Acute Kidney Injury Is there a Best Practice?

Transcription

1 Acute Kidney Injury Is there a Best Practice? M I T C H E L L R O S N E R, M D C h a i r m a n, D e p a r t m e n t o f M e d i c i n e U n i v e r s i t y o f V i r g i n i a H e a l t h S y s t e m

2 Disclosures Consultant: Johnson and Johnson, Otsuka America, Novartis

3 Overview Epidemiology Diagnosis: Definitions and role of biomarkers Prevention strategies Therapeutic issues 3

4 AKI: Increased Frequency 4 Medicare S.M. Bagshaw, Div Critical Care U. Edmonton A. Ishani, ASN 2009 and USRDS Annual Report, 2009

5 Epidemiology: A large multicenter observational study of 29,260 patients: -5.7 % incidence of severe ARF requiring RRT -Overall hospital mortality of ARF in setting of sepsis was 60.3% Most common contributing factors: sepsis and major surgery. Importantly, druginduced ARF in 19% Uchino, S. et al. JAMA 2005;294:

6 % Patients with ARF Epidemiology: Patients with AKI are becoming more complex 40 Low Co-morbidity P<0.001 High Co-morbidity P< P< D-CI = 0 D-CI Mechanical Ventilation D-CI: Deyo-Charlson Index (0-5+) S. S. Waikar et al JASN 17: , April 2006

7 AKI (%) Mortality (OR) Defining AKI: Problematic in the Past 50% 20 40% 16 30% 12 20% 8 10% 4 0% 0.3 mg/dl 0.5 mg/dl 0.5 mg/dl or 1.0 mg/dl* 1.0 mg/dl 2.0 mg/dl 25% 50% 100% 50% AND creatinine 2.0 mg/dl Depending upon the definition, AKI is associated with variable mortality 0

8 Definition of AKI: What is baseline Cr? New definitions of AKI (RIFLE, AKIN) use change in serum creatinine (SCr) from baseline to ascertain disease AKIN RIFLE Newer KDIGO criteria combine these definitions 8 R.Mehta Crit Care 11 : R31, 2007 R. Bellomo Crit Care. 2004; 8(4): R204 R212.

9 Sepsis and Mortality: AKIN and RIFLE Hoste et al CCM 2008

10 AKI: Long-term Outcomes 10 Cerda et al, CJASN 3: 881-6, 2008

11 Risk of Progressive CKD (Stage 4 or Higher) after AKI ,799 patients with MDRD GFR 45 ml/min/1.73m2 before hospitalization Dialysis-requiring AKI/ARF defined as both: Peak inpatient SCr 50% higher than the last observed preadmission outpatient SCr AND Receipt of dialysis during hospitalization (ICD-9 procedure codes 54.98, 39.95; CPT codes 90935, 90937, 90945, and 90999) AKI Cases (included 41 cases of ESRD) Non-AKI Controls (No ESRD cases) Lowell J. Lo et al. CJASN 2010

12 2 AKI and Progression of CKD following Coronary Angiography 70 APPROACH coronary angiography 12 registry: All patients undergoing coronary angiography in Alberta n=20,640 final cohort study n=9,819) No AKI No No AKI AKI 0.1 ml/min/1.73m 2 /yr AKI Stage 1 AKI Mild Stage AKI ml/min/1.73m 2 /yr Moderate AKI Stage / severe 2/3 AKI AKI Stage 2/3 3.1 ml/min/1.73m 2 /yr 40 Pre angiogram months months M.T. James. Kidney Injury and Progression of Chronic Kidney Disease following Coronary Angiography

13 Biomarkers and AKI

14 Courtesy of Dr. Mark Okusa Need for Biomarkers Benefit of therapies may be limited by a narrow time period of efficacy High risk Prerenal AKI AKI By the time Scr rises, the injury Therapeutic Window has already occurred and interventions may be too late - Sensitive + Creatinine Biomarkers GFR Rises hours after AKI is established Sensitive biomarkers to detect early and sub-lethal injury

