A. Characteristics

1. Abrupt reduction in renal function (usually within 2 weeks) manifest as:
   1. Increase in blood urea nitrogen (BUN) and creatinine = "azotemia"
   2. Reduction in glomerular filtration rate (GFR)
   3. Associated with polyuria, oliguria or anuria
2. Optional
   1. Hematuria
   2. Dysuria
3. Uremia [5] - symptomatic azotemia (see below)
   1. Neural effects
   2. Muscle effects
   3. Endocrine and metabolic effects
   4. Electrolyte abnormalities
   5. Miscellaneous effects
4. ARF requires duration <3 months (chronic renal failure >3 months)
5. Distinguish in-hospital versus outpatient ARF

B. Etiologies

1. Location of Lesion
   1. Pre-Renal - ~70% of cases outpatient; 35% inpatient
   2. Intrarenal - ~10% of cases oupatient; 60% inpatient
   3. Post-Renal (obstructive) - <20% of cases outpatient; ~5% inpatient
2. Pre-Renal
   1. Renal Artery Stenosis: atherosclerosis, fibromuscular dysplasia
   2. Congestive Heart Failure - reduced ejection fraction, hypoperfusion, cardiogenic shock [4]
   3. Hepatorenal syndrome (cirrhosis with ascites may show similar picture)
   4. Shock - renal hypoperfusion (usually hypovolemia and/or hypotension)
   5. Sepsis Syndromes [19] - contributes to ~50% of ARF in intensive care units [28]
   6. Cardiopulmonary bypass, CABG (>3 hours)
3. Parenchymal Damage
   1. Nephritis (inflammation): glomerular (glomerulonephritis) versus interstitial
   2. Acute Tubular Necrosis (ATN): usually follows pre-renal insult
   3. Rhabdomyolysis and myoglobinuria can also cause ATN and ARF [3]
   4. Nephrotic Syndrome
4. Post-Renal (~5%)
   1. Urinary Tract Infection (UTI) with pyelonephritis
   2. Urinary calculus disease (renal stones)
   3. Crystal deposition (see below)
   4. Bladder tumors with extensive invasion
   5. Prostatic Enlargement: Benign Prostatic Hyperplasia (BPH) and/or Carcinoma
   6. Unilateral obstruction with only one functioning kidney
5. Vascular
   1. Hypotension (insufficient perfusion)
   2. Hypertension
   3. Atherosclerotic (atheroembolism) - 5-10% of hospitalized ARF
   4. Cholesterol Emboli (Renal Atheroemboli) [29]
   5. Trauma
   6. Vasculitides
   7. Post-operative - aortic aneurysm repair, aortic cross-clamping
   8. Vasoconstricting Agents - NSAIDs, vasopressors, ischemia
6. Pharmacologic Agents
   1. Aminoglycosides
   2. Non-steroidal anti-inflammatory drugs (NSAIDs) - similar for nonspecific and COX-2 selective agents (both vascular and interstitial effects [8,9,10]
   3. ACE Inhibitors (ACE-I) and angiotensin II receptor blockers (AT2RB)
   4. Radiocontrast Dye
   5. Interstitial Nephritis - sulfonamides, NSAIDS, antibiotics [6]
   6. Amphotericin [11]
   7. Cis-Platinum more than carboplatin
   8. Ischemia acutely damages tubules (medulla) more than cortex
7. Crystal Induced ARF [12]
   1. Acyclovir - high dose intravenous (dehydrated patients)
   2. Sulfonamides - high dose oral (usually with HIV)
   3. Methotrexate - high dose intravenous
   4. Indinavir - alkaline urine, renal insufficiency (HIV)
   5. Triampterene - overdoses, urine pH <7.0, concurrent NSAIDs
   6. Others: primidone, ciprofloxacin, vitamin C, cephalexin, foscarnet, others
8. Pathophysiology
   1. Ischemia is the underlying problem in many patients with ARF
   2. This leads to depletion of cellular ATP and release of calcium
   3. Reactive oxygen species are produced leading to further cell death [14]
   4. Calcium release leads to phospholipase activation
   5. Neutrophils may mediate reperfusion injury (ICAM-1 is involved)
   6. Many nephrotoxins are renal vasocontrictors including cyclosporine, radiocontrast

