Risk factors

• Creatinine clearance < 60 mL/min/1.73 m² (stages III–V chronic kidney disease), diabetes mellitus (with renal insufficiency), hypertension, chronic heart failure, cirrhosis, nephrosis, age > 75 years, cholesterol emboli syndrome, multiple myeloma (questionable)

• Hypovolemia, intraprocedural volume depletion, use of large volumes of contrast, intra-aortic balloon pump

• Urine albumin/creatinine ratio > 30, proteinuria

• Concurrent nephrotoxin use (e.g., aminoglycosides, polymixins, amphotericin B, foscarnet, cyclosporine, tacrolimus, NSAIDs)

• Other medications (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, diuretics)

• Intra-arterial contrast administration may have a higher prevalence than the intravenous route

Prevention strategies

The first preventative strategy is to address any reversible risk factor(s)^b

• Saline hydration

• Ensure euvolemia and good urine output

• Use if there are no contraindications to volume expansion

• Hold diuretics the day before and of the procedure

• Isotonic saline preferred over 0.45 % saline

   ○ Start 2 h (up to 12 h in high-risk patients) before procedure

     ■ 1 mL/kg/h

   ○ Continue for at least 6 h after the procedure

   ○ Target urine output around 150 mL/h

• Sodium bicarbonate found to be more effective than isotonic saline hydration^c; some clinicians have questioned this trial’s methodology

   ○ Sodium bicarbonate 3 amps in 1 L D5W

   ○ 3 mL/kg/h for 1 h before contrast

   ○ 1 mL/kg/h for 6 h after the procedure

Choice of contrast agent

• Use nonionic and either low or iso-osmolar products

   ○ E.g., iodixanol

• Use the least amount of volume to complete the procedure

   ○ A total volume that is >5 mL/kg divided by the patient’s serum creatinine in mg/dL is associated with increased risk of nephropathy

• Avoid studies that are closely spaced. Optimal time not well delineated; prudent to wait a few days between studies when possible

Pharmacotherapy

• N-acetylcysteine (NAC)

   ○ 600 mg enterally every 12 h (24 h before and 24 h after the procedure)

     ■ For emergent procedures, 1 g of NAC administered 1 h before and 4 h after the procedure may have some value^d

   ○ Intravenous

     ■ 150 mg/kg in 500 mL DSW over 30 min before the procedure, followed by 50 mg/kg in 500 mL DSW over 4 h following the procedure^e

Limited if any value based on the available literature

• Forced diuresis with either a loop diuretic or mannitol

• Renal dose dopamine

• Aminophylline/theophylline (adenosine receptor antagonists)

• Calcium-channel blockers

• Fenoldopam

• Hemodialysis or hemofiltration

Fluid control ( must assess patient’s volume status)

In “stable” patients with oliguric acute kidney injury (AKI): medical therapy (for pH, K⁺, fluid control = HD = CVVH)

• Hypovolemic

   ○ Administer crystalloid fluid resuscitation

• Volume overloaded

   ○ Concentrate intravenous medications

   ○ Evaluate maintenance fluids

   ○ Concentrate parenteral nutrition

   ○ Use concentrated enteral nutrition products

Avoid and/or discontinue nephrotoxins wherever possible

Diuretic pharmacotherapy (strict avoidance of intravascular volume depletion)

• Loop diuretics (dose depends on severity of renal insufficiency)

   ○ Furosemide intermittent IV

     ■ Infusion rate ≤ 4 mg/min for doses > 40 mg

     ■ 40–200 mg intravenous administration

       □ If net hourly diuresis is ≥ 1 mL/kg/h and pharmacotherapeutic end point is achieved, then no further diuretic

       □ If net hourly diuresis is ≥ 1 mL/kg/h and pharmacotherapeutic end point is not achieved, then continue same dose every 6 h

       □ If net hourly diuresis is < 1 mL/kg/h, double the previous dose of diuretic and administer within 2 h; maximum single dose is 200 mg

         ♦ Consider combining with a distal tubule acting diuretic (i.e., chlorothiazide IV or metolazone PO) to overcome the “ceiling” effect

   ○ Furosemide continuous IV infusion

     ■ 40–200 mg intravenous bolus X 1

     ■ Initiate at 0.1 mg/kg/h continuous IV infusion (can be adjusted based on GFR)

       □ Increase hourly by 0.1 mg/kg/h increments until net hourly diuresis is ≥ 1 mL/kg/h

       □ Maximum infusion rate is 0.4–0.5 mg/kg/h or 40 mg/h

       □ Continue until pharmacotherapeutic end point is achieved

         ♦ Consider combining with distal tubule acting diuretic (i.e., chlorothiazide IV or metolazone PO) to overcome the “ceiling” effect if large doses of furosemide are required