15 What Can An Ideal AKI Biomarker Teach Us? 15 Predict and diagnose AKI early (before increase in serum creatinine) Identify the primary location of injury (proximal tubule, distal tubule, interstitium) Pinpoint the type (pre-renal, AKI, CKD), duration and severity of kidney injury Identify the etiology of AKI (ischemic, septic, toxic, combination) Predict clinical outcomes (dialysis, death, length of stay) Monitor response to intervention and treatment Expedite the drug development process (safety) P. Devarajan: Biomarkers in Acute Kidney Injury :Search for a Serum Creatinine Surrogate, ASN 2009

16 Novel Renal Biomarkers 1. Normal epithelium 2. Tubular damage Renal injury 3. Cell death 4. Renal function Modified from Vaidya et al. Annu Rev Pharmacol Toxicol 2008

17 Urinary Biomarker Performance Biomarker performance Time from insult Baseline egfr Complex sensitivity Complex specificity More studies required Endre et al. Kidney Int 2011: 79: 1119

18 Preventing AKI

19 Prevention Given the impact of AKI, it is important to prevent or hasten the resolution of even mild forms of AKI Goals: Preserve renal function Prevent death Prevent complications of AKI (volume overload, acidbase/electrolyte abnormalities) Prevent need for chronic dialysis Minimize adverse effects Relies on implementation of: Nonpharmacological strategies Pharmacological strategies Renal replacement strategies

20 Steps in a preventive strategy 1. Identify high-risk patients 2. Non-pharmacological techniques 3. Pharmacological techniques 4. Cause-specific therapies Often, other care measures not directly targeted to the kidney may have great impact but are not well studied For example: time to antibiotic initiation, correct antibiotic choice, packed red blood cell transfusions, etc.

21 Cumulative Effective Antimicrobial Therapy (%) Incidence AKI (%) Competing influences on outcomescomplex background of care < >24 Time from Onset of Hypotension (hrs) Antimicrobial Therapy AKI Adapted from Bagshaw S, Curr Drug Targets 2009

22 Common risk factors for AKI Clinical settings: ICU/multiple organ failure Sepsis/infection Post-operative (esp. cardiac and vascular) Trauma/Burns HIV Non-renal solid organ transplantation Bone marrow transplantation Liver disease Nearly 2/3rds of patients with AKI suffer more than one insult Patient-specific factors: Advanced age (more than 70% of cases occur in those age > 70) Diabetes mellitus Impaired renal function (most powerful risk) Impaired cardiac function Volume depletion/hypotension Multiple nephrotoxic medications Radiocontrast exposure

23 Risks for AKI- cont d Medications/toxins NSAIDS/Cox-2 inhibitors Aminoglycoside antibiotics Amphotericin B ACE-inhibitors/ARBS Calcineurin inhibitors Chemotherapeutic agents (cisplatin, ifosfamide) Toxic ingestions Occupational toxins (solvents, heavy metals) Herbal remedies Once daily dosing Liposomal/lipid formulations Specific antidotes (fomepizole)

24 Risk assessment tools Identification of risk factors has been used to develop risk stratification tools These tools are most useful where a potential nephrotoxic exposure occurs at a defined time (surgery, contrast exposure) Identify patients that will benefit from close observation and renal protective strategies Good negative predictive power but poor positive predictive power

25 Example: Risk for development of contrast-induced nephropathy (CIN) according to CIN risk score Variables: 2 points for each of the following: Creatinine clearance < 60ml/min Urgent PCI Intra-aortic balloon pump 1 point for each of the following: Diabetes Mellitus Congestive heart failure Hypertension Peripheral vascular disease Contrast volume > 260 ml Bartholomew et al. Am J Cardiol 93: , 2004

26 Integrated structure-process framework for computer decision support -Knowledge base -Inference engine -Communication Chang, Rosner et al. Nature Rev Nephrol 7: (2011)

27 Computer decision support systems in nephrology Only one study has examined the impact of CDSS on the prevention of AKI Demonstrated one of the greatest reductions in the rate of AKI seen in any intervention study In this study, an alert was generated for a patient prescribed a potentially nephrotoxic medication when there was an increase in serum creatinine of >44.2 μmol/l (>0.5 mg/dl) from baseline after starting the medication. This alert system resulted in a significant decrease in renal impairment in the group that received these alerts as compared with the group that did not receive alerts (relative risk 0.45, 95% CI ). Rind, D. M. et al. Effect of computer-based alerts on the treatment and outcomes of hospitalized patients. Arch. Intern. Med. 154, (1994).

