2Acute Kidney Injury in the ICU Susan L. Evans, MDAssociate Director Surgical ICU Assistant Professor of Trauma, Surgical Critical Care and Acute Care SurgeryThe F. H. Sammy Ross Trauma CenterCarolinas Medical CenterCharlotte, NCBased on the 2005 presentation by John A. Kellum, MDProfessor of Critical Care Medicine and MedicineVice Chair for ResearchDirector, Molecular Core, CRISMA LaboratoryDepartment of Critical Care MedicineUniversity of PittsburghSlide Sub-Title
3Learning Objectives Upon completion of this module you should: Be able to define acute kidney Injury and sub-classify it into its main forms.Understand the clinical consequences of acute kidney Injury.Be able to list common risk factors for acute kidney Injury.Be able to identify which agents are likely to be useful and which agents are likely to be ineffective or harmful in the prevention and treatment of acute kidney Injury.Understand the basic principals of Renal Replacement Therapy
4Outline Epidemiology and Definitions Etiology/Diagnosis Outcome PreventionTreatment
5Acute Kidney InjuryGlomerular filtration rate (GFR) = rate of transfer of protein free plasma filtrate (ultrafiltration) across the walls of the glomerular capillaries.In its most severe form AKI is referred to as acute renal failure.
7RIFLE Criteria for Acute Kidney Injury GFR Criteria*Urine Output CriteriaIncreased creatinine x 1.5 or GFR decrease >25%UO <.5ml/kg/hx 6 hrsHighSensitivityRiskIncreased creatinine x 2or GFR decrease >50%UO <.5ml/kg/hx 12 hrsInjuryIncrease creatinine x 3or GFR dec >75%or creatinine 4mg/dl(Acute rise of 0.5 mg/dl)UO <.3ml/kg/hx 24 hrs oranuria x 12 hrsOliguriaHighSpecificityFailureLossPersistent AKI** = complete loss of renal function > 4 weeksEnd Stage Renal DiseaseESRDBellomo R, et al. Crit Care Med. 2004;8:R204-R212
8RIFLE Comparisons Creatinine is expressed in mg/dL and (mcmol/L). Baseline0.5 (44)1.0 (88)1.5 (133)2.0 (177)2.5 (221)3.0 (265)Risk0.75 (66)2.3 (200)3.8 (332)---InjuryFailure4.0 (350)Creatinine is expressed in mg/dL and (mcmol/L).Bellomo R, et al. Crit Care Med. 2004;8:R204–R212.
9Epidemiology of AKIUchino et al. Crit Care Med. 2006;34:
10Epidemiology of AKIEvans et al. Crit Care Med. 2008;35:A156.
11Epidemiology of AKIThe prevalence of AKI among patients in the intensive care unit is not known.As many as 70% of critically ill patients experience some degree of AKI.Approximately 5% of patients in the ICU receive renal replacement therapy (e.g., hemofiltration, hemodialysis).Hospital mortality in this group is %.Cruz Clin J Am Soc Nephrol 2007;2:Bagshaw Nephrol. Dial Transplant 2008;23(4):Hoste CCM 2006;10(3):R73
12Risk Factors for AKI Hypovolemia Hypotension Sepsis Frequently as part of multiple organ failurePre-existing renal, hepatic, or cardiac InjuryDiabetes mellitusExposure to nephrotoxinsAminoglycosides, amphotericin, immunosuppressive agents, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, intravenous contrast mediaTwo or more risk factors are usually present!
