Acute Kidney Injury in the Hospitalized Patient Biff F. Palmer, - - PDF document

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Acute Kidney Injury in the Hospitalized Patient

Biff F. Palmer, M.D. Professor of Internal Medicine University of Texas Southwestern Medical Center, Dallas Texas

Classification of Acute Kidney Injury

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RIFLE Classification for Acute Renal Failure

Stage GFR criteria (over 7d) Urine output criteria Risk SCr increased 1.5-2 times baseline or GFR decreased >25% UO < 0.5 ml/kg/h <6h Injury SCr increased 2-3 times baseline or GFR decreased >50% UO < 0.5 ml/kg/h >12h Failure SCr increased >3 times baseline or GFR decreased >75% or SCr ≥4 mg/dl; acute rise ≥ 0.5 mg/dl UO < 0.3 ml/kg/h 24h

• r anuria 12 h

Loss of Function Persistent acute renal failure: complete loss of kidney function >4 wks ESRD Complete loss of kidney function >3 months

Crit Care. 2004; 8(4): R204–R212

Acute Kidney Injury Network

• Introduces term acute kidney injury (AKI)
• Classification into stage 1-3 (replaces R,I,F)

– Abrupt (within 48 h) reduction in kidney function: increase SCr of 0.3 mg/dL or more (≥26.4 µmol/L) or – A percentage increase in SCr of >50% or more (1.5-fold from baseline) or – A reduction in urine output (documented oliguria of < 0.5 mL/kg/h for >6 h)

• Differences from RIFLE

– Changes within 48h vs 7d – Less severe injury – Avoids using GFR criteria

Crit Care. 2007; 11(2): R31.

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Kidney Disease Global Outocmes Acute Kidney Injury (KDIGO) Classification

Stage SCr Criteria Urine output criteria 1 1.5-1.9 times baseline or ≥0.3 mg/dl above baseline < 0.5 ml/kg/h for 6-12h 2 2.0-2.9 times baseline < 0.5 ml/kg/h >12h 3 ≥3 times baseline, ≥4.0 mg/ dl, or intiation of renal replacement therapy < 0.3 ml/kg/h for ≥24h or anuria for ≥12 h

Kidney Intl 2:1-138, 2012

The Incidence of AKI is Increasing

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Incidence of AKI is Increasing in Hospitalized Patients

J Am Soc Nephrol 17:1135-1142, 2006

Data from Medicare beneficiaries, 1992-2001

Why is the incidence of AKI is increasing?

Probably increasing as high-risk patients are exposed to diagnostic and interventional procedures and nephrotoxic agents and/or develop sepsis or other hemodynamic disturbances

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Risk Factors For AKI

• Advanced age
• Diabetes mellitus
• Black race
• Preexisting chronic kidney disease

– Up to 10 times the risk vs absence of CKD

N Engl J Med 371:58-66, 2014

A Graded Relationship Exists Between the ↑SCr and Risk of CKD and Mortality

∆Cr severity % ∆Cr severity %

Arch Intern Med 171:226-233, 2011

Incident CKD CKD progression Mortality

∆Cr severity %

Years ¡A/er ¡Index ¡Surgery ¡

Study of 29,388 VA patients undergoing cardiac surgery between 1999-2005

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Post-op RF in Cardiac Surgical Patients Predicts In- Hospital Mortality and Long Term Survival

• Cardiac surgery in 843 patients , 145 with

post-op AKI

• AKI (>25% change in SCr) associated with

increased in hospital mortality and higher 5 year mortality

• This long term effect persisted even if SCr

had returned to baseline at discharge

J Am Soc Nephrol 16:195-200,2005

Post-op AKI in Cardiac Surgical Patients Predicts In- Hospital Mortality and Long Term Survival

J Am Soc Nephrol 16:195-200,2005

Stable ≥ 25%

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Acute Kidney Injury Chronic Kidney Disease Increased cardiovascular events Increased risk of ESRD Increased mortality

N Engl J Med 371:58-66, 2014

Case

• 71 year old women with stage 3 CKD,

hypertension, and coronary artery disease is admitted with urosepsis. On admission she is hypotensive and is resuscitated with 4.2 L of NS and low-dose norepinephrine and started

• n broad spectrum antibiotics. One day later

she is noted to have trace pedal edema and basilar crackles. Hemodynamics have

• improved. Urine output ranges from 600-750

ml/day. Furosemide was withheld for fear of worsening renal function.