• Thiazide diuretics

   ○ Potentiates the effects of a loop diuretic

   ○ Chlorothiazide

     ■ 500–1,000 mg IV every 12 h (works even in the setting if reduced GFR [author’s and editor’s opinion])

• In “sulfa” allergic patients:

   ○ Identify the implicated agent and the severity of the reaction

   ○ Ethacrynic acid may be a safe alternative to furosemide

     ■ 40 mg furosemide = 50 mg ethacrynic acid

   ○ Refer to the following review article on sulfonamide allergies^a

Management of diuretic-resistant edema

• Evaluate excessive sodium intake

   ○ Dietary, intravenous fluids, medications (e.g., ticarcillin, metronidazole)

• Switch to parenteral diuretic pharmacotherapy

• Increase dose of loop diuretic

• Consider continuous infusion of a loop diuretic

• Consider combining the loop diuretic with a thiazide diuretic

• Discontinue medications that may decrease renal blood flow

   ○ E.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers, NSAIDs

• Combine loop diuretic with albumin 25 % (data supporting efficacy is limited)

   ○ Albumin 12.5–25 g IV every 8–12 h

   ○ May be warranted in patients with hypoalbuminemia (<2.5 g/dL)

• Acute hemodialysis not effective

• Packed red blood cell transfusion (PRBCs)

   ○ Goal hematocrit ≥ 28–30 % (patient specific)

   ○ Higher hematocrit may improve platelet-vessel wall interaction

• Cryoprecipitate (in life-threatening hemorrhage)

   ○ 10 units every 12–24 h

   ○ To replenish von Willebrand factor (vWF)

• Desmopressin

   ○ 0.3 mcg/kg IV over 15–30 min

   ○ May repeat every 12 h for 2–3 total doses

     ■ Will increase endothelial release of vWF

     ■ Tachyphylaxis develops with repeat doses; activity may return after a 3-day drug-free period

• Conjugated estrogen in severe cases

   ○ 0.6 mg/kg IV daily for 5 days

Functional acute kidney injury (abnormal intrarenal hemodynamics that can be potentiated by hypovolemia or effective arterial volume depletion)

• Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, NSAIDs

Glomerular disease

• Gold, hydralazine, NSAIDs

• Chlorpropamide, penicillamine, phenytoin, quinidine

Interstitial nephritis

• Acute allergic

   ○ β-lactam antimicrobials, erythromycin, nitrofurantoin, rifampin, sulfonamide antimicrobials, vancomycin

   ○ Diuretics (all classes), NSAIDs

• Chronic

   ○ Cyclosporine, ifosfamide, lithium

Obstructive nephropathy

• Intratubular crystallization

   ○ Acyclovir, foscarnet, indinavir, sulfonamide antimicrobials

   ○ Acetazolamide, ascorbic acid, methotrexate, triamterene

• Outflow obstruction

   ○ Anticholinergic agents, disopyramide

• Nephrolithiasis

   ○ Allopurinol, indinavir, sulfadiazine, topiramate, triamterene, zonisamide

• Rhabdomyolysis

   ○ Azathioprine, colchicine, doxylamine, niacin (in combination with a statin), statins

Papillary necrosis

• Acetaminophen

Pseudorenal failure (increase in blood urea nitrogen or serum creatinine without a change in glomerular filtration rate)

• Increase protein catabolism

   ○ Corticosteroids, tetracyclines

• Impairs proximal tubular secretion of creatinine

   ○ Cimetidine, pyrimethamine, trimethoprim

• Interactions with laboratory assay (Jaffe method)

   ○ Ascorbic acid

   ○ Cephalosporins (e.g., cefaclor, cefazolin, cefoxitin, cephalexin, cephalothin)

Tubular damage

• Acute tubular necrosis

   ○ Aminoglycosides, amphotericin B, carboplatin, cisplatin, foscarnet, intravenous contrast dyes, drugs associated with rhabdomyolysis

• Osmotic damage

   ○ Dextrans, hetastarch, mannitol, intravenous immunoglobulins that contain sucrose

• Animal models of critical illness suggest ionized hypocalcemia is universal and treatment to achieve normal levels associated with increased mortality (author suggests treating symptomatic patients only)

• Correct serum calcium in the presence of hypoalbuminemia

   ○ Corrected serum calcium (mg/dL) = measured serum calcium (mg/dL) + 0.8 (4 g/dL–measured serum albumin [g/dL])

   ○ Measure ionized calcium levels (normal 4–5.2 mg/dL or 1–1.3 mmol/L)

     ■ Preferred approach in critically-ill patients

• Evaluate and manage etiology

   ○ Check parathyroid hormone (PTH), vitamin D and precursors, magnesium, and phosphate levels

   ○ Pharmacological causes of decreased ionized calcium may include excess infusions of citrate, EDTA, lactate, fluoride poisoning, foscarnet, cinacalcet, bisphosphonates, or unrelated increase in serum phosphate or decrease in serum magnesium levels