14Types of Kidney Injury pre - renal renal osm u (mOsm/kg) > 500 < 400Na u (mmol/L or meq/L)< 20> 40BUN/s creatinine> 20< 10u/s creatinine> 40< 20u/s osmolality> 1.5> 1FeNa (%)*<1> 2________________________________________________________________* ( (u Na / s Na) / (u creat / s creat) ) X 100u for urinary, s for serum, Fe = fractional excretion
15Etiology of (intra-renal) AKI and Typical* Urinalysis Findings Acute Tubular Necrosis (ATN) [~ 90% of AKI cases]urine sediment benign, mild proteinuria/hematuriamuddy-brown castsAllergic Interstitial Nephritisurine eosinophilsvariable urine sediment, proteinuria and hematuriaRhabdomyolysisbrown urine, dip stick (+) blood but RBC (-) by microscopymyoglobin (+)Glomerulonephritismarked proteinuriaRBC casts (highly specific)* urinalysis is often non-diagnostic
16Cellular Injury and Repair in acute tubular necrosis (ATN) ProliferationAndRedifferentiationInjuryNormalTubularCellsPropagationInflammationRecovery(rapid)Injured CellsRecovery(slow)De-DifferentiatedCellsNecrotic *CellsApoptoticCellsExfoliationInto theUrine* very few necrotic cells are observed from patients with ATN
17Presence of AKI is Strongly Associated with Hospital Mortality AKI = 5.5x mortality!!
19Renal Replacement Therapy (RRT) The need for renal replacement therapy (rrt) is strongly associated with hospital mortalityMetnitz et al. Crit Care Med. 2002
20Goals of therapy are to prevent AKI or need for RRT Prevention of AKIGoals of therapy are to prevent AKI or need for RRTEffectiveHydrationPrevent hypotensionAvoid nephrotoxinsUnknownN-acetylcysteineSodium BicarbonateProphylactic HemofiltrationIneffective/harmfulDiureticsDopamineOther renal vasoactive drugsDA-1 agonistsPDE inhibitorsCa++ blockersAdenosine antagonistsNatriuretic peptidesKellum et al. Clinical Evidence. 2004;11:
21Prevention Maintain hydration (Isotonic IVF) Reducing risk from nephrotoxinsSingle vs. multiple daily doses of aminoglycosidesLipid complex vs. standard amphotericinIso-osmomotic vs. standard or “low” osmolality radiocontrast mediaMaintain perfusion pressureKellum JA, et al. Clinical Evidence ;11:
22Should We Use Loop Diuretics to Prevent ATN? Radiocontrast ATNFor prevention (no)Ischemic ATNVascular surgery (no)Other settings (?)Strength of EvidenceLevel ILevel I *No data in humans* diuretics were begun after surgeryKellum JA. Crit Care Med. 1997;1:53-59
23Dopamine Can Increase Urine Output by Various Mechanisms Direct renal vasodilatation (DA-1 receptors)Increased cardiac output (-receptors)Increased renal perfusion pressure (-receptors)Inhibition of Na-K ATPase at the tubular epithelial cell level resulting in natriuresisSeri I et al. Am J Physiol. 1988;255:F
24Dopamine is not Effective 328 patients in 23 ICUsDopamine 2ug/kg/minPlaceboPeak Creatinine245umol/L147umol/L# with ARF56# needing RRT3540ICU LOS13 days14 days# Deaths6966Bellomo et al. Lancet. 2000;356:
25Dopamine is not Effective 0.1110DeathAll StudiesExcludes Radio-contrastHeart Disease OnlyARFHemodialysisExcludes OutliersKellum & Decker, Crit Care Med. 2001;29:HarmBenefit
26Risks of “Low-dose” Dopamine Bowel mucosal ischemiaDigital necrosisPro-arrhythmicHypo-pituitarismImmune suppression
28N-acetylcystein (NAC) 83 patients with CRI (mean Creat. 2.4)CT scans with low-osmolal contrast agentNAC600mg PO BIDPlacebo% with Creatinine rise2%21%Mean CreatinineDecreased!!IncreasedTepel M et al. N Engl J Med. 2000;343:
30NAC reduces the risk of AKI (increased creatinine) by 50%. Birck et al. Lancet. 2003;362:
31Does NAC prevent AKI or just decrease Serum creatinine? Hoffman et al. J Am Soc Nephrol. 2004;15:Healthy volunteers given NAC showed a fall in serum creatinine without any change in cystatin CNAC increases creatinine kinase activityIncreases tubular secretion of creatinine?Decreased muscle production of creatinine?