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Hospital Course

1 2 3 4 5 6 Serum creatinine (mg/dl) 1.17 1.02 1.10 1.17 1.24 1.3

Hospital Course

1 2 3 4 5 6 Serum creatinine (mg/dl) 1.17 1.02 1.10 1.17 1.24 1.3 UA Nl 1+ protein, 3-5 RTEC/hpf 1+ protein, 5-8 RTEC/ hpf, 1-3 RTC casts/lpf Weight 52 kg 55.5 kg 57.5 kg

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By the KDIGO, serum creatinine and urine output criteria do not qualify as clinically defined AKI. However, the proteinuria and renal tubular cells and casts suggest some degree of renal injury

PGC PGC PGC

Continuum of Renal Injury

At risk kidney Clinical AKI Incipient AKI

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Need For Biomarkers in AKI

• Lack of early biomarkers has impaired ability

to initiate timely preventive and therapeutic measures

Neutrophil Gelatinase-Associated Lipocalin (NGAL): A Novel Early Biomarker of Renal Injury

• NGAL is one of the maximally induced

genes and proteins immediately after injury

• NGAL is easily detected in the urine very

early after injury

Am J Nephrol 24:307-15,2004

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Urine NGAL is Increased 2 Hours After CPB In Patients Who Later Develop AKI

Post CPB Time (hours)

Lancet 365:1231-38,2005 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Do increased NGAL levels predict adverse

• utcomes in the setting of a normal serum

creatinine concentration?

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In Absence of Increased SCr NGAL Predicts Increased Risk for Adverse Outcomes

J Am Coll Cardiol 57:1752-61, 2011

Pooled data from 2,322 patients with predominately cardiorenal syndrome from 10 prospective observational studies of NGAL

Outcome of NGAL Positive Patients with Subclinical AKI

J Am Coll Cardiol 57:1752-61, 2011

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Urinary Biomarkers of Nephron Injury Are Predictive

• f Adverse Outcomes During Hospitalization

J Am Coll Cardiol 59:246-55, 2012

Multicenter prospective cohort study in of 1635 ER patients at time of admission (Event rates: Dialysis initiation or death during hospitalization)

Need For Biomarkers in AKI

• Availability of biomarkers can facilitate early

identification of AKI and allow initiation of preventive and or therapeutic measures: – Avoid nephrotoxins – Ensure hemodynamic stability, maintain MAP of at least 65 mmHg – Closely monitor fluids, urine output, CVP – Reno-protective agents

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PGC PGC PGC

Continuum of Renal Injury

At risk kidney Clinical AKI Incipient AKI Early recognition and rapid renal recovery

Feasible Strategies to Minimize Further Kidney Injury

• Preferential use of balanced physiologic

solutions for patients requiring fluid resuscitation

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Types of Crystalloid Solutions

• Balanced

– A physiologic mixture of electrolytes and buffers designed to approximate makeup of plasma

• Unbalanced

– Typically contains NaCl and no other electrolytes

• r buffers

Crystalloid Solutions

Na+

(mEq/L)

K+

(mEq/L)

Ca2+

(mEq/L)

Mg2+

(mEq/L)

Cl-

(mEq/L)

Buffer

(mEq/L)

Glucose

(mg/dl)

pH pOsm

(mOsm/L)

Plasma 141 4.5 5 2 103 HCO3 70-110 7.4 290

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Crystalloid Solutions

Na+

(mEq/L)

K+

(mEq/L)

Ca2+

(mEq/L)

Mg2+

(mEq/L)

Cl-

(mEq/L)

Buffer

(mEq/L)

Glucose

(mg/dl)

pH pOsm

(mOsm/L)

Plasma 141 4.5 5 2 103 HCO3 70-110 7.4 290 Normal Saline 154

• 154
• 6.0

308

Crystalloid Solutions

Na+

(mEq/L)

K+

(mEq/L)

Ca2+

(mEq/L)

Mg2+

(mEq/L)

Cl-

(mEq/L)

Buffer

(mEq/L)

Glucose

(mg/dl)

pH pOsm

(mOsm/L)

Plasma 141 4.5 5 2 103 HCO3 70-110 7.4 290 Normal Saline 154

• 154
• 6.0

308 Lactated Ringer’s solution 130 4 4

• 109

Lactate 28 (mEq/ L)