28 % Incidence of ARF Hydration as a preventative strategy Hydration/Fluid Therapy Volume depletion is a clear risk factor for ARF Clearly important in the prevention of contrast nephropathy, pigmentinduced ARF and prevention of drug-induced injury (amphotericin B, methotrexate, acyclovir) Role in contrast nephropathy: 78 patients with CKD (Scr 1.6 mg/dl or CCl <60 ml/min) undergoing coronary angiography Diabetic Non-diabetic Saline Mannitol Furosemide Solomon et. al. NEJM 331: , 1994

29 Sepsis and AKI: Management Issues

30 Sepsis: Can AKI be prevented? No good predictive scoring system Significant renal damage occurs very early and often before overt signs/symptoms of sepsis are seen In the Rivers et al trial of early goal directed therapy (EGDT): Presenting serum creatinine was 2.6 +/- 2.0 signifying that a large percentage of patients present already in AKI. How can AKI in complex scenarios be prevented?

31 Pathogenesis- An example of an ICU patient Toxins Drugs Heme proteins Contrast media Hypoperfusion Altered NO-ET balance Reperfusion injury Increased RVR AKI Ischemia Sepsis Spectrum of kidney injury Systemic inflammation LPS/endotoxin Activated leukocytes Activated monocytes Cytokines Complement activation Coagulation activation Prerenal Sublethal Injury Apoptosis Necrosis

32 Oliguric AKI due to sepsis- A crossroads Fluid Challenge: crystalloid/colloid Vasopressors: Norepinephrine/vasopressin What does oliguria represent? Prerenal state Reversible early injury Irreversible injury Diuretics OLIGURIA ENTRY POINT: SEPSIS Early goal directed therapy Can AKI be prevented? Renal replacement therapy The imperative: maintain renal blood flow even if initial injury not due to ischemia?

33 Renal Blood Flow in Sepsis Renal blood in sepsis actually increases and thus methods targeted to increase RBF may not be necessary Brenner M, et al. Chest 1990; 98:

34 Early goal directed therapy (EGDT) Protocol to reverse early hemodynamic perturbations- must occur early in the processgeneral consensus that acute and aggressive early resuscitation is important: Rivers et al New Engl J Med 345: 1368, 2001 Should be targeted to physiologic end-points: Mean arterial pressure (MAP > 65 mm Hg) Central venous pressure (CVP > 8-12 mm Hg) Urine output ( > 0.5 ml/kg/hour) Cardiac output ScvO 2 (> 70%)

35 EGDT and AKI? In the Rivers trial: no data on cumulative fluid balance, urine output, diuretic therapy, and renal outcomes Recent study from this group looked at biomarkers: TNF-α, caspase-3, IL-8, ICAM-1 and showed that early correction of hemodynamic derangements corrected some parameters that could impact on the development of AKI (Rivers et al Crit Care Med 35: 2016, 2007) Need a study that addresses effects of EGDT on renal outcomes Other factors that are likely critical in decreasing renal failure (but have not been well studied) include: early and appropriate antibiotic therapy.