C. Initial Evaluation

1. Consider possible etiologies and direct evaluation towards these
2. Medications should always be suspected in contributing to or causing ARF (see above)
3. Standard Blood Testing
   1. Electrolyte and renal panel, Ca2+, Phosphate, Mg2+, Albumin
   2. Complete Blood Count (± reticulocyte count and ESR)
   3. Estimate GFR using creatinine clearance equation [24]
   4. Creatinine clearance (men) ={140-age in year)x(weight kg)}÷ (72 x serum creatinine mg/dL)
   5. Creatinine clearance for women = above result x 0.85
   6. This provides a reasonable estimate of renal function (normal >90 mL/min)
   7. However, estimates are not accurate for rapidly changing (deteriorating) GFR [24]
   8. In acutely oliguric and anuric patients, estimates are very unreliable
4. Cystatin C [23,24,25]
   1. Cysteine protease inhibitor (molecular weight 13K) freely filtered by glomerulus
   2. May provide a better estimate of GFR than serum creatinine
   3. Levels are independent of age, sex and lean muscle mass (unlike creatinine)
   4. Increased cystatin levels are associated with death and cardiac disease in elderly
   5. May precede changes in creatinine by 1-2 days but may not aide in differential [13]
5. Lipocalcin [13]
   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
6. Foley catheter must be placed to rule out bladder obstruction
7. Urine for electrolytes, dipstick and microscopic analysis
   1. Osmolality, creatinine, Na+, K+, Cl-
   2. Urine spot protein to creatinine ratio (normal is <17mg/g men, <25mg/g women)
   3. Pigment: Hemoglobin (myoglobin)
   4. Cells, Casts, Crystals, Organisms
   5. Consider Urine culture
   6. 24 hour urine collections are generally not reliable
8. Fractional Excretion (FE) of Sodium (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
9. Renal and Pelvic Ultrasound - stones, hydronephrosis, mass compression
10. Consider abdominal radiograph if ultrasound is not done to rule out stones
11. Consider Additional Causes of ARF
    1. Inflammatory including vasculitis: sedimentation rate, CRP
    2. Streptococcal infection: ASO titer
    3. Lupus and other related syndromes: ANA, complement Levels
    4. Glomerular basement membrane disease: Anti-GBM Abs, ANCA
12. Renal Biopsy should be considered in rapidly progressing disease
    1. ANCA and Anti-GBM diseases - consider cyclophosphamide + glucocorticoids
    2. Idiopathic rapidly progressive glomerulonephritis is often ANCA positive
    3. However, other inflammatory diseases such as bacterial endocarditis can given ANCA+
13. Urine Eosinophilia
    1. Interstitial nephritis
    2. Cholesterol emboli
    3. Adverse drug reaction
14. Early Nephrology Consultation is as associated with improved outcomes over delay [15]

D. Prerenal Versus Renal ARF (Table 2, Ref [1])

1. Glomerular Involvement
   1. Diffuse: all glomeruli in a tissue section are diseased
   2. Focal: some glomeruli in a section are diseased
   3. Segmental: some parts of an individual glomerulus are affected
2. Focal Glomerulonephritis
   1. Some of the glomeruli are dead
   2. Death can include necrosis, collapse, or sclerosis
   3. Acute or chronic inflamation is often seen
3. Crescent Glomerulonephritis
   1. Crescent (moon shaped) formation in glomerulus
   2. Affected glomeruli are non-functional
   3. Very poor prognosis
4. Focal and Segmental Glomerulosclerosis: portions of many glomeruli are destroyed
5. Minimal Change Glomerulonephritis
   1. Glomeruli appear okay, but function is poor
   2. Electron microscopic evidence of basement membrane disease
   3. Response to glucocorticoids is usually very good
6. IgA Deposition
   1. IgA nephropathy
   2. Deposition of IgA immune complexes
   3. Differential includes Systemic Lupus (SLE) and Henoch-Schonlein Purpura (HSP)
7. Proliferative Glomerulonephritis
   1. Increase in mesangeal cell number
   2. Usually follows insults (eg. Post-Streptococcal)
   3. May be seen in collagen vascular disease, especially Systemic Lupus
8. Collapsing Glomerulonephritis
   1. Major form seen in HIV nephropathy
   2. Usually late stage
   3. Rapid progression to renal failure (weeks to months)
   4. No effective therapy to date
9. Tubular Necrosis
   1. Tubular cells die and slough off basement membrane
   2. The dead tubular cells form casts which can occlude lumen
   3. Glomular basement membrane may also be damaged
10. Staphylococcal associated glomerulonephritis - immune complex, superantigen [31]