• Symptomatic (e.g., dysrhythmias, hypotension, tetany, and seizures)

   ○ Usually associated with an ionized calcium level < 2.8 mg/dL or < 0.7 mmol/L

   ○ Calcium chloride 1 g (10 mL of a 10 % solution) IV over 5–10 min

     ■ Contains 272 mg/13.6 mEq elemental calcium per gram product

     ■ Severe desiccant → must give through a central line

   ○ Calcium gluconate 1–3 g (10–30 mL of a 10 % solution) IV over 5–10 min

     ■ Contains 93 mg/4.5 mEq elemental calcium per gram product

     ■ Preferred product for peripheral venous administration

   ○ Measure serum calcium every 6 h during acute therapy

   ○ A continuous IV infusion of 0.3–2 mg/kg/h may be initiated to achieve and maintain normocalcemia if warranted (see critically ill setting above)

   ○ Change to enteral therapy once serum calcium is ≥ 8.5 mg/dL or ionized calcium normalizes

   ○ Use cautiously in patients on digitalis glycoside pharmacotherapy

   ○ Correct concomitant hypomagnesemia

   ○ Initiate calcitriol 0.25 mcg enterally daily if suspect vitamin D or PTH deficiency

   ○ If present and clinically feasible, treat acute severe hyperphosphatemia before calcium administration (i.e., with phosphate binders and/or with hemodialysis in acute tumor lysis syndrome)

• Asymptomatic

   ○ Enteral calcium 1–3 g daily

   ○ Various salts

     ■ Carbonate: 250 mg elemental calcium per 500 mg tablet

     ■ Citrate: 200 mg elemental calcium per 950 mg tablet

     ■ Gluconate: 90 mg elemental calcium per 1 g tablet

     ■ Lactate: 60 mg elemental calcium per 300 mg tablet

   ○ Calcium citrate and gluconate do not require an acidic medium for maximal bioavailability (i.e., appropriate salt with concomitant acid suppressive therapy)

• Identify and manage etiology (e.g., hyperparathyroidism, malignancy, excessive vitamin D effect)

   ○ Drug-induced causes can include:

     ■ Thiazide diuretics, calcium-containing antacids, vitamin D, lithium

• Intravenous 0.9 % saline (if no contraindications are present)

   ○ 200–300 mL/h initial therapy (patient-specific)

   ○ 100–200 mL/h once patient is adequately hydrated

   ○ Maintain urine output between 100 and 150 mL/h

• Potassium and magnesium supplementation

• Loop diuretics

   ○ Patient must be euvolemic before use and remain as such

     ■ Any resulting hypovolemia may increase serum calcium by promoting tubular calcium reabsorption

   ○ E.g., furosemide 40–80 mg IV (1 mg/kg) every 2–4 h

• Salmon calcitonin 4 units/kg SQ every 12 h

   ○ Onset within 1–2 h (effects on bone and calciuretic)

   ○ A test dose should be considered before therapy is initiated

     ■ In a tuberculin syringe dilute 10 units in 1 mL 0.9 % saline

     ■ Inject 1 unit (0.1 mL) intradermally on the flexor surface of the forearm

       □ The appearance of erythema or a wheal within 15 min indicates a positive reaction, and calcitonin salmon should not be administered

   ○ If an inadequate response is observed after 1–2 days, may increase the dose to 8 units/kg SQ every 12 h

   ○ Tachyphylaxis may develop (limit use to 48 h)

• Bisphosphonate

   ○ Slow onset (1–2 days)

   ○ Use cautiously in patients with renal insufficiency

   ○ Etidronate 7.5 mg/kg IV over 2–4 h for 3–5 days

   ○ Pamidronate 60–90 mg IV × 1 dose over 2 h

     ■ 60 mg for calcium levels ≤ 13.5 mg/dL

     ■ 90 mg for calcium levels > 13.5 mg/dL

   ○ Zoledronate 4 mg IV in one dose over 15 min (preferred agent-associated with increased events than pamidronate but no difference in severe renal toxicity)

• Other agents

   ○ Gallium nitrate 200 mg/m²/d by continuous IV infusion for ≤ 5 days

     ■ May be superior to bisphosphonates for humoral hypercalcemia of malignancy (PTHrp)

   ○ Glucocorticoids (for hypercalcemia associated with increased vitamin D activity)

     ■ Prednisone 20–40 mg enterally daily or equivalent in hypervitaminosis D, lymphoma or granulomatous disease-related

   ○ Chelating agents (rarely used)

     ■ EDTA 10–50 mg/kg over 4 h up to a maximum of 3 g in 24 h

• Hemodialysis with calcium-free dialysate

   ○ In life-threatening situations or if the patient is anuric

• Evaluate etiology