5 Acute Kidney Injury2nd Century AD: Galen surmises urine formed from kidneysAD: Byzantine physicians describe oliguria as symptom of AKI, as well as detailed urine findings in AKI; also, the transition to polyuric phase as late finding in AKI is recognizedAD: likely precursors to ATN described:Aetius: “..the reasons for the destruction of the kidney are the toxic influence of remedies and poisons, and external pressure”Nonus: “…hematuria results from poisonous drugs and serpent venom…” (Eftychiadis AC, Am J Nephrol 1997)
6 Acute Kidney Injury1827: English physician Richard Bright describes microscopic hematuria, oliguria, and edema in acute and chronic renal inflammatory states, gives eponymic definition for .acute/chronic GN
7 Acute Kidney InjuryWWI & WWII: Post-traumatic oliguria seen in combatants, crush syndrome evolves as an AKI dx ’s: AKI found retrospectively in ~20% of post-op open heart/aortic surgery
8 Acute Kidney InjuryWW I: observations of thirst and oliguria in combat victims led to relationship between blunt trauma and AKI (Better, OS 1997)WWII: Spanish surgeon Joseph Trueta observes same in Spanish Civil War, WWII combatantsInduces renal cortical vasospasm experimentally (Trueta, et al., 1947)WWII: Bywaters and Beall link myoglobin to AKI in crush syndrome during London Blitz (1940)
10 UK Renal Association 5th Edition, 2011 Acute kidney injury (AKI) has now replaced the term acute renal failure and an universal definition and staging system has been proposed to allow earlier detection and management of AKI. The new terminology enables healthcare professionals to consider the disease as a spectrum of injury. This spectrum extends from less severe forms of injury to more advanced injury when acute kidney failure may require renal replacement therapy (RRT)
11 Clinically AKI is characterised by a rapid reduction in kidney function resulting in a failure to maintain fluid, electrolyte and acid-base homoeostasis.
12 Definition of AKIThere are more than 35 definitions of AKI (formerly acute renal failure) in literature!Mehta R, Chertow G: Acute renal failure definitions and classification: Time for change? Journal of American Society of Nephrology 2003; 14:
13 Acute Kidney Injury 2001 : Acute Dialysis Quality Initiative (ADQI) Risk: 1.5x inc in SCr, GFR dec 25%, UOP<0.5 ml/kg/h x 6hInjury: 2x inc SCr, GFR dec 50%, UOP<0.5 ml/kg/h x 12hFailure: 3x inc SCr, GFR dec 75%, UOP<0.5/kg/h x 24hAlso anuria x 12 hrLoss: complete loss (inc need for RRT) > 4 wksESRD: complete loss (inc need for RRT) > 3 months2007: Acute Kidney Injury Network (AKIN)Modified RIFLE to include ΔSCr o.3 mg/dL from baseline, within 48hr, based on 80% mortality risk
14 Definition of AKI As per the Acute Kidney Injury Network: An abrupt (within 48hrs) reduction in kidney function defined as an increase in serum creatinine level of 0.3mg/dl OR An increase in serum creatinine ≥ 50%Urine output is < 0.5ml/kg/hr for >6 consecutive hours There are no consensus criteria for defining AKI, but it is worth KNOWING the above criteria to identify which of your patients has an AKI.
15 Definition of AKIRIFLE classification AKIN classification
16 RIFLE classificationBellomo R, Ronco C, Kellum J, 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 Initiative (ADQI) Group. Critical Care 2004; 8:R204-R212.
17 AKIN classificationModification of the RIFLE classification by Acute Kidney Injury Network (AKIN).Recognizes that small changes in serum creatinine (>0.3 mg/dl) adversely impact clinical outcome.Uses serum creatinine, urinary output and time.Coca S, Peixoto A, Garg A, et al.: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. American Journal of Kidney Diseases 2007; 50:
18 AKIN classification AKIN stage Serum Creatinine Criteria Urinary Output CriteriaTime1 Cr ≥ 0.3 mg/dL or ≥ % from baseline< 0.5 mL/kg/hr> 6 hrs2 Cr to > % from baseline> 12 hrs3Cr to > 300% from baseline or Cr ≥ 4mg/dL with an acute rise of at least 0.5 mg/dLor anuriaX 24 hrsX 12 hrs*Patients needing RRT are classified stage 3 despite the stage they were before starting RRTMehta R, Kellum J, Shah S, et al.: Acute kidney Injury Network: Report of an Initiative to improve outcomes inAcute Kidney Injury. Critical Care 2007; 11: R31.