32Bicarbonate as Prophylaxis for RCN? Merten et al. JAMA. 2004;291(19):
33Hemofiltration for RCN? ProMarenzi et al. N Engl J Med. 2003;349(2)n = 114, hydration alone vs. hydration plus hemofiltration> 25% rise in Scrt: 5% vs. 50% P < 0.001Need for acute RRT post-procedure: 3% vs. 25% P < 0.001In-hospital mortality: 2% vs. 14% P = 0.02Results not consistent with hemodialysis studiesConHsieh et al. Int J Cardiol. 2005;101(3):N=40, hemodialysis after PCINo difference in 3 & 6 month creatinine riseNo difference in # patients progressing to ESRD
34Aspelin et al. N Engl J Med. 2003;348:491-99. Radio-contrastSo-called “low osmolality” radio-contrastIohexol: mOSMIodixanol: mOSM (iso-osmolar)Incidence of AKI was 3% (iodixanol) compared with 26% (iohexol) (p = 0.002).Aspelin et al. N Engl J Med. 2003;348:
35Treatment of AKI Effective Hemodialysis Biocompatible membranes More dialysisUnknownCRRT vs. IHDEarlier dialysisIneffective/harmfulDiuretics *Dopamine* Diuretics are never a treatment for oliguria but are sometimes required for management of volume overload.Kellum J et al. Clin Evid.2004;11:
36Goals of Renal Replacement Therapy (RRT) Substitute for renal functionControl VolumeCorrect acid-base abnormalitiesImprove Clearance of toxins (e.g. uremia)Reduce complicationsHasten/Permit RecoveryPrevent death
37Techniques of RRT Fluid Removal water efflux through semi-permeable membraneSolute RemovalConvection – ultrafiltrateDiffusion - dialysis
38HemofiltrationForni et al. NEJM 336(18): , 1997.
45More Intensive RRT Is Not Associated With Increased Survival Favors higher doseFavors standard dose
46What is Standard Dose RRT? In the ATN studyControl patients received thrice weekly IHD with a delivered Kt/Vurea of 1.3.Control patients received 95% of the prescribed dose of CRRTIn practiceIHD patients in the ICU receive a delivered Kt/Vurea of 1.1 or lessCRRT patients in the ICU receive ~80% of the prescribed dose.
47Continuous vs. Intermittent RRT Bagshaw et al. Crit Care Med. 2008;36(2):
48Treatment: Diuretics Diuretics: Effects on outcome (small RCTs) 66 patients randomized to receive furosemide ( mg/kg)No significant differences in recovery or need for HD.~ Kleinknecht et al. Nephron. 1976;17:51-58.58 patients randomized to single dose (1g) vs. continued dosing of furosemide (3g/day).Oliguria was reversed in 2/30 vs. 24/28.No differences in mortality, renal recovery, or need for RRT.Permanent deafness in one patient.~ Brown et al. Clin Nephrol. 1981;15:90-6.
49Treatment: DiureticsDiuretics: Effects on outcome (large observational studies)4-center, retrospective analysis of patients referred for nephrology consults ( ; n = 552)With adjustments for co-variates and propensity score, diuretic use was associated with:Significantly increased risk of death or non-recovery of renal function (odds ratio 1.77; 95% CI )~ Mehta et al. JAMA. 2002;288:52-center, prospective inception cohort of ICU patients (n = 1743)No differences in mortality, or renal recovery, even after adjustment for the same co-variates and propensity scoreOdds ratio 1.22 (p = 0.15)However, no benefit associated with diuretics either!~ Uchino et al. Crit Care Med. 2004;32:1669 –77.
50Conclusions/Recommendations AKI is a common ICU syndrome.As many as 70% of ICU patients develop AKI.Approximately 5% of ICU patients receive RRT.AKI in the critically ill carries a very high mortality, and current treatment is disappointing.Inflammation likely plays a significant role in the development of AKI.
