Definitions

• General Definition: sudden decline in kidney function causing disturbances in fluid, electrolyte, and acid-base balance because of a loss in small solute clearance and decreased glomerular filtration rate (GFR)
• Acute Kidney Injury Network (AKIN) Definition: abrupt (within 48 hrs) reduction in kidney function, defined as an absolute increase in serum Cr of greater than or equal to 0.3 mg/dL, a percentage increase in serum Cr of greater than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of <0.5 mL/kg/hr for >6 hrs

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Physiology

• Kidneys normally receive up to 25% of CO and are exquisitely sensitive to hypoperfusion
• In AKI, the kidney’s ability to auto-regulate (maintain constant renal blood flow over a wide range of renal perfusion pressures) is compromised

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Epidemiology

• Incidence of AKI
  • Hospitalized Patients: occurs in 7% of hospitalized patients
  • ICU Patients: occurs in 36-67% of ICU patients
  • Incidence of AKI is increasing
  • 5-6% of ICU patients with AKI require HD
• Morbidity of AKI in the ICU:
  • Increased ICU length of stay
  • Increased risk of CKD (however, true incidence of CKD following AKI is unknown)
• Mortality of AKI in the ICU:
  • Mortality in severe AKI (requiring HD): 50-70%
  • Mortality is correlated with severity of AKI
  • Even small changes in serum Cr in hospitalized patients are correlated with increased mortality
• Etiology of AKI in the ICU:
  • AKI is commonly multi-factorial in the ICU, resulting from hypoperfusion + sepsis + medications
  • Nephrotoxic medications have been implicated in up to 25% of all AKI cases in the ICU

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Staging of AKI: RIFLE Staging

(Acute Dialysis Quality Initiative, 2002 Staging: excludes patients with primary kidney disease, such as glomerulonephritis)

• Risk: Cr increase >1.5x or urine output <0.5 mL/kg/hr x 6 hrs
• Injury: Cr increase >2x or urine output <0.5 mL/kg/hr x 12 hrs
• Failure: Cr increase >3x or urine output <0.5 mL/kg/hr x 24 hrs (or anuria x 12hrs)
• Loss: persistent loss of kidney function for >4 wks
• End-Stage Kidney Disease: persistent loss of kidney function for >3 mo

Staging of AKI: Acute Kidney Injury Network (AKIN) Staging

• Stage 1 (similar to Risk): Cr increase at least 0.3 mg/dL (or at least 1.5-2x increase from baseline) or urine output <0.5 mL/kg/hr for >8 hrs
• Stage 2 (similar to Injury): Cr increase at least 2-3x from baseline or urine output <0.5 mL/kg/hr for >12 hrs
• Stage 3 (similar to Failure): Cr increase at least 3x from baseline (or Cr at least 4 mg/dL with an acute rise of at least 0.5 mg/dL) or urine output <0.5 mL/kg/hr for 24 hrs (or anuria x 12 hrs)

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Etiology: Pre-Renal

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Etiology: Renal (Intrinsic)

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Etiology: Post-Renal

Ureteral Obstruction

• External Ureteral Compression
  • Inadvertent Ureteral Ligation During Surgery
  • Retroperitoneal Fibrosis
• Sloughed Papillae

• Ureteral Blood Clot
• Ureteral Calculi
• Ureteral Cancer

Bladder Neck Obstruction

• Neurogenic Bladder (see Neurogenic Bladder, [[Neurogenic Bladder]])
• Benign Prostatic Hypertrophy (BPH) (see Benign Prostatic Hypertrophy, [[Benign Prostatic Hypertrophy]])
• Bladder Neck Calculi
• Bladder Neck Cancer (see Bladder Cancer, [[Bladder Cancer]])
• Bladder Neck Blood Clot