F. Uremia - Signs and Symptoms (Table 2, Ref [5])

1. Neural effects
   1. Fatigue
   2. Peripheral neuropathy
   3. Mental Status changes
   4. Seizures
   5. Anorexia and nausea
   6. Decreased sense of smell and taste
   7. Sleep disturbances
   8. Delirium and coma; may progress to death if untreated
2. Muscle effects
   1. Muscle cramps
   2. Restless legs
   3. Reduced muscle membrane potential
3. Endocrine and Metabolic Effects
   1. Amenorrhea and sexual dysfunction
   2. Hyperparathyroidism (secondary)
   3. Phosphate retention (hyperphosphatemia, hypophosphaturia)
   4. Hypocalcemia
   5. Elevated phosphate-calcium product associated with uremic bone disease
   6. Insulin resistance
   7. Increased protein-muscle catabolism
4. Electrolyte and Fluid Abnormalities
   1. Hyperkalemia - may be life threatening
   2. Abnormal magnesium levels
   3. Lactic acidosis (may induce compensatory tachypnea)
   4. Volume overload
   5. Hyponatremia
   6. Hypertension
5. Miscellaneous effects
   1. Immunosuppression - mainly reduced cellular immunity
   2. Serositis, especially pericarditis
   3. Pruritus
   4. Hiccups
   5. Anemia due to EPO deficiency and shortened red blood cell lifespan
   6. Platelet dysfunction - bleeding diathesis
6. Uremic Solutes (Table 1, Ref [5])
   1. Urea - causes only small part of uremic syndrome
   2. ß2-microglobulin - associated with amyloid deposition
   3. Guanidines
   4. Phenols: p-cresol
   5. Indoles: indican
   6. Aliphatic amines: dimethylamine
   7. Furans: CMPF
   8. Polyols: myoinositol
   9. Nucleosides: pseudouridine
   10. Dicarboxylic acis: oxalate
   11. Carbonyls: glyoxal

G. Management

1. Inpatient versus outpatient management
   1. Inpatients usually sicker with more concomitent problems
   2. Inpatient ARF usually superimposed on CRF after procedure or medication
   3. Outpatient ARF often related to new medication or cardiac dysfunction
   4. Specific treatments are not yet available
   5. Remove underlying problem or offending agent(s)
   6. Severe ARF and/or volume overload may necessitate renal replacement therapy (see below)
2. Identify and Modify Contributing Factors
   1. Adjust medication dosages for the renal failure
   2. Correct acidosis
   3. Correct electrolyte abnormalities
   4. Maintain appropriate blood pressure
   5. Monitor intravascular and total fluid status
   6. Renal function may deteriorate based on hypovolemic status
   7. Dialysis or ultrafiltration may be required for hypervolemia
3. Adjust Medication Dosages
   1. In new oliguric or anuric ARF, adjust medication dosages for GFR <10mL/min
   2. 24 hour urine collection for accurate GFR determination
   3. Discontinue NSAIDs and other nephrotoxic medications
4. Electrolytes
   1. Hyperkalemia represents most serious immediate complication
   2. Aggressive treatment often required
   3. Sodium polystyrene sulfonate (Kayexelate®) reduces total body potassium
   4. Correction of acidosis will reduce serum potassium levels
   5. Hypocalcemia and hyperphosphatemia must be monitored
   6. Serum albumin level must be followed to correct for ionized calcium
   7. Magnesium levels must also be assessed
5. Volume Overload
   1. Attempt to maximize cardiac output and improve intravascular volume
   2. Diuretics often worsen renal failure but may be necessary to prevent pulmonary edema
   3. General use of diuretics in critically ill patients with ARF is discouraged [7,16]
   4. Furosemide (Lasix®) of no overall clinical benefit in prevention or treatment of ARF [7]
   5. High dose furosemide associated with ototoxicity in adults [7]
   6. For volume reduction, dopamine or mannitol can be tried after or in addition to standard diuretics, but are usually not effective
   7. "Renal range" (<5µg/kg/min) dopamine transiently improves urine output but has no overall clinical effect on intensive care unit (ICU) patients [17,18,30]
   8. Improving cardiac output is most likely responsible for increased urine production in some ICU patients with oliguria and ARF on renal range dopamine
   9. Fednoldopam, a dopamine DA-1 agonist, reduced acute kidney injury and death in critical illness in a meta-analysis and should be considered strongly [32]
   10. Albumin infusions are probably not helpful, but may help diuresis in low albumin states
   11. Potassium sparing diuretics should be avoided due to high risk of hyperkalemia
   12. Dialysis may be required particularly in severe volume overload situations
6. Acidosis
   1. Renal tublar acidosis (RTA) is common in early renal failure
   2. Oral bicitra (citrate replaces bicarbonate) may be used
   3. Bicitra is contraindicated in edematous states due to high sodium content
7. Hypertension (HTN)
   1. ACE inhibitors should generally not be used with creatinine >2.5-3.0mg/dL
   2. Dihydropyridine calcium blockers such as amlodipine or felodipine are effective
   3. Labetolol is also very effective but patient should have LV EF>50% and no bronchospasm
   4. Diuretic agents may improve hypertension and volume overload
   5. Dialysis may be required to reduce intravascular volume
8. Phosphate and Calcium
   1. Dangerous if product of Calcium and Phosphage > ~70 (mg/dl) (will lead to precipitation)
   2. If product is close to 70, then phosphate should be lowered with aluminum compounds
   3. These compounds should be given with meals to bind the phosphate directly
   4. If product is <60, then calcium should be given 500-1000mg po tid with meals
   5. If calcium is low but phosphate normal, then calcium should be given before meals
   6. Consider using 1,25 dihyroxyvitamin D supplements
9. Hyperuricemia
   1. Check uric acid levels
   2. Uric acid deposition in renal tubules may worsen progression of renal failure
   3. Allopurinol may be given (100-200mg po qd) to attempt normalization of uric acid
10. Renal Diet
    1. Low phosphate, potassium, sodium, protein
    2. High calcium and vitamin D
    3. Various multivitamin formulas available for renal patients, such as Nephrovit®
    4. Low protein diet may slow progression slightly in chronic renal failure (CRF)
11. Protein Load
    1. Reducing protein load is thought to reduce incidence of azotemia
    2. Patients with moderate renal disease - some decrease in progression on low protein diet
    3. Patients with severe renal disease show no benefit on low protein diet
12. Atrial natriuretic Peptide (ANP)
    1. ANP is a vasodilator with diuretic activities
    2. Recombinant ANP (Auriculin®) may have some efficacy in oliguric ARF
    3. ANP may increase renal dysfunction in diabetics receiving radiocontrast
    4. Brain derived natriuretic factor (BNP) may be effective some patients
    5. Other vasodilators (such as calcium channel blockers) are not effective
    6. Renal growth and regeneration factors are under investigation
13. N-Acetylcysteine (NAC)
    1. NAC is an antioxidant which may have some activity in ARF [14]
    2. NAC given IV 150mg/kg 30 minutes before and 50mg/kg over 4 hours after radiocontrast reduced incidence of creatinine rise >0.5mg/dL by 65-90% [26]
    3. Perioperative NAC (4 doses of 600mg each IV) did not reduce the risk of renal dysfunction (creatinine increase >0.5mg/dL) in high risk CABG patients [27]
14. Renal Replacement Therapies [33]
    1. Continuous venovenous hemofiltration - ultrafiltrate replaced but net volume loss
    2. Continuous venovenous hemodialysis - fluid replacement not routinely administered
    3. Continous venovenous hemodiafiltration - fluid losses replaced in part or completely
    4. Hemodialysis - intermittent daily or alternating days
15. Kidney Transplantation