20 Epidemiology AKI occurs in ≈ 7% of hospitalized patients. 36 – 67% of critically ill patients (depending on the definition).5-6% of ICU patients with AKI require RRT.Nash K, Hafeez A, Hou S: Hospital-acquired renal insufficiency. American Journal of Kidney Diseases 2002; 39:Hoste E, Clermont G, Kersten A, et al.: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Critical Care 2006; 10:R73.Osterman M, Chang R: Acute Kidney Injury in the Intensive Care Unit according to RIFLE. Critical Care Medicine 2007; 35:
21 Data from the Intensive Care National Audit Research Centre (ICNARC) suggests that AKI accounts for nearly 10 percent of all .ICU bed days
24 Common causes of AKI in ICU SepsisMajor surgeryLow cardiac outputHypovolemiaMedications (20%)Uchino S, Kellum J, Bellomo R, et al.: Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005; 294:
25 Nephrotoxins NSAIDs Aminoglycosides Amphotericin Penicillins Acyclovir CytotoxicsRadiocontrast dyeDennen P, Douglas I, Anderson R,: Acute Kidney Injury in the Intensive Care Unit: An update and primer for the Intensivist. Critical Care Medicine 2010; 38:
32 Mortality according to RIFLE Mortality increases proportionately with increasing severity of AKI (using RIFLE).AKI requiring RRT is an independent risk factor for in-hospital mortality.Mortality in pts with AKI requiring RRT 50-70%.Even small changes in serum creatinine are associated with increased mortality.Hoste E, Clermont G, Kersten A, et al.: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Critical Care 2006; 10:R73.Chertow G, Levy E, Hammermeister K, et al.: Independent association between acute renal failure and mortality following cardiac surgery. American Journal of Medicine 1998; 104:Uchino S, Kellum J, Bellomo R, et al.: Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005; 294:Coca S, Peixoto A, Garg A, et al.: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. American Journal of Kidney Diseases 2007; 50:
33 Acute kidney injury has a poor prognosis with the mortality ranging from 10%-80% Patients who present with uncomplicated AKI, have a mortality rate of up to 10%. In contrast, patients presenting with AKI and multiorgan failure have been reported to have mortality rates of over 50%. If renal replacement therapy is required the mortality rate rises further to as high as 80%
34 Non-Oliguric vs. Oliguric vs. Anuric Oliguric renal failure.Functionally, urine output less than that required to maintain solute balance (can’t excrete all solute taken in).Defined as urine output < 400ml/24hr.Anuric renal failure.Defined as urine output < 100ml/24hr.Less common – suggests complete obstruction, major vascular catastrophy, or more commonly severe ATN.
35 Non-Oliguric vs. Oliguric vs. Anuric Classifying by urine output may help establish a cause.Oliguria – more common with obstruction, prerenal azotemiaNonoliguric – intrarenal causes – nephrotoxic ATN, acute GN, AIN.More importantly, assists in prognosis.Significantly higher mortality with oliguric renal failure.80% vs. 25% mortality in Oliguric vs. non-oliguric ARFNonoliguric renal failure may also suggest greater liklihood of recovery of function.
37 BIOMARKER RESEARCH IN DEFINITIONS AND GOALS a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic interventiona biomarker is “any substance, structure or process that can be measured in the body or its products and influence or predict the incidence or outcome of disease”
38 What is GFR? How is it Calculated? The Glomerular Filtration Rate (GFR) is the volume of fluid filtered from glomerular capillaries into the Bowman’s capsule per unit timeThere are a number of different formulas to estimate the GFR. The Cockcroft-Gault formula is given above. It is perhaps more important to know what are the variables in this formula than the actual formula.By looking at this equation, one can appreciate how serum creatinine, age, weight, gender, and race can influence the GFR and thus how one interprets renal function.
39 Suspect AKI in a sick patient with a modest rise in their creatinine Large acute drop in GFR with oligoanuriaGFR falls rapidly to near zero- only shown by oliguriaSlow rise in Cr untileventually a new steady state is reachedOnly a small early rise in Cr: not easy to recognise as AKI
40 Limitations to Serum Creatinine as a Reflection of GFR The serum creatinine concentration does not increase above the normal range until the GFR declines below 50 mL/min, and large declines in GFR may occur above this level without a concomitant increase in the serum .creatinine value
41 Limitations to Serum Creatinine as a Reflection of GFR In a cachectic patient with very low muscle mass, creatinine generation may be so feeble that the serum creatinine level remains “normal” (<0.9 mg/dL) even in the presence of a GFR less than 25 mL/min.
42 Serum creatinine is a useful marker of stable renal function, but it is unreliable when GFR is .rapidly changing
43 Because it may take up to 48 hours for GFR to return to baseline, in the postoperative period the serum creatinine value may still increase for a few days while GFR is actually recovering.