• 6.5

274

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Crystalloid Solutions

Na+

(mEq/L)

K+

(mEq/L)

Ca2+

(mEq/L)

Mg2+

(mEq/L)

Cl-

(mEq/L)

Buffer

(mEq/L)

Glucose

(mg/dl)

pH pOsm

(mOsm/L)

Plasma 141 4.5 5 2 103 HCO3 70-110 7.4 290 Normal Saline 154

• 154
• 6.0

308 Lactated Ringer’s solution 130 4 4

• 109

Lactate 28 (mEq/ L)

• 6.5

274 Plasma- Lyte 140 5

• 3

98

Acetate 27 mEq/L, gluconate 23

7.4 294

Normal Saline

• Most commonly used crystalloid
• The term “normal saline” comes from in vitro

study of RBC lysis performed by Dutch physiologist Hartog Hamburger in 1890’s

• His studies suggested 0.9% was concentration
• f salt in blood rather than true value of 0.6%

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Potential Consequences of High Cl- Concentration in Normal Saline

• Hyperchloremic metabolic acidosis

– Dilution of extracellular fluid HCO3 concentration – Volume expansion leading to decreased proximal HCO3 reabsorption – Increased Cl-/HCO3 exchange in β-intercalated cell (pendrin) – Plasma Cl- increases to greater extent than Na+ narrowing strong ion difference thus causing increased H+ generation to aid in restoring charge equilibrium

Comparison of Rapidly Infused Crystalloids on Acid-base Status in Dehydrated Patients in ED

• Prospective DB

randomized trial in 90 patients with diagnosis

• f dehydration of

varying causes

• Blindly allocated to

receive either normal saline, lactated Ringer’s,

• r Plasmalyte at 20 ml/

kg/h for 2 hours

7.32 7.34 7.36 7.38 7.4 7.42 7.44 0 Hr 1 Hr 2 Hr

Plasamalyte Lactated Ringer’s Normal Saline

Int J Med Sci 9: 59-64, 2012

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Adverse Effects Attributed to Hyperchloremic Metabolic Acidosis

• Immune dysfunction

– Hyperchloremic acidosis increases lung and intestinal injury in normal rats1 – In experimental sepsis, resuscitation with NS vs RL is associated with decreased survival which is inversely correlated to increase in plasma [Cl-]2 – Circulating levels of IL-6, IL-10, and TNF increase to greater extent with NS vs RL3

1J Lab Clin Med 138:270-276, 2001 1Am J Respir Crit Care Med 159:397-402, 1999 2Chest 125:243-248, 2004 3Chest 130:962-967, 2006

Potential Consequences of High Cl- Concentration in Normal Saline

• Hyperchloremic metabolic acidosis
• Increase in renal vascular resistance leading to

renal dysfunction

– Increased tubuloglomerular feedback – Potentiate vascular response to AII

J Clin invest 71:726-735, 1983 Br J Pharmacol 108:106-110, 1993

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Comparison of NS and Plasma-Lyte on Renal Function in Normal Subjects

• Twelve subjects

received 2-L intravenous infusion

• ver one hour of 0.9

saline or Plasma-Lyte 148 in a randomized double blind fashion

• MRI scan used to

measure renal artery flow velocity and renal cortical perfusion

Ann Surgery 256:18-24, 2012

Normal saline Normal saline

Comparison of NS and Plasma-Lyte on Renal Function in Normal Subjects

Ann Surgery 256:18-24, 2012

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Comparison of Cl- Liberal vs Cl- Restrictive Fluid Strategy on AKI in Critically Ill Adults

Prospective, open label sequential (6mo) period study

Control period: 760 ICU patients received standard IV fluids Intervention period: 733 ICU patients received IV fluids restricted in Cl-

• Hartmann solution
• Plasma-Lyte 48
• Cl--poor 20% albumin

Cl- use significantly decreased in restricted group 694 mmol/l to 496 mmol/l

JAMA 308:1566-1572, 2012

10 20 Control Low Cl-

Incidence of injury and Failure class of RIFLE (%)

10 20 30 Control Low Cl- 5 10 15 Control Low Cl-

Comparison of Cl- Liberal vs Cl- Restrictive Fluid Strategy on AKI in Critically Ill Adults