Urethral Obstruction

• Phimosis
• Urethral Congenital Valve
• Urethral Stricture

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Multifactorial Etiologies

• Post-Cardiac Surgery/Cardiopulmonary Bypass (occurs in up to 42% of cases without pre-existing kidney disease): associated with increased morbidity and mortality
• Trauma (occurs in 31% of cases): due to [[Hemorrhagic Shock]], [[Rhabdomyolysis]], and [[Abdominal Compartment Syndrome]]

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Diagnosis

Urinalysis (see Urinalysis, [[Urinalysis]])

Urine Microscopy

• General Comments
  • Nephrologist Review of Urine Microscopy is Superior to Clinical Laboratory Review [MEDLINE]: nephrologists were likely to recognize the presence of renal tubular epithelial cells, granular casts, renal tubular epithelial cell casts, and dysmorphic red blood cells in urine
• Urinary Scoring System [MEDLINE]: urine microscopy is highly predictive to differentiate prerenal azotemia from acute tubular necrosis
• Pre-Renal Azotemia
  • Normal/Near Normal Urine Microscopy: hyaline or fine granular casts may be present
• Acute Tubular Necrosis (ATN)
  • Muddy-Brown (Brown Pigmented) Granular Casts and Renal Tubular Epithelial Cell Casts
    • However, the presence of muddy brown granular casts and renal tubular epithelial cell casts are usually seen relatively late and thus are not sensitive for the early detection of AKI
    • In addition, the absence of casts deos not exclude the diagnosis of ATN: cell sloughing and cast formation may be less prominent in patients with less severe disease and non-oliguric ATN
• Glomerular Injury
  • Cellular Casts
• Acute Interstitial Nephritis
  • Eosinophiluria
    Urate Nephropathy
  • Uric Acid Crystals
• Atheroembolic AKI

Serum Creatinine

• Creatinine is limited as an real-time estimate of GFR in critically ill patients (as creatinine is not in steady state in these patients)
  • Rate of Cr production, apparent volume of distribution of creatinine, and rate of creatinine elimination are all variable
  • Some medications (trimethoprim, dronedarone, cimetidine) impair creatinine secretion
• Use of creatinine lacks sensitivity and underestimates the degree of kidney dysfunction in critically ill patients
• Increases in serum creatinine lag behind reductions in GFR -> large changes in GFR result in only small changes in creatinine (due to non-linear, exponential relationship of GFR and creatinine)

Biomarkers for the Early Detection of Acute Kidney Injury

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

• General Comments
  • NGAL Rapidly Increases in Response to Renal Ischemia: it may function to attenuate tubular toxicity by increasing the normal proliferation of renal tubular cells and by inducing heme oxygenase (which provides additional tubular cell protection)
  • NGAL is More Sensitive than Serum Creatinine for the Detection of Early AKI
  • Urine and Serum NGAL are Correlated with Increasing Length of ICU and Hospital Stay [MEDLINE]
• Serum NGAL
• Urinary NGAL
  • Sensitivity/Specificity (Using Cutoff Value of 50 microg/L) [MEDLINE]: sensitivity 100%/specificity 98%

Serum or Urinary Cystatin C

• General Comments
  • Cystatin C is More Sensitive than Serum Creatinine for the Detection of Early AKI
• Serum Cystatin C
• Urinary Cystatin C

Kidney Injury Molecule-1 (KIM-1)

• xxx

Urinary IL-18

• xxx

Fractional Excretion of Sodium (FENa) (see xxx)

• FENa is frequently useful for differentiating “pre-renal” (diminished renal perfusion, FENa <1%) from “intra-renal” (ischemia or nephrotoxins, FENa >2%)
• However, pre-renal and intra-renal causes often co-exist in critically ill patients

Fractional Excretion of Urea (FE Urea) (see xxx)

• xxx

Urinary Uric Acid:Urinary Creatinine Ratio

• Ratio >1 -> suggests urate nephropathy
• Ratio <1 -> suggests AKI due to other causes