51Conclusions/Recommendations For Prevention of AKI in the ICU:Avoid nephrotoxins, hypotension, and dehydration.Grades B - D for various optionsDon’t use diuretics, dopamine, or other vasoactive drugs.Grade A +Fluids for high-risk patients undergoing radio-contrast studies.Grade A -Consider N-acetylcysteine, or bicarbonate-based fluids for prevention of radio-contrast induced AKI.Grade A-, and C
52Conclusions/Recommendations For Treatment of AKI in the ICUAvoid further injury from nephrotoxins, hypotension, and dehydration.Grades B - D for various optionsDon’t use dopamine or other vasoactive drugs.Grade A +Avoid diuretics.Grade DAvoid under-dialyzing patients: use at least 25 ml/kg/hr for CRRT and ensure delivery of >1.2 Kt/V for IHD.Grade BUse CRRT or modified IHD for hypotensive patients
53AKI – Special Circumstances: Hepatorenal Syndrome HRSarterial hypotension (very low SVRI)Splanchnic arterial vasodilationvery high renin, NE and ADHvasoconstriction inKidneysBrainmuscle and skin.Arroyo V, Jimenez W. J Hepatol. 2000;32:
54AKI - Special Circumstances: Hepatorenal Syndrome profound renal vasoconstrictionlow RBF and low GFRmarked Na and water retention“pre-renal” urine chemistriesbland pathology and urine sedimentType I (rapid renal failure) and Type II (diuretic-resistant ascites)
55AKI – Special Circumstances: Hepatorenal Syndrome Managementlow Na diet and diureticsparacentesisshuntaquaretic agents (? effectiveness)AVP - V2 receptor antagonists (ornipressin, terlipressin, vasopressin)selective kappa-opioid agonists (midodrine)vasopressorsliver transplant
56Case StudiesThe following are two case studies that can be used for review following this presentation if you prefer you can answer the short review.Case StudiesQuestion ReviewSkip to End
57Case 1A.B. is a 53-year-old male with a past medical history of “poorly controlled” hypertension (taking an ACE inhibitor and a Ca++ channel blocker). He weighs 80 kg and presents with a two-day history of fever and cough, and his chest radiograph shows an RLL infiltrate. His BP on admission is 88/54, and he is given IV fluids (saline) and antibiotics (ampicillin sulbactam).His admission labs show a serum creatinine of 1.5 mg/dL (133 mcmol/L) and his BUN is 42. Six months ago, his serum creatinine was 1.2. Over the next six hours his urine output is ml/hr. He is given 2L of 0.9% saline and 500 ml of 5% hetastarch. His BP improves to 110/60 and his pulse decreases from 128 to 109. He is admitted to the ICU and you are called to see him.
58Case 1The patient’s UO has been < 0.5ml/kg/hr for more than 6 hours. This indicates AKI (“risk” category for urine output by RIFLE criteria), but it may represent inadequate circulating blood volume or (much less likely) an obstructive uropathy.You place a Foley catheter and there is only 20 ml of urine. While this does not rule out obstructive uropathy, it makes it very unlikely. Additional testing (e.g., renal ultrasound) might be indicated if there is still a diagnostic question but pre-renal or intra-renal disease (or both) is far more likely.You send the urine for electrolytes and this reveals a uNa of 10 mmol/L, uCr of 50 mg/dL, and you calculate a fractional excretion (FE) of Na of 0.5%. These results are consistent with pre-renal disease but urine studies are not themselves diagnostic.Examination of the urine reveals no WBCs or casts. These findings make interstitial or glomerulular nephritis very unlikely. The absence of muddy brown casts do not exclude the diagnosis of ATN.
59Case 1You also send a repeat BUN and serum creatinine which are 40 and 1.8 mg/dL. The ratio of BUN/creatinine > 20 is consistent with (but not diagnostic of) pre-renal disease.You decide to give additional fluid (1L 0.9% saline) over the next hour, but the urine output remains low and the BP decreases to 90/55.You now need to establish the etiology of the persistent hypotension. Possibilities include: hypovolemic (even though the patient has received 3.5 L of fluid), septic (distributive), cardiogenic, and obstructive. Options for determining the etiology range from noninvasive (e.g., echocardiography) to invasive (e.g., pulmonary arterial catheterization). No technique is completely failsafe but if cardiac output is increased, the diagnosis must be distributive.