Mean SCr increase (µmol/L)

p = 0.03 p < 0.001

Use of RRT (%)

p = 0.005 Patients receiving NS/High Cl- solutions had double the odds of RIFLE-defined AKI requiring dialysis after adjusting for covariates

JAMA 308:1566-1572, 2012

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Feasible Strategies to Minimize Further Kidney Injury

• Preferential use of balanced physiologic

solutions for patients requiring fluid resucitation

• Intelligent use of diuretics

Case

• 71 year old women with stage 3 CKD,

hypertension, and coronary artery disease is admitted with urosepsis. On admission she is hypotensive and is resuscitated with 4.2 L of NS and low-dose norepinephrine and started

• n broad spectrum antibiotics. One day later

she is noted to have trace pedal edema and basilar crackles. Hemodynamics have

• improved. Urine output ranges from 600-750

ml/day. Furosemide was withheld for fear of worsening renal function.

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There is a perception among many clinicians that diuretics, particularly loop diuretics, are nephrotoxic

Are Diuretics Harmful in Decompensated CHF

• Observational studies have shown associations

between high dose diuretics and adverse clinical

• utcomes to include renal failure, progression of

heart failure, and death

• High dose loop diuretics may be harmful

secondary to activation of renin-angiotensin and sympathetic nervous system

Am Heart J 147:331-8, 2004 Eur J Heart Fail 9:1064-9, 2007 Circulation 100:1311-5, 1999

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Potential Adverse Effects of Diuretics in CHF

Loop diuretics

↑ Urine K+, Mg2+ ↑ PRA, AII, Aldosterone ↑ SNS ↑AVP ↓ EABV Hypomagnesemia Hypokalemia ↑ Urine Na+ ↑ Risk of arrhythmias Na+ and H2O retention ↑ Uric acid Long term adverse effects On cardiac remodeling

Norepinephrine (ng/mL) 900 ¡ 800 ¡ 700 ¡ 600 ¡ C 10' 20' 1H 2H Plasma Norepinephrine Activity (ng · mL-1 · h-1) 18 16 14 12 10 C 10' 20' 1H 2H Plasma renin activity Arginine AVP (pg/ml) Plasma AVP 10.00 ¡ 9.00 ¡ 8.00 ¡ 7.00 ¡ 6.00 ¡ 5.00 ¡ C 10' 20' 1H 2H Time

Ann Intern Med 103:1-6, 1985

Effects of Aggressive Decongestion During Treatment of ADHF on Renal Function and Survival

No hemoconcentration Hemoconcentration 433 patients from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) Trial

Circulation 20;122:265-72, 2010

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Diuretic Optimization Strategies Evaluation (DOSE) Trial

• 308 patients with decompensated CHF

randomized to low dose (previous oral dose given IV) or high dose (2.5x), Q 12h vs continuous infusion

• High dose superior in:

– Global assessment (p=0.06) – Net fluid loss – Dyspnea – ↓ NT-proBNP (p=0.06) – ↓ Adverse events

0.05 0.1 Bolus Contin LD HD Change in creatinine at 72 h (mg/dl) P = 0.45 P = 0.21

N Engl J Med 364:797-805, 2011

No significant difference at 72h or 60d

Diuretic Optimization Strategies Evaluation (DOSE) Trial

• High dose diuretics are safe and effective

– No difference in low vs high with respect to the clinical composite of death, re-hospitalization,

• r ER visit
• In patients with decompensated CHF, no

clear advantage of loop diuretics given as a bolus vs continuous infusion (no bolus)

• Not a study of diuretic resistant patients, no

forced titration, no bolus preceding CI

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The Facts

• Studies suggest more aggressive use of loop

diuretics to achieve greater volume removal is associated with improved outcomes despite induction of more AKI in some studies

Circulation 20;122:265-72, 2010 Clin J Am Soc Nephrol 6:966-973, 2011 Eur J Heart Fail 13:877-884, 2011

Which is better in Acute Decompensated Congestive Heart Failure: Diuretics or Ultrafiltration

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Ultrafiltration vs IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure: UNLOAD Trial

• Prospective randomized clinical trial of 200

patients with ADHF with mean SCr 1.5 mg/dl

• UF used exclusively for first 48 hrs at maximal

rate of 500 ml/hr versus IV diuretics using twice daily admitting oral dose

• 90 day follow up

J Am Coll Cardio 49:675-683, 2007

UNLOAD Trial: Primary Endpoint

2 4 6 8 Weight loss at 48 hrs p=0.001 UF Diuretic 2 4 6 8 Change in dyspnea score at 48 hrs p=0.35 UF Diuretic

