. J.W.’s serum bicarbonate

concentration reveals slight acidemia that does not require correction at this time.

Commonly used treatments for metabolic acidosis include bicarbonate administration

and dialysis. Bicarbonate therapy may be administered as first corrective therapy, in

non–life-threatening and non–fluid-overloaded metabolic acidosis. Severe metabolic

acidosis (pH < 7.1) in the presence of anuria or oliguria and a fluid overload state

should be corrected with dialysis, since worsening volume overload can occur with

the administration of sodium bicarbonate therapy.

Uremia can interfere with platelet aggregation resulting in hemorrhagic diathesis.

Uremic patients display increased bleeding sensitivity to aspirin compared to normal

patients taking aspirin. Patients with uremia and major hemorrhagic bleed may

benefit from using desmopressin (dDAVP) 0.3 mcg/kg intravenously or

subcutaneously for one or two doses. Desmopressin produces a dose-related

increase in von Willebrand factor VII and t-PA levels; this shortens activated

antithromboplastin time (aPTT) as well as bleeding time. The improvement in

bleeding time typically begins within about 1 hour to 4 to 8 hours. Tachyphylaxis

typically develops after the second dose. Other modalities that can improve platelet

function and reduce bleeding in an AKI patient include dialysis, conjugated

estrogens, and cryoprecipitate.

95

Clinicians should closely monitor the patient’s vital signs (e.g., weight,

temperature, BP, pulse, and respirations) several times per day. The patient’s volume

status should be assessed daily, and all fluids should be adjusted based on laboratory

chemistries to detect fluid and electrolyte abnormalities, urine output, and

gastrointestinal and insensible losses. Pharmacists should pay attention to nutritional

support for patients with AKI to provide adequate amounts of energy, protein, and

nutrients, while being sensitive to the electrolytes, acidosis, and volume balance

issues. The patient’s medication profile should be reviewed daily to assess for

appropriate dosage adjustment in renal dysfunction. Because estimation of ClCr is

difficult in patients with changing renal function, therapeutic drug monitoring should

be performed when using drugs with narrow therapeutic indices. When possible,

nephrotoxic drugs should be avoided, but this may be difficult in patients who are

septic or hypotensive and require nephrotoxic antibiotics and vasopressors.

Preventive measures to reduce the likelihood of AKI should be used, such as

monitoring volume status to ensure adequate renal perfusion, using dosing strategies

or products that are associated with less nephrotoxicity, and avoiding drug therapy

combinations that enhance nephrotoxicity (e.g., NSAID, aminoglycosides).

Extracorporeal Continuous Renal Replacement

Therapy

RRT is not always indicated in AKI. The A-E-I-O-U mnemonic is used to help

remember the indications for RRT, where ‘A’ stands for intractable refractory

acidosis, ‘E’ refers to electrolyte abnormalities, specifically potassium with EKG

changes, ‘I’ refers to ingestion of toxins such as salicylates and ethylene glycol, ‘O’

stands for fluid overload causing pulmonary edema, and ‘U’ refers

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to symptomatic uremia with confusion, platelet dysfunction and severe bleed, and

seizures.

The risks associated with RRT are hypotension, arrhythmias, vascular access

placement complications, and increased risk of ESRD. Hence, the decision to initiate

RRT has to be carefully discussed. The timing of optimal initiation of RRT is also

lacking. Early initiation may decrease mortality in critically ill patients and the need

for permanent RRT at discharge.

96

RRT can be divided into intermittent hemodialysis or CRRT, such as continuous

peritoneal dialysis or extracorporeal CRRT. The decision to use one versus the other

is most often decided by the nephrologist’s experience and comfort level. CRRT may

be preferred in patients who are hemodynamically unstable or requiring vasopressor

support. Extracorporeal CRRT differs from peritoneal and hemodialysis in its

mechanism of solute removal; dialysis modalities rely primarily on solute diffusion

across a semipermeable membrane, whereas CRRT relies primarily on convective

ultrafiltrate production. This discussion will be limited to extracorporeal (hemofilter

membrane is outside of the body) CRRT therapies (see Chapter 30, Renal Dialysis,

for a complete overview of peritoneal and hemodialysis).

Not all extracorporeal CRRT is alike

97

; many variations exist and include

modalities such as continuous arteriovenous hemofiltration (now obsolete),

continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis

(CVVHD), and continuous venovenous hemodiafiltration (CVVHDF; Fig. 29-5).

Differences among these modalities are illustrated in Table 29-9. Drug dosing can be

difficult in patients receiving these therapies, especially in those who are undergoing

both dialysis and hemofiltration modalities (i.e., CVVHDF).

Figure 29-5 Schematic of continuous venovenous hemodiafiltration (CVVHDF). Blood is accessed by a duallumen catheter in a central vein and is pumped through the extracorporeal circuit by a roller blood pump. The blood

pump maintains a constant hydrostatic pressure to create ultrafiltration, even in hypotensive conditions. Dialysate

flows in a countercurrent direction to blood flow. Patients receiving CVVHDF are most often in the intensive care

unit and often receive concomitant parenteral nutrition.