Urine Osm

• Contrast Nephropathy: urine osm around 300 (isosthenuria)

Diagnostic Volume Challenge

• May be useful to determine if AKI is pre-renal

Renal Biopsy

• Not necessary in contrast nephropathy (diagnosis is clinical)
• May be useful in cases of GN or vasculitis

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Prevention of Acute Kidney Injury (AKI)

• In contrast to community-acquired AKI, ICU-acquired AKI is usually associated with more than one insult -> since the first insult may not predictable, much of prevention effort is aimed at preventing second or concurrent insults
  • Predictable causative events: cardiopulmonary bypass, contrast dye exposure, large volume paracentesis, nephrotoxic exposure, or chemotherapy

Prevention of Contrast Nephropathy

• Hydration: meta-analyses provide strong evidence that sodium bicarbonate is superior to isotonic saline to decrease incidence of contrast nephropathy
  • Mix 3 amps bicarb in 1 L D5W -> run at 3 cc/kg/hr x 1 hr prior to contrast -> run at 1cc/kg/hr x 6 hrs after contrast
• N-Acetylcysteine (Mucomyst): 600 mg BID on the day before and day of the administration of contrast (alternatively, can use IV mucomyst)
  • Free radical scavenger
  • Conflicting data in prevention of contrast nephropathy
• Use of Low-Volume, Non-Ionic, Low-Osmolar or Iso-Osmolar Contrast Agents: proven to decrease risk of contrast nephropathy, as compared to high-osmolar agents
  • Although these agents have lower osmolality (600 to 850 mOsm/kg H2O) than first-generation ionic contrast agents (1,500 to 1,800 mOsm/kg H2O), they are significantly hyperosmolar relative to plasma
  • Studies of a new iso-osmotic (approximately 290 mOsm/kg H2O) contrast medium, iodixanol, have demonstrated decreased nephrotoxicity as compared to iohexol (3% vs 26%, respectively)
• Avoid Concurrent Angiotensin Converting Enzyme Inhibitor Exposure (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]]): might increase risk of contrast nephropathy
• Peri-Procedural Ultra-Filtration or Hemodialysis: might decrease the risk of contrast nephropathy (however, studies are limited by fact that the clinical endpoint, Cr, is decreased by the intervention itself) -> not recommended without further studies
• Fenoldopam (see Fenoldopam, [[Fenoldopam]]): selective dopamine-1 receptor agonist -> renal vasodilato
  • Currently approved for the treatment of hypertensive crisis
  • No benefit in prevention of contrast nephropathy
• Theophylline (see Theophylline, [[Theophylline]]): no clear benefit in prevention of contrast nephropathy

Prevention of Alcoholic Hepatitis-Associated AKI

• Pentoxifylline (see Pentoxifylline, [[Pentoxifylline]]): decreases incidence of AKI in setting alcoholic hepatitis
  [Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial. Gastroenterology 2000; 119:1637–1648]

Prevention of End-Stage Liver Disease-Associated AKI in Setting of SBP

• Albumin (see Albumin, [[Albumin]]): decreases incidence of AKI in setting of SBP
  [Intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. NEJM 1999; 341:403– 409]

Prevention of ESLD-Associated AKI in Setting of Large-Volume Paracentesis

• Albumin (see Albumin, [[Albumin]]): decreases incidence of AKI after large-volume paracetesis
  [Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988; 94: 1493–1502]