J Am Coll Cardio 49:675-683, 2007

Kilogram

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UNLOAD Trial: Secondary Endpoints

10 20 30 40 50 Rehospitalization for heart failure by 90 days p=0.037 UF Diuretic 1 2 3 4 5 Mean number of hospitalization days p=0.009 UF Diuretic

J Am Coll Cardio 49:675-683, 2007

Percentage Days 43% reduction favoring UF 63% reduction favoring UF

Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF)

• Prospective randomized trial of ADHF patients

who developed CRS defined as ↑ SCr of ≥ 0.3 mg/dl from baseline while demonstrating signs and symptoms of congestion

• Patients (188) randomized to UF (200 ml/hr)
• r stepped IV loop diuretics with target UOP
• f 3-5 L/d

N Engl J Med 367:2296-304, 2012

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CARESS-HF: Primary Endpoint

N Engl J Med 367:2296-304, 2012

Enrollment stopped early due to lack of treatment benefit and adverse events in the UF group

Mean Weight Change from Baseline (Lbs) p<0.05 Mean Creatinine Change from Baseline (mg/dl)

CARESS-HF: 60 Day Event Rates

N Engl J Med 367:2296-304, 2012

Death or HF Rehospitalization Death or Serious Adverse Event Days post randomization Days post randomization

Adverse events: AKI, bleeding and catheter complications

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CARESS-HF: Summary

• Pharmacologic care was superior to ultrafiltration at

96 hours for preservation of renal function with similar weight loss

• Ultrafiltration, as administered in this study, had

higher rates of adverse events and therefore offers no advantage to stepped pharmacologic care in patients with ADHF, worsened renal function, and persistent congestion

Strategies to Overcome Diuretic Resistance

• Avoid reduction in GFR
• Add thiazide diuretic to loop diuretic

– Long duration of action – Carbonic anhydrase inhibition – Inhibits transport in hypertrophied segments

• Continuous infusion (bolus dose should

precede continuous infusion)

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Feasible Strategies to Minimize Further Kidney Injury

• Preferential use of balanced physiologic

solutions for patients requiring fluid resucitation

• Intelligent use of diuretics
• Do not reflexively discontinue renin-

angiotensin blockers

PGC

Continuum of Renal Injury

At Risk Kidney Incipient AKI

Reduced Oxygen Delivery ↓ PGC Preserved Oxygen Delivery

Ang II Ang II ACEI, ARB

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AII Blockade Augments Renal Cortical Microvascular pO2

Cortical microvascular pO2 measured in Sprague-Dawley rats with and without enalaprilat

After a fall in pO2 of 5 mm Hg

Enalaprilat Enalaprilat Control

Nephron Physiol 94:39-46, 2003

Change in RBF After ACEI, ARB or B2 Blocker in Dogs Fed Low Na+ Diet

Am J Physiol Renal Physiol 279:F289-F293, 2000 ICAT = icatibant

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Effect of ARB Pretreatment in Wistar Rat Model of Ischemic AKI

Nephron Exp Nephrol 112: 10-19, 2009

RAAS blockade ameliorates renal injury by improving peritubular capillary perfusion. Antioxidant and antiproliferative effects of these agents may also contribute to the reduction in renal injury

Eur Rev med Pharmacol Sci 16:600-9, 2012 Am J Physiol Renal Physiol 293: F78-86, 2007 Pharmacol Res 37:23-29, 1998

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Initial Change in eGFR and Long Term Renal Function

Kidney Intl 80: 282–287, 2011

Post Hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial

Early Worsening of Renal Function After Initiation of ACEI in CHF

Studies of Left Ventricular Dysfunction (SOLVD) Trial

20% ↓ eGFR at 14 d Placebo: adverse effect Enalapril (no adverse prognostic effect) Circ Heart Fail 4:685-691, 2011

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Summary

• AKI is common and ↑ in hospitalized patients
• Diagnostic staging systems exist for AKI
• Incipient AKI is renal injury manifested by new

proteinuria and urine sediment activity in absence

• f clinical data that meet current diagnostic

criteria

• Management considerations should consider:

– Use of low chloride IV solutions – Use of diuretics to control intravascular volume – Consider continued use of RAAS blockers