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Table 29-9

Comparison of Extracorporeal Continuous Renal Replacement Therapies

Continuous

Venovenous

Continuous

Arteriovenous

Continuous

Venovenous

Continuous

Venovenous

Parameter

Hemofiltration

(CVVH)

Hemofiltration

(CAVH)

Hemodialysis

(CVVHD)

Hemodiafiltration

(CVVHDF)

Volume control in

hypotensive patients

Good Variable Good Good

Solute control in

highly catabolic

patients

Adequate Inadequate Adequate Adequate

Blood flow rates in

hypotensive patients

Adequate Poor Adequate Adequate

Ease of drug dosing Published

recommendations

Difficult Difficult Difficult

Dialytic solute

clearance

None None Moderate Moderate

Convective solute

clearance

Good Good Minimal Moderate

Corresponding GFR

(mL/minute)

15–17 10–15 17–21 25–26

Blood pump required Yes No Yes Yes

Replacement fluid

required

Yes Yes Yes Yes

Pharmacy expense High High High High

GFR, glomerular filtration rate.

Estimating Drug Removal

CASE 29-9, QUESTION 2: Are there ways to calculate drug removal in extracorporeal CRRT modalities?

Recent reviews provide an excellent background on dosing drugs in patients

receiving CRRT.

9,32,98–100 The principles for drug removal in hemofiltration are

basically identical with those for removal in hemodialysis. Drug removal during

CRRT may occur by convection, diffusion, and adsorption. Convection and diffusion

have the greatest influence on drug removal. Drug removal is inversely proportional

to the percentage of drug that is protein bound. If a drug is >80% plasma protein

bound, little will be removed. This principle holds true for convection and diffusion.

Ultrafiltration and dialysis flow rates (UFR/DFR) also affect drug clearance.

Because CRRT uses highly permeable membranes, the molecular weight (MW) of

most drugs has little impact on overall clearance. During convection, clearance of an

unbound drug can be dramatic since CVVH can remove easily compounds with MW

<15,000 Da. The impact of MW on drug removal during CVVHD is greater than the

impact seen during CVVH. Solute clearance during CVVHD is dependent on

diffusion and given that diffusion is inversely proportional to MW, the greatest

impact is seen with drugs having a low MW <500 Da. Many drugs have low MW and

hence CVVHD can impact their removal significantly. Clearance during CVVH is

accomplished through the process of convection. The ultrafiltrate produced is

replaced either in part or completely. Clearance of unbound drugs during CVVH can

be dramatic and dose adjustments are required to prevent underdosing.

The sieving coefficient (SC) of a drug is the non–protein-bound fraction of the

drug that is in plasma. SC ranges from 0 to 1 (zero representing no convective

clearance). For example, a SC of 0.8 means that 80% of the drug is unbound in

plasma. Drug SC can be obtained from the literature or by measuring concentrations

simultaneously in the prefilter blood and ultrafiltrate. The ratio of the ultrafiltrate

concentration to plasma concentration is the SC. Drug clearance can be calculated by

multiplying the SC by the ultrafiltration rate. For example, if a patient is receiving

CVVH at an ultrafiltration rate of 1 L/hour, and he or she is receiving vancomycin

(which has an SC of 0.8) 1 g/day, the vancomycin clearance while receiving CVVH

is 0.8 × 1,000 mL/hour = 800 mL/hour or 13 mL/minute.

Calculating drug clearance is much more difficult in hemodiafiltration modalities

(CVVHDF) because both convection and diffusion account for drug clearance, and it

is difficult to predict drug clearance precisely. The use of SC can be useful for smallmolecular-weight drugs, but the accuracy declines with larger drug molecules, such

as vancomycin. When possible, therapeutic drug monitoring should be performed to

maintain therapeutic concentrations and to maximize drug therapy.

Drug references such as Drug Prescribing in Renal Failure provide useful

guidelines in a concise tabular format.

101

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references for this chapter, with

the corresponding reference number in this chapter found in parentheses after the

reference.

Key References

Bellomo R et al. Acute kidney injury. Lancet. 2012;380:756. (1)

Churchwell MD et al. Drug dosing during continuous renal replacement therapy. Semin Dial. 2009;22:185. (98)

González PM. Acute interstitial nephritis. Kidney Int. 2010;77:956. (85)

Heintz BH et al. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving

continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29: 562. (99)

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p. 650

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical

Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1. (9)

Lapi F et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor

blockers with nonsteroidal anti-inflammatory drugs and risk of acute kidney injury: nested case control study.

BMJ. 2013;346:e8525. (39)

Massicotte A. Contrast medium-induced nephropathy: strategies for prevention. Pharmacotherapy. 2008;28:1140.

(68)

Matzke GR et al. Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update

from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:1122. (32)

Rahman M. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician. 2012;86:631. (22)

Thomas ME et al. The definition of acute kidney injury and its use in practice. Kidney Int. 2015;87:62. (3)

Key Website

KDIGO Clinical Practice Guideline for Acute Kidney Injury. http://www.kidney-international.org.

COMPLETE REFERENCES CHAPTER 29 ACUTE KIDNEY

INJURY

Bellomo R et al. Acute kidney injury. Lancet. 2012;380:756.