Prevention of ESLD-Associated AKI

• Albumin + Terlipressin (a splanchnic vasoconstrictor, not available in US): may decrease mortality in hepatorenal syndrome
  [Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev 2006:CD005162]
  [Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study. Hepatology 2002; 36:941–948]
• Terlipressin or Norepinephrine (vasoconstrictors): improve renal function in hepatorenal syndrome (however, mortality benefit was demonstrated only in subset of patients who were “responders”)
  [A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008; 134:1360-1368]
  [Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003; 18:152-156]
  [Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: A randomized study. Gastroenterology 2008; 134: 1352-1359]
  [Noradrenalin vs terlipressin in patients with hepatorenal syndrome: A prospective, randomized, unblinded, pilot study. J Hepatol 2007; 47:499 –505]
  [An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol 2008; 103:1689-1697]
• Vasopressin: improves renal function, as compared to octreotide alone
  [Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: A retrospective study. Nephrol Dial Transplant 2005; 20:1813–1820]
• Octreotide + Midodrine + Albumin (OMA) Therapy: midodine + octreotide improve mortality and may result in reversal of hepatorenal syndrome
  [Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999; 29:1690-1697]
  [Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci 2007; 52:742-748]
  [Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009; 43:680-685]

Maintenance of Renal Perfusion

• Goal: maintain MAP greater than or equal to 65 (although actual MAP required in AKI is unknown and depends on age, underlying vascular disease, etc) using fluids/pressors
• Renal-Dose Dopamine: may cause a trasient increase in urine output, but does not decrease incidence of AKI, need for HD, or improve outcome in AKI
  • Renal-dose dopamine may worsen renal perfusion in AKI, increases myocardial O2 demand, increase incidence of atrial fibrillation, and produce negative immunomodulatory effects
• Crystalloid vs Colloid -> SAFE trial demonstrated no mortality difference or need for HD between crystalloid vs colloid groups
  [A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256]

   

  • Higher mortality with colloid in subgroup with traumatic brain injury
  • Trend toward lower mortality with colloid in subgroup with septic shock
• Hydroxyethyl Starches
  • Systematic review demonstrated increased risk of AKI in setting of sepsis
    [Systematic review of randomized clinical trials on the use of hydroxyethyl starch for fluid management in sepsis. BMC Emerg Med 2008; 8:1]
  • SOAP Study: no adverse effect of hydroxyethyl starches on incidence of AKI or need for HD
    [Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34: 344 –353][Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216 –224]
  • Lowest molecular weight starches appear to be the safest
• Fluid-Conservative Management Strategy in ARDS (CVP <4, PCWP <8) does not impact ALI/ARDS mortality, as compared to fluid-liberal management strategy (CVP 10-14, PCWP 14-18)
  [The NHLBI Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. New Engl J Med 2006;354(24):2564-2575]

   

  • However, fluid-conservative management improves oxygenation, ventilator-free days, and ICU-free days
  • No increase in shock, nonpulmonary organ failure, or need for HD in the fluid-conservative group of patients

Management of Hyperglycemia

• Tight Glucose Control: multiple studies have demonstrated a decreased incidence of AKI and a decreased requirement for HD
  [Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449-461]
  [Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359-1367]
  [Tight blood glucose control is renoprotective in critically ill patients. J Am Soc Nephrol 2008; 19:571–578]
  [Tight perioperative glucose control is associated with a reduction in renal impairment and renal failure in non-diabetic cardiac surgical patients. Crit Care 2008; 12:R154]
• Tight Glucose Control: however, recent large trial did not demonstrate decreased need for HD (although the incidence of AKI was not reported in this study)
  [Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283-1297]

Fenoldopam (see Fenoldopam, [[Fenoldopam]])

• Selective dopamine-1 receptor agonist -> renal vasodilator
• Currently approved for the treatment of hypertensive crisis
• Low-Dose Fenoldopam (less than 1 ug/kg/min): increases renal blood flow without systemic effects
• In Sepsis: fenoldopam had no impact on need for HD (despite a smaller increase in Cr)
  [Prophylactic fenoldopam for renal protection in sepsis: A randomized, double-blind, placebo-controlled pilot trial. Crit Care Med 2005; 33:2451–2456]
• In At-Risk Patients: meta-analyses demonstrated that fenoldopam decreased mortality and need for HD
  [Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007; 49:56–68]

   