44 Urine flow rate is an unreliable marker of acute renal failure and may vary from anuric (zero flow), to oliguric (urinary flow rate <15 mL/hr), to nonoliguric (15-80 mL/hr), to polyuric (>80 mL/hr).
45 Indices of Tubular Injury β2-MicroglobulinUrinary N-Acetyl-β-d-glucosaminidaseNeutrophil gelatinase-associated lipocalin (NGAL)
48 Risk Factors for AKI Age > 75 yrs Chronic kidney disease (CKD, eGFR < 60 mls/min/1.73m2)Cardiac failure Diabetes mellitusHypovolemiaNephrotoxic medicationAtherosclerotic peripheral vascular diseaseLiver diseaseSepsisPatients may present to hospital with an AKI or it may arise while in hospital. It is thus important to understand which of your patients are at risk. Knowing these risk factors can often be helpful when determining the cause and tailoring the treatment to the patient.
50 Radiocontrast-Induced Acute Renal Failure Induces renal vasoconstriction and direct cytotoxicity via oxygen free radical formationRisk factors:Renal insufficiency - DiabetesAdvanced age - > 125 ml contrastHypotensionUsually non-oliguric ARF; irreversible ARF rare
51 Prevention of Radiocontrast Nephropathy InterventionStrength of EvidenceClarity of Risk-BenefitGrade of RecommendationVolume expansion with normal salineGoodClearA: Intervention is always indicatedand acceptableVolume expansion with sodium bicarbonateFairB: Intervention may be effective and is acceptableIso-osmolar contrastTheophyllineUnclearC: May be considered; minimal orno relative impactN-acetylcysteineHemofiltrationI: Insufficient evidence to recommend for or againstFenoldopamD: Not usefulHemodialysis
52 Prevention of Contrast-Induced Nephropathy Avoid use of intravenous contrast in high risk patients if at all possible.Use pre-procedure volume expansion using isotonic saline (?bicarbonate).NACAvoid concomitant use of nephrotoxic medications if possible.Use low volume low- or iso-osmolar contrastDennen P, Douglas I, Anderson R,: Acute Kidney Injury in the Intensive Care Unit: An update and primer for the Intensivist. Critical Care Medicine 2010; 38:
53 Prevention of AKI in ICU Recognition of underlying risk factorsDiabetesCKDAgeHTNCardiac/liver dysfunctionMaintenance of renal perfusionAvoidance of hyperglycemiaAvoidance of nephrotoxinsDennen P, Douglas I, Anderson R,: Acute Kidney Injury in the Intensive Care Unit: An update and primer for the Intensivist. Critical Care Medicine 2010; 38:
54 Prevention of AKI in hepatic dysfunction Intravenous albumin significantly reduces the incidence of AKI and mortality in patients with cirrhosis and SBP.Albumin decreases the incidence of AKI after large volume paracentesis.Albumin and terlipressin decrease mortality in HRS.Sort P, Navasa M, Arroyo V, et al.: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. New England Journal of Medicine 1999; 341:Gines P, Tito L, Arroyo V, et al.: Randomised comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988; 94:Gluud L, Kjaer M, Christensen E: Terlipressin for hepatorenal syndrome. Cochrane Database Systematic Reviews 2006; CD
55 KDIGO Clinical Practice Guideline for Acute Kidney Injury 4.4.3: We suggest using oral NAC, together with i.v. isotonic crystalloids, in patients at increased risk of CI-AKI.4.4.4: We suggest not using theophylline to prevent CI-AKI.4.4.5: We recommend not using fenoldopam to prevent CI-AKI.4.5.1: We suggest not using prophylactic intermittent hemodialysis (IHD) or hemofiltration (HF) for contrast-mediaremoval in patients at increased risk for CI-AKI.VOL 2 | SUPPLEMENT 1 | MARCH 2012
57 Baseline Set of Laboratories to Consider Biochemistryurea and electrolytesHematologyCBCUrinalysis (+/- microscopy, eosinophils)Urinary Biochemistryelectrolytes, urea, osmolalityMicrobiologyurine/blood culture when/if infection suspectedImagingrenal ultrasoundCXR, abdominal x-rayECGThe above list of labs can be useful in narrowing down the differential diagnosis, the severity of the injury and in the initiation of treatment. As the problem is with kidney function, you can appreciate how many of these tests are focused on analysis of the urine.Knowing patterns of urine characteristics associated with certain causes can narrow down the differential diagnosis (slide to follow with typical patterns).Eosinophiluria is not a very specific test for interstitial nephritis and has a very poor positive predictive value. However, the value of eosinophiluria in interstitial nephritis is in ruling out the disease, the negative predictive value for patients with AKI is > 90%. Microscopy can be useful when poisoning/crystalluria is suspectedA CXR can help one assess volume status. An ultrasound can very quickly indicate if obstruction is the cause of the injuryAn ECG has value in that one might be able to determine if a particular electrolyte disturbance is influencing the conduction system of the heart.
