A. Epidemiology

1. Most common cause of acute renal failure (ARF) in hospitlized patients
2. Most common form of ARF in intensive care unit patients
3. Mortality rate in ATN patients who require dialysis is 50-80%
4. Usually defined as 50% decline in calculated glomerular filtration rate (GFR)
5. Also defined as a 0.5mg/dL (40 µmol/L) increase in serum creatinine

B. Pathophysiology [3,6]

1. Renal medulla receives blood supply after oxygen has been extracted in the cortex
2. In addition, blood flow in medulla is required to maintain osmotic gradients
3. Therefore, medulla is especially susceptible to hypoxia, usually from hypoperfusion
4. Even minor hypotension can lead to ATN, particularly with concomitant insults
5. Renal vasodilators help prevent ischemic injury
   1. Nitric oxide
   2. Prostaglandin - especially PGI2 (prostacyclin)
   3. Adenosine
   4. Dopamine
   5. Urodilatin
   6. Atrial natriuretic peptides
   7. These are important for maintaining afferent arterial vasodilation
6. Renal Vasoconstrictors
   1. Endothelin
   2. Angiogensin II (mainly efferent arteriolar vasoconstriction)
   3. Vasopressin
   4. Adenosine (afferent arteriolar vasoconstriction)
7. Expression of cell adhesion molecules and inflammation follows initial insult [4]
   1. Loss of integrity of tight junctions and desmosomes occurs early
   2. Tubule cells sloughed into lumen
   3. P-selectin expression increases early in ishcemic tissue
   4. E-selectin expression follows
   5. ICAM-1 appears to play a significant role in recruiting leukocytes
   6. Leukocytes are recruited and release proinflammatory products
   7. These include IL-1, IL-2, IL-6, TNF alpha, and TGFß
   8. Ischemic damage leads to decreased nitric oxide production
   9. Nitric oxide normally reduces cell adhesion molecule expression and inflammation
8. Electrolyte transport inhibitors can also limit damage (by reducing energy needs)
   1. Prostaglandin E2
   2. Adenosine
   3. Dopamine
   4. Platelet activating factor
9. Ischemia induced ATN appears to be more damaging to kidney than toxin induced [6]
10. Apoptosis may also play a role in ATN, including both ischemic and toxic injuries [3]

C. Etiology

1. Usually due to a combination of ischemic, toxic, and/or septic insults to kidney [6]
2. Drugs
   1. Aminoglycosides
   2. Cisplatin (cis-platinum), mitomycin, ifosfamide
   3. Cyclosporine A (Tacrolimus less frequently)
   4. Radiocontrast Agents (Intravenous)
   5. Amphotericin B
   6. Acyclovir (high dose, intravenous)
   7. Non-steroidal anti-inflammatory agents (NSAIDS)
3. Hypoperfusion: Ischemia and Hypotension [6]
   1. Hemorrhage
   2. Shock from any cause
   3. Sepsis (with or without systemic hypotension) [17]
   4. Pre-renal azotemia prolonged (including dehydration, hypotension) [17]
   5. Anesthesia (intubation)
   6. Obstetric Complications
   7. Cardiopulmonary Bypass Surgery
   8. Hepatorenal Syndrome
4. Pigmented Toxins
   1. Myoglobinuria due to muscle breakdown (rhabdomyolysis) [5]
   2. Less commonly associated with hemoglobinuria due to massive erythrocyte hemolysis
5. Factors Contributing to Likelihood of Renal Damage []
   1. Underlying renal disease - especially diabetes mellitus, hypertension, myeloma
   2. Non-steroidal anti-inflammatory drugs (NSAIDS)
   3. Baseline hypoxemia - COPD mainly
   4. Ischemic damage appears to be more detrimental to kidney than toxin damage
   5. Cardiopulmonary bypass >3 hours associated with much higher risk
   6. Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers
   7. Underlying left ventricular dysfunction also predisposes to ATN and ARF
   8. Reactive oxygen species (ROS) may contribute to tubular dysfunction and apoptosis [7]

D. Signs and Symptoms

1. Urine Output [8]
   1. Oliguria or anuria
   2. Present in about 30% of patients with ATN
   3. Oliguria is <400mL/day urine output
2. Rapidly progressive azotemia - creatinine elevation 0.5-1mg/dL per day
3. Previous Toxin Exposure
4. Uremia