  • Trials in cardiac surgery patients are ongoing [clinicaltrials.gov ID: NCT00557219]

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Clinical Manifestations

Neurologic Manifestations

• Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]])

Renal Manifestations

• Anuria: rare in contrast nephropathy cases
• Creatinine Elevation: usually peaks at 1 wk in contrast nephropathy cases
• Normal Osmolal Gap (see Serum Osmolality, [[Serum Osmolality]]): variable
  • May be elevated in cases where AKI results from an intoxication (such as ethylene glycol, methanol, etc)
• Oliguria: present in 50% of contrast nephropathy cases

Other Manifestations

• xxx

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Prognosis

• Contrast nephropathy is associated with a risk-adjusted odds rato of death of 5.5

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Treatment

Diuretics

• Diuretics increase Na excretion and may increase urine output in AKI
• Oliguric AKI has worse outcome than non-oliguric AKI
  [Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group. J Am Soc Nephrol 1998; 9:692– 698]

   

  • However, there is no evidence that diuretics convert oliguric -> non-oliguric AKI
• Diuretics do not improve mortality, shorten duration of AKI, or decrease the need for HD
  [The role of diuretic agents in the management of acute renal failure. Contrib Nephrol 2001: 158 -170]
• Failure to Respond to Diuretics: associated with increased mortality and non-recovery of renal function
  [Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002; 288:2547–2553]
• In patients in recovery from AKI (after receiving HD), furosemide increased urine output but did not impact renal recovery
  [van der Voort PH, Boerma EC, Koopmans M, et al. Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: A double-blind randomized controlled trial. Crit Care Med 2009; 37:533-538]

Optimization of Nutrition

• See [[Nutrition]]

Renal Replacement Therapy (RRT)

• Types of RRT
  • Peritoneal Dialysis (PD):
  • Hemodialysis (HD):
  • Ultrafiltration (UF):
  • Continuous Renal Replacement Therapy (CRRT): also known as continuous veno-venous HD (CVVHD)
  • Slow Low-Efficiency Dialysis (SLED): slower solute and fluid removal than CRRT
• Indications for HD
  • Hyperkalemia
  • Uremia
  • Acidemia
  • Volume Overload
  • Drug Intoxications: ethylene glycol, etc
• Timing of RRT
  • Studies are controversial as to effect of early vs late initiation of HD
• RRT Modality
  • CRRT (CVVHD) has lower mortality rate than PD
    *[Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002; 347:895-902]
  • There is no evidence that the form of dialysis (CRRT vs intermittent HD vs SLED), affects mortality or renal recovery
  • Daily dialysis is not better than intermittent
  • Continuous therapies are consistently more expensive than intermittent therapies
• Dose of RRT
  • There is a suggestion that the minimum dose of each dialysis treatment may have an impact on mortality -> studies suggest that a UF rate of at least 35 ml/kg/hr had lower mortality rate (43%) than 20 ml/kg/hr (59%)
• Heparin vs Citrate Anticoagulation
  • Citrate may have same filter life and lower bleeding risk and mortality rate than heparin -> citrate is probably preferred

Atial Natriuretic Peptide (ANP) (Experimental)

• ANP decreases the need for HD and improves dialysis-free survival in post-cardiopulmonary bypass-associated AKI without pre-existing CKD
  [Recombinant human atrial natriuretic peptide in ischemic acute renal failure: A ran- domized placebo-controlled trial. Crit Care Med 2004; 32:1310–1315]

Erythropoetic Agents (Experimental)

• The endothelium plays a central role in the initiation and maintenance phases of AKI
• Animal models demonstrate a renal-protective effect of erythropoietin on endotoxin-related kidney injury
• Decreased severity of AKI is proposed to occur through tubular regeneration from the direct effects of erythropoietin on tubular epithelial cells
• Trials are ongoing (clinicaltrials.gov NCT00476619).