58 Acute Kidney Injury LABORATORY DATA Creatinine; also BUN/Cr ratio CBC: anemia, thrombocytopeniaHCO3ˉ: anion gap, lactic acid, ketonesKCPK/LDH/Uric acid/liver panelSerologies:ComplementESR, RF, ANA, ANCA, AntiGBMElectrophoresisToxicology studies
59 Evaluation of Renal Failure Is the renal failure acute or chronic?laboratory values do not discriminate between acute vs. chronicoliguria supports a diagnosis of acute renal failureClues to chronic diseasePre-existing illness – DM, HTN, age, vascular disease.Uremic symptoms – fatigue, nausea, anorexia, pruritis, altered taste sensation, hiccups.Small, echogenic kidneys by ultrasound.
60 Diagnostic Evaluation of Renal Failure 100-80-60-40-20-0-15%25%Cumulative% CorrectDiagnosis60%Hx, PE, LabsTherapeuticTrialsRenalBiopsy
61 Renal Biopsy-When?Exclude pre- and post-renal failure, and clinical findings are not typical for ATNExtra-renal manifestations that suggest a systemic disorderHeavy proteinuriaRBC casts
62 AKI Physical Exam. Assessing volume status. Is the patient intravascularly volume depleted?Neck veins – JVPPeripheral edema or lack of.Orthostatic vitals.Not always straightforward.Pt. may be edematous (low albumin) or have significant right sided heart disease.
63 Creatinine in anephric state typically only rises 1mg/dl/day. BUN/Creatinine ratio.> 20:1 – suggest prerenal or obstruction.Can be elevated by anything leading to increased urea production/absorption.GI bleedTPNSteroidsDrugs – Tigecycline.Creatinine in anephric state typically only rises 1mg/dl/day.If greater – should be concerned for rhabdomyolysis
64 AKI: Diagnostic studies-urine Urinalysis for sediment, castsResponse to volume repletion with return to baseline SCr hr c/w prerenal eventUrine Na; FENaFENa (%) = UNa x SCr x 100SNa x UCrFENa < 1%: PrerenalFENa 1-2%: MixedFENa > 2%: ATNHansel’s stain
65 Classic Lab Findings in AKI CausesUNaFeNa*FeUreaBUN/CrPrerenal<10<1%<35%>20Renal>2%>50%<15Postrenal>40>4%>15Increased levels of BUN and creatinine are the hallmarks of renal failure, however the rate of rise is dependent on the degree of renal insult as well as on protein intake with respect to BUN.The ratio of BUN to creatinine is an important finding, because the ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contraction); this suggests prerenal acute kidney injury (AKI).*Unlike the FeNa, the FeUrea is not affectect by diuretics and metabolic alkalosis. It is thus the preferred calculations when a patient is on diuretics or has a metabolic alkalosis
66 Urine Patterns in Renal Disease Urinary PatternRenal DiseaseHematuria with red cell casts, heavy proteinuria, or lipiduriaGlomerular disease or vasculitisGranular and epithelial casts with free epithelial cellsAcute Tubular NecrosisPyuria with white cell and granular casts and no/mild proteinuriaTubular or interstitial disease or obstructionHematuria and pyuria with no or variable casts(excluding red cell casts)Acute interstitial nephritis, glomerular disease, vasculitis, obstruction, renal infarctionPyuria aloneUsually infections, sterile pyuria suggests TBThis slide demonstrates the utility of microscopy. Urinary sediment analysis can be a powerful non-invasive diagnostic test.
68 Obtain a thorough history and physical; review the chart in detail 5 Key Steps in Evaluating Acute Renal FailureObtain a thorough history and physical; review the chart in detailDo everything you can to accurately assess volume statusAlways order a renal ultrasoundLook at the urineReview urinary indices
69 ManagementImportantly, manangement of AKI is varied and depends on the cause. Given no effective pharmaceutical options, management of AKI is primarily supportive.Prerenal azotemia is usually responsive to isotonic fluid repletion Managament of ATN includes discontinuation of nephrotoxic agents, optimization of hemodynamics, continued monitoring of renal function (acid/base status, electrolyte abnormalities).Postrenal causes warrant removal of the obstruction.Intravenous hydration and volume status assessment is a reasonable first step in managing prerenal causes.Postrenal causes can be ruled out with imaging and Foley catheter placement.