E. Diagnosis

1. High suspicion
   1. Oliguria is UO < 400cc/day or <25cc/hr
   2. May have non-oliguric OR oliguric ATN
2. Urinary Sediment in ATN
   1. Epithelial ("muddy brown") casts are classical but not very common
   2. Renal tubular epithelial cells
   3. Granular casts
3. Laboratory testing required for confirmation of diagnosis
4. Major differential is prerenal azotemia versus ATN ([6] and Table 1, Ref [1])
   1. Urine osmolality >500 mOsm/kg in prerenal, <400 mOsm/kg in ATN
   2. Urine sodium (Na) <20 mEq/L prerenal versus >40 mEq/L in ATN
   3. Urine:plasma creatine ratio: >40 prerenal versus <20 ATN
   4. Fractional Excretion of Na (FENa): <1% prerenal versus >2% ATN
   5. Plasma BUN to creatinine ratio: >15 prerenal, <10 in most ATN
5. FENa
   1. FENa = (U/P Na ÷ U/P Creatinine) x 100 where U=urine, P=plasma
   2. Measures resorption activity of tubules
   3. In prerenal failure, Na is actively resorbed and FENa <0.5
   4. With intrinsic renal disease, kidney cannot resorb Na well so that Na is lost, FENa >2.0
6. Estimation of Creatinine Clearance [18]
   1. Men CrCl (mL/min) ~ (140-Age)x(weight in kg)/(72 x serum creatinine)
   2. Women CrCl (mL/min) ~ equation above for men x 0.85
   3. Several other equations are also available
   4. Cystatin C is being evaluated instead of creatinine
7. Lipocalcin []
   1. Neutrophil gelatinase-associated lipocalcin (NGAL) is secreted into urine by thick ascending loop of Henle and collecting ducts
   2. NGAL plays a host-defense role and chelates iron-siderophore complexes
   3. Urinary NGAL is expressed in proportion to acute injury in kidney
   4. NGAL is not expressed in in prenal azotemia, with volume depletion, or with diuretics
   5. NGAL is also not increased in stable CRF, only with progressive intrinsic renal dysfunction
   6. A single measure of urinary NGAL helps distinguish acute renal injry from normal function, prerenal azotemia, CRF, and predicts inpatient outcomes
   7. NGAL measurements superior to creatinine, FeNa, alpha1-acid glycoprotein for prognosis

F. Prerenal Versus Intrarenal ARF (Table 2, Ref [1])

1. Discontinue any renal toxins and implicated medications
2. Hydration
   1. Usually the most effective method, least toxicity
   2. Caution in patients with sepsis and other volume overloaded states
   3. Accumulation of fluid in the lung increases risk for requiring mechanical ventilation
3. Benefit of Diuresis is Unclear
   1. Mannitol: increases lumen fluids, may prevent obstruction by casts and dead cells
   2. Furosemide: increases toxin removal, theoretical sparing of tubules by blocking ATPase
   3. Furosemide initial 100-200mg IV ± 10-40mg/hr IV drip may convert to nonoligouria
   4. Thiazide or other loop-type diuretic may be added to enhance urine output
   5. Mannitol and furosemide are not effective in preventing contrast nephropathy
   6. General use of diuretics in critically ill patients with ARF is discouraged [9]
   7. Atrial Natriuretic Peptide (ANP; Auriculin®) has not shown efficacy [10,11]
   8. If loop diuretics are tried, ensure appropriate volume and optimal cardiac status
4. Dopamine (low dose, 2-4µg/kg/min) may improve urinary flow
   1. Especially in patients with poor renal perfusion such as heart failure
   2. However, no clear benefit in patients after major vascular surgery [13]
   3. No clear benefit of routine use in patients with ARF [14]
   4. Use reasonable in patients who require diuresis with poor cardiac function and perfusion
   5. Dopamine is worth trying in some patients to improve diuresis and cardiac function [8]
   6. In general, if no response within 6 hours of initiating IV dopamine, then discontinue [8]
5. Rhabdomyolysis and Myoglobinuria [15,16]
   1. Massive rhabdomyolysis usually due to traumatic crush injury [5]
   2. Also due to drugs, overexertion, alcohol abuse, various toxins, some muscular dystrophies
   3. Drugs include statins (usually in combination with fibrates), cocaine, alcohol
   4. High dose atorvastatin, pravastatin, simvastatin alone have very low rhabdomyolysis risk [12]
   5. Cerivstatin (no longer marketed) had much higher incidence of rhabdomyolysis
   6. Confirm diagnosis with urine dipstick myoglobin with urine microscopy
   7. Infusion of intravneous fluids before extrication or soon after may lessen severity
   8. Establishment of stable intravascular volume is primary modality
   9. Give normal saline up to 1.5L per hour; confirm urine flow at 300 mL/hour
   10. Forced mannitol-alkaline (bicarbonate) diuresis if oliguria develops with high fluid loads
   11. Prophylaxis against hyperkalemia and ARF
   12. Concern for compartment syndrome acutely or developing over time
   13. Crystalloid should be used for volume infusion
6. Radiocontrast Nephropathy
   1. Intravenous hydration 6-12 hours prior to contrast reduces risk
   2. N-acetylcysteine (NAC) 600mg bid reduces risk of ATN [6,7]
   3. Sodium bicarbonate infusion also reduces risk
   4. Forced diuresis is no longer recommended
7. Improving renal oxygenation (perfusion) may improve outcomes in ischemic ATN [6,9]
8. To date, medical therapy has been disappointing in improving outcomes in ATN
9. Nutrition critical: Enteral feeding is always preferable to parenteral wherever possible [6]
10. Renal replacement therapy (usually hemodialysis) may be required

H. Hemodialysis [1,2]

1. Likely optimal method for modulating volume status in severe ATN
   1. May prolong course of ATN overall, but with significant benefits
   2. Use of biocompatible membranes and bicarbonate dialysis may improve outcomes
   3. No difference with intensive versus standard dialysis
2. Optimal timing and duration is unclear
3. Probable Indications for Hemodialysis in Critical Illness [2]
   1. Oliguria: urine output <200mL in 12 hours
   2. Anuria: urine output <50mL in 12 hours
   3. Hyperkalemia: K+ >6.5mmol/L
   4. Severe acidemia: pH <7.0
   5. Azotemia: BUN >30mmol/L (>70mg/dL)
   6. Uremia: encephalopathy, neuropathy/myopathy, pericarditis
   7. Severe hypo- or hypernatremia
   8. Hyperthermia
   9. Drug overdose with dialyzable toxin

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