H. Dialysis and Ultrafiltration [28,33]

1. Introduction
   1. Hospital intensive care unit (ICU) patients with ARF have 50-60% mortality [28]
   2. Consider DAILY dialysis which likely reduces mortality rate for in-hospital ARF
   3. Daily dialysis resulted in better uremia control, reduced hypotensive episodes during dialysis, and more rapid resolution of ARF in-hospital than alternating day dialysis
   4. Ultrafiltration may be used for volume reduction
   5. Femoral or jugular venous access have similar levels of nosocomial events in patients requiring acute renal replacement therapy [35]
2. Indications
   1. Unresponsive serum abnormalities, uremia, volume overload
   2. Serum abnormalities unresponsive to medical therapy: acidosis, hyperkalemia
   3. Uremia: Mental status changes (usually delirium), nausea, vomiting, pericaridits
   4. Prophylactic hemodialysis after coronary angiography improves renal outcomes in patients with advanced renal failure (CRF or ARF) [34]
3. Hemofiltration or Hemodialysis for Renal Recovery after ARF [20]
   1. Average duration of need for these therapies was 9-16 days in ARF
   2. After this time, kidneys regain function and increase urine output
   3. Daily hemodialysis is more effective than alternating day [20]
   4. Hemofiltration also very effective for preventing radiocontrast nephropathy [22]
4. Chronic Dialysis
   1. Failed recovery of renal function necessitates chronic dialysis
   2. Native kidneys may continue with minimal function for 6-12 months of hemodialysis
   3. After that, native kidneys usually shut down permanently
5. Comparison of Renal Replacement Therapies [33]
   1. No differences between intermittent hemodialysis and continuous renal replacement therapy
   2. Continuous venovenous hemofiltration at dose of 25mL/kg/hr should be provided
   3. Intensive renal support in critically ill patients with renal failure did not improve outcomes compared with less intensive dialysis with continuous renal replacement at 20mL/kg/hr [36]

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