70 Management of AKI in ICU Maintain renal perfusionCorrect metabolic derangementsProvide adequate nutrition? Role of diuretics
71 Maintaining renal perfusion Human kidney has a compromised ability to autoregulate in AKI.Maintaining haemodynamic stability and avoiding volume depletion are a priority in AKI.Kelleher S, Robinette J, Conger J: Sympathetic nervous system in the loss of autoregulation in acute renal failure. American Journal of Physiology 1984; 246: F
72 Maintaining renal perfusion Current studies do not include patients with established AKI.The individual BP target depends on age, co-morbidities (HTN) and the current acute illness.A generally accepted target remains MAP ≥ 65.Bourgoin A, Leone M, Delmas A, et al.: Increasing mean arterial pressure in patients with septic shock: Effects on oxygen variables and renal function. Critical Care Medicine 2005; 33:
73 Volume resuscitation – which fluid? SAFE study – no statistical difference between volume resuscitation with saline or albumin in survival rates or need for RRT.Post – hoc analysis – albumin was associated with increased mortality in traumatic brain injury subgroup and improved survival in septic shock patients.Finfer S, Bellomo R, Boyce N, et al.: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. New England Journal of Medicine 2004; 350:
74 Which inotrope/vasopressor? There is no evidence that from a renal protection standpoint, there is a vasopressor agent of choice to improve kidney outcome.Dennen P, Douglas I, Anderson R,: Acute Kidney Injury in the Intensive Care Unit: An update and primer for the Intensivist. Critical Care Medicine 2010; 38:
75 KDIGO Clinical Practice Guideline for Acute Kidney Injury 3.5.1: We recommend not using low-dose dopamine to prevent or treat AKI.3.5.2: We suggest not using fenoldopam to prevent or treat AKI.VOL 2 | SUPPLEMENT 1 | MARCH 2012
76 Renal vasodilators?“Renal” dose dopamine doesn’t reduce the incidence of AKI, the need for RRT or improve outcomes in AKI.It may worsen renal perfusion in critically ill adults with AKI.Side effects of dopamine include increased myocardial oxygen demand, increased incidence of atrial fibrillation and negative immuno-modulating effects.Lauschke A, Teichgraber U, Frei U, et al.: “Low-dose” dopamine worsens renal perfusion in patients with acute renal failure. Kidney 2006; 69:Argalious M, Motta P, Khandwala F, et al.: “Renal dose” dopamine is associated with the risk of new onset atrial fibrillation after cardiac surgery. Critical Care Medicine 2005; 33:
77 KDIGO Clinical Practice Guideline for Acute Kidney Injury 3.4.1: We recommend not using diuretics to preventAKI.3.4.2: We suggest not using diuretics to treat AKI, exceptin the management of volume overload VOL 2 | SUPPLEMENT 1 | MARCH 2012.
78 Management Cont. Things to do for patients with AKI Renally dose medicationsAvoid nephrotoxinsMonitor I/OsSerial assessment of serum creatinineRenal Replacement Therapy (i.e dialysis) is the central component of care for patients with severe AKI The generally accepted indications for renal replacement therapy in the setting of AKI include:AcidosisElectrolyte disturbanceIngestion/IntoxicationVolume OverloadOvert UremiaIf the insult to the kidney is severe, it is best to consult nephrology sooner rather than later as dialysis may be indicated.AEIUO is a mnemonic often used to remember indications for dialysis.
79 Acute Kidney Injury INDICATIONS FOR RENAL REPLACEMENT THERAPY Consensus generally includes:Refractory volume overloadSevere metabolic acidosis; HCO3 may be variable, but declining level of factor; also falling pH toHyperkalemia, with levels > 6.5, or documented rapid rise refractory to medical therapyMajor uremic target organ manifestations i.e. pericarditis, progressive neuropathy, seizurePlatelet dysfunction, bleeding diasthesisAKI in setting of dialyzable drug/toxin
80 Guideline 8.6 – AKI : Vascular access for RRT We recommend that subclavian access should be avoided in patients at risk of progressing to CKD stage 4 or 5 due to the risks of compromising future, permanent vascular access.
81 Guideline 8.7 – AKI : Vascular access for RRT We suggest that non-dominant arm upper limb vasculature should be preserved as a contingency for future permanent access.
82 When to call nephrology Any known dialysis patient admittedAny known renal transplant patient admittedAny case of AKI where cause not clearWorsening AKIEmergency dialysis indicationsSuspect glomerulonephritis