Calcium nephrolithiasis constitutes approximately 70% to 80% of all kidney
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-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.
QUESTION 1: T.C., a 25-year-old male with a past medical history of schizophrenia, was seen in an
markedly lower than usual. Which drugs can crystallize in the urine and cause AKI?
Commonly Used Drugs that Cause Crystal-Induced Acute Kidney Injury
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.
SUPPORTIVE MANAGEMENT OF ACUTE
laboratory tests reveal the following:
Spot urine albumin:creatinine ratio, 350 mg/g
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
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.
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
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
to symptomatic uremia with confusion, platelet dysfunction and severe bleed, and
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.
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
; 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).
unit and often receive concomitant parenteral nutrition.
Comparison of Extracorporeal Continuous Renal Replacement Therapies
Adequate Inadequate Adequate Adequate
Adequate Poor Adequate Adequate
Blood pump required Yes No Yes Yes
Pharmacy expense High High High High
GFR, glomerular filtration rate.
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
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
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.
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
Bellomo R et al. Acute kidney injury. Lancet. 2012;380:756. (1)
González PM. Acute interstitial nephritis. Kidney Int. 2010;77:956. (85)
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)
from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:1122. (32)
KDIGO Clinical Practice Guideline for Acute Kidney Injury. http://www.kidney-international.org.
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