36 A modified goal-directed protocol improves clinical outcomes Randomized 224 patients with established sepsis to a protocol using central venous pressure, mean arterial pressure, and urine output as therapeutic goals (similar to Rivers et al) Reduced mortality (53.7 v. 71.6% p = 0.006) Decreased ICU length of stay (14.3 v p = 0.003) Decreased ventilator days (12.9 v p = 0.003) Incidence of AKI fell from 55.2% to 38.9% (p = 0.015) Lin et al. Shock 26: 551, 2006

37 After early resuscitation in the oliguric patient: Fluid management to prevent AKI An obvious therapeutic option for those patients who remain oliguric is a fluid challenge: Problems: Oliguria is not a necessarily an indication for volume expansion. May represent a stage of irreversible injury. Although added fluids may temporarily increase urine flow there is no evidence that this improves renal outcomes Typical hemodynamic measures (CVP, PaOP) do not allow us to predict volume responsiveness (more dynamic measures such as respiratory variation in systolic pressure are better). Most importantly: liberal use of fluid therapy is associated with harm and a positive cumulative fluid balance has been shown in several studies to predict hospital mortality. Need to be very cautious in continuing volume therapy unless using a dynamic measure and continually assessing the response to fluids.

38 Restrictive v. liberal fluid management in ARDS. ARDSNet FACCT Trial The mean (±SE) cumulative fluid balance during the first seven days was 136±491 ml in the conservative-strategy group and 6992±502 ml in the liberal-strategy group (P<0.001). Globally, no difference in mortality at 60 days Improved lung function, increased ventilator free days, reduced ICU LOS, and no increase in rate of nonpulmonary organ failure. TREND for reduced need for renal replacement therapy (10% restrictive v. 14% for liberal, p = 0.06) despite higher BUN and creatinine in the restrictive group. NEJM 354: 2564, 2006

39 Cumulative daily fluid balance for days 1 through 7 following the onset of septic shock Non-survivors Survivors Murphy C V et al. Chest 2009;136:

40 Fluid Balance in AKI Payen D et al. Crit Care 2008; 12: R74

41 Fluid Balance and Outcomes in AKI Dialysis Pts. Non- Dialysis Pts. Bouchard J et al. Kidney Int 2008; 76: 422

42 Vasopressors: Is there a best option? Maintaining renal perfusion (?) Most significant threats are systemic arterial hypotension and increased intra-abdominal pressure. To achieve adequate renal perfusion, often need pressors to maintain mean arterial pressure at mm Hg (may need higher mean pressures in those patients with a history of hypertension or CKD who have impaired renal autoregulation). Studies have shown no benefit of increasing MAP > 65 mm Hg (may not be true for those with long-standing hypertension) Is there a preferred pressor for renal protection?

43 Effects of norepinephrine on renal and systemic hemodynamics in sepsis Di Giantomasso: Crit Care Med, Volume 31(10).October

44 Vasopressin? Early small (24 subjects) trial demonstrated that vasopressin in septic shock was associated with improved urine output, increased creatinine clearance (unlike norepinephrine) Patel BM et al. Anesthesiology 96: 576, 2002 VASST Trial: vasopressin and norepinephrine showed equivalence in all outcomes including need for renal replacement. Trend toward better survival in less severe septic patients receiving vasopressin. Brunkhorst et al. N Engl J Med. 10:125-39, 2008.

45 Abdominal Compartment Syndrome Renal Effects Increased intra-abdominal pressure leads to: Compression of renal vein and parenchyma Increased renal vascular resistance Decreased renal blood flow and fall in glomerular filtration Oliguria and anuria Occurs as IAP rises above mm Hg (measured through bladder pressures) Early therapy of moderately elevated IAP is with IVF May require decompressive surgery Recent study documents significant rise in IAP in acute decompensated heart failure that correlated with changes in GFR (J Am Coll Cardiol 51: 300, 2008) Shear and Rosner, Am J Nephrol 19:

46 Diuretic use and AKI Theoretically, very attractive Inhibits Na+/K+/2Cl- pump on luminal cell membrane surface in medullary thick ascending loop of Henle and can reduce oxygen demands Aids management of volume overload: Augments natriuresis and diuresis Helps maintain potassium and acid-base homeostasis Aids in ability to deliver maximal nutritional support Survey data from intensivists and nephrologists: 50-70% of ICU patients receive loop diuretics Bagshaw et al. Contrib Nephrol 156: 236, Many small studies that do not demonstrate benefit Two large observational studies with discrepant results