60Case 1You determine that the cardiac output is increased and you also measure an arterial lactate (2.7) and mixed venous oxygen saturation (72%). You also determine that the central venous pressure is 14 mm Hg. These findings make hypovolemia unlikely.At this point, even though the mean arterial pressure is 62 mm Hg, you are concerned that the patient’s BP is too low and that he may not have adequate perfusion pressure for his organs (including the kidneys). This is a significant concern, especially in a chronic hypertensive. Atherosclerotic disease is likely and a decreased blood pressure may result in insufficient flow. The slight elevation in the arterial lactate also suggests this diagnosis.This scenario is further supported by this combination of urine chemistries (pre-renal) and systemic hemodynamics (hyperdynamic). You decide to increase the mean arterial pressure to 70 mm Hg using norepinephrine.
61Case 1The patient is given activated protein C and his adrenal axis is evaluated using a short ACTH stimulation test (his response is normal).Over the course of the next 12 hours, you maintain his mean arterial pressure > 70 mm Hg with 0.02 – 0.04 mcg/kg/min of norepinephrine. His urine output gradually increases, and his central venous pressure falls to 8 mm Hg. You administer additional fluids (lactated Ringers this time to avoid giving additional saline, which may cause acidosis) and continue supportive care.The next day, the patient’s Crt increases to 2.2 (BUN falls to 32). Repeat urine electrolytes show an Na of 35 and the FeNa is 1.8. Muddy brown casts appear in the urine. The next day the serum creatinine decreases to 2.0 and his blood pressure improves. You discontinue the norepinephrine and by the next day he is requiring antihypertensive therapy. He makes a complete recovery.
62Case 2C.D. is a 64-year-old female with a history of hypertension, 3-vessle coronary artery disease, and poor left ventricular function (ejection fraction: 20%). She weighs 80 kg and undergoes coronary arterial revascularization. The surgery is uneventful but she requires fluids and vasoactive medications (epinephrine and dobutamine) to come off of cardiopulmonary bypass.Her initial postoperative care is unremarkable except that she a borderline urine output ml/hr and her blood pressure is very labile.Her admission labs (drawn 24 hours before surgery) showed a serum creatinine of 1.5 mg/dL (133 mcmol/L). Over the first 24 hours after surgery, she makes 200 mL of urine. Her serum creatinine increases to 2.0 mg/dL (177 mcmol/L). She is maintained on vasoactive medications but is weaned from mechanical ventilation and extubated. Her cardiac function remains poor but cardiac index is 2.2 on epinephrine and dobutamine. She has not received any nephrotoxic agents. Urine chemistries and microscopy are consistent with a diagnosis of ATN.
63Case 2The following day her serum creatinine increases to 3.0 mg/dL (266 mcmol/L) and her BUN increases to 65 mg/dL. She has made 300 mL of urine in the last 24 hours, and her total fluid intake has exceeded all output by 11L since the surgery. Her weight is now 90 kg and she has edema on physical exam.Furosemide is administered but she does not respond. The next day the creatinine is 4.0 mg/dl and she is started on continuous veno-venous hemofiltration at an ultrafiltration rate of 25 ml/kg/hr based on her admission weight. Initially 100 mL of fluid are removed per hour and this is increased to 150 mL/h, but her blood pressure becomes unstable, and the removal rate is returned to 100.Over the course of the next five days 8L of fluid are removed, and her heart function improves such that all vasoactive medications are discontinued. She is converted to intermittent dialysis and is discharged form the ICU.A week later renal function gradually recovers, and one month later her serum creatinine has returned to baseline.
64Case StudiesThe following are case studies / review questionsthat can be used for this presentation.Case StudiesQuestion ReviewSkip to End
66ReferencesLameire N. The pathophysiology of acute renal failure. Crit Care Clin. 2005;21(2):Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med. 2002;30:2051–2058.Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212.Kellum JA, Leblanc M, Venkataraman R. Acute renal failure. Clin Evid. 2004;(11):
67ReferencesUchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med. 2004;32:Uchino S, Bellamo R, Goldsmith D, et al. An Assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med. 2006;34:O’Reilly P, Tolwani A. Renal Replacement Therapy III: IHD, CRRT, SLED. Crit. Care Clin. 2005;21:Cruz D, Bellamo R, Kellum J, et al. The future of extracorporeal support. Crit. Care Med. 2008;36(4 Suppl.):SPalevsky PM, Zhang JH, O'Connor TZ, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med Jul 3;359:7-20.