Renal Tubule Assist Device (Experimental)

• Ongoing trials

Hemofiltration for Sepsis (Experimental)

• Ongoing trials

Stem Cells (Experimental)

• Ongoing trials

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References

General

• Acute kidney injury in the intensive care unit: An update and primer for the intensivist. Crit Care Med 2010; 38:261-275

Diagnosis

• Comparison and interpretation of urinalysis performed by a nephrologist versus a hospital-based clinical laboratory. Am J Kidney Dis 2005; 46:820–829 [MEDLINE]
• Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.  Lancet 2005; 365:1231-1238 [MEDLINE]
• Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med 2008;36(4):1297-1303 [MEDLINE]
• Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin J Am Soc Nephrol 2008; 3:1615–1619 [MEDLINE]
• N-GAL: Diagnosing AKI as soon as possible. Critical Care 2007;11:1 [MEDLINE]
• Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients.  Clin J Am Soc Nephrol 2008; 3:1615-1619 [MEDLINE]
• Biomarkers of acute kidney injury: an evolving domain. Anesthesiology 2010; 112(4): 998-1004 [MEDLINE]
• The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: A multicenter pooled analysis of prospective studies.  J Am Coll Cardiol  2011; 57:1752-1761 [MEDLINE]

Contrast Nephropathy

• Low Fractional Excretion of Sodium With Contrast Media-Induced Acute Renal Failure. Arch Int Med 1980; 140: 531-533
• Prevention of contrast media-induced nephropathy by isotonic sodium bicarbonate: A meta-analysis. Wien Klin Wochenschr 2008; 120:742–748
• Use of isotonic sodium bicarbonate to prevent radiocontrast ne- phropathy in patients with mild pre- existing renal impairment: A meta-analysis. Anaesth Intensive Care 2008; 36:646 – 653
• Current role of sodium bicarbonate-based preprocedural hydration for the prevention of contrast-induced acute kidney injury: A meta-analysis. Am Heart J 2008; 156: 414 – 421
• Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: A meta-analy- sis. BMC Med 2009; 7:23
• Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: A systematic review and meta-analysis. Am J Kidney Dis 2009; 53:617-627
• Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: A randomized trial. JAMA 2008; 300:1038 –1046
• Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180 –184
• Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med 2008; 148:284-294
• A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: Unsupervised clustering to resolve heterogeneity. BMC Med 2007; 5:32
• The value of N-acetylcysteine in the prevention of radiocontrast agent-induced ne- phropathy seems questionable. J Am Soc Nephrol 2004; 15:407– 410
• N-Acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant 2008
• Prevention of contrast media-associated nephropathy. Arch Intern Med 2002; 162:329-336.
• A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003; 93:C29-C34
• Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet 2003; 362:598-603.
• Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: A meta-analysis of randomized, controlled trials. Am J Kidney Dis 2004; 43:1-9
• Systemic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int 2004; 65:1366-1374.
• Fenoldopam mesylate for the prevention of contrast-induced nephropathy: A randomized controlled trial. JAMA 2003; 290:2284-2291.
• Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003; 348:491-499.
• Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 2001; 111:692-698.

Dialysis

• Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002; 347:895-902
• A randomized clinical trial of continuous versus intermittent hemodilaysis for acute renal failure. Kidney Int 2001; 60:1154-1163
• Continuous versus intermittent renal replacement therapy: a meta analysis. Intensive Care Med 2002; 28:29-37
• Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002; 40:875-885
• Effects of different doses of continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial. Lancet 2000; 356:26-30
• Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346:305-310
• Renal replacement therapy in patients with acute renal failure. JAMA. 2008;299:793-805
• Intensity of renal support in critically ill patients with acute kidney injury. N Engl Med. 2008;359:7- 20
• Continuous venous-venous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368:379-85
• Renal Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl Med 2009;361:1627-1638
• Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: A double-blind randomized controlled trial. Crit Care Med 2009; 37:533-538