47 Diuretics, mortality and nonrecovery of renal function in acute renal failure All patients had nephrology consultation and received diuretics on/before the day of consultation JAMA 288: 2547, 2002

48 Key point: If there is no increase in urine output to a diuretic, continuing the diuretic may be harmful Patients who do not respond to diuretics with increased urine output have the worse outcome. If patients responded, then there was no difference in mortality Uchino et al. studied a cohort of 1743 ICU patients with AKI and could not demonstrate a significant impact of diuretic use on mortality with oddsratio of 1.2 (NS) Crit Care Med 32: 1669, 2003

49 Pharmacological Therapies Multiple agents have been studied with little success Currently, the only FDA approved therapy for the treatment of AKI is dialysis Two recent studies have addressed the dosing of dialysis for critically ill patients and both demonstrated no benefit of more intensive dosing regimens (VA-ATN and RENAL trial) In studies comparing CRRT and IHD in patients with AKI, there have been no studies demonstrating superiority of one modality over another Individualized decision

50 Delivered CRRT Dose: Best Practice Window Kellum and Ronco, Nature Revs Nephrol 2010

51 When should we begin RRT? What specific criteria exist for beginning RRT in ICU patients? Little agreement with regard to optimal timing of initiation of RRT Majority of literature uses surrogate biochemical markers (BUN or creatinine) and demonstrates better outcomes with initiation prior to retention of uremic solutes (BUN < 70 mg/dl) Other timing: duration of oliguria, timing from ICU admission, fluid volume status, electrolyte disarray, severe acidosis

52 Timing of RRT Initiation (< or > 2 days after ICU admission): Effect on Outcome Payen et al, Crit Care 2008 Fluid Balance: Early +150 ml over ICU stay Late ml over ICU stay

53 Timing of RRT Initiation: Effect on Outcome Bagshaw et al, J Crit Care 2008 Timing of Initiation Crude Mortality (%) OR for Death Early (< 2 days) Delayed (2-5 days) Late (> 5 days) * *: Significantly greater than Early group

54 Timing of RRT Initiation: Meta-Analysis Seabra et al, AJKD 2008

55 Recovery from dialysis dependence Recovery from Dialysis Dependence: BEST Kidney 1 CRRT.8.6 IRRT.4 Data consistent with other RCTs: CRRT associated with improved renal recovery.2 Note that the likelihood of recovering renal function after approximately 50 days is very low, Uchino et al., Int J Artif Organs 2007 Days

56 Renal Recovery after Post-Operative AKI Lin et al, Am J Surg 2010

57 Recovery of Renal Function Strong suggestion from RENAL v. VA/ATN that CRRT improves the likelihood of renal recovery over IHD May be an under recognized benefit of the use of CRRT

58 Fluid management: CRRT v. IHD Several observational studies have shown a direct relationship between fluid accumulation and mortality in critically ill patients. PICARD Study: Those with > 10% fluid accumulation had higher mortality and those needing RRT who had significant fluid accumulation at the time of initiation had an OR of death of 2.07 v. those with less fluid accumulation Fluid removal in IHD patients approximated 6-9L/week Fluid removal in CRRT patients approximated > 20L/week

59 Neurotrauma: A unique benefit of CRRT Goal to maintain cerebral perfusion and manage intracranial hypertension CRRT: Slower reduction in serum urea and minimizes changes in serum osmolality Ability to maintain high-normal serum sodium Regional citrate anticoagulation Fletcher JJ et al. Neurocrit Care 2009; 11: 101-5

60 Summary The incidence of AKI is increasing AKI is associated with increased mortality, morbidity and risk for progressive CKD Biomarkers are needed for rapid, early diagnosis of AKI and to allow early therapeutic intervention Preventative strategies should be employed wherever possible The patient with sepsis and AKI is especially challenging and fluid/volume management is critical Data supports early nephrology consultation and institution of renal replacement therapies CRRT may offer some advantages Novel therapeutics are needed to treat AKI