Acute Kidney Injury

Acute Kidney Injury
Mario F. Rubin, MD

Dr. Mario Rubin reports:
•That he does not have any financial
relationships with commercial
entities producing, marketing, reselling,
or distributing health care
goods or services consumed by, or
used on, patients relevant to the
content he is planning, developing,
presenting or evaluating.

Acute Renal Failure
It is characterized by a deterioration of renal function
over a period of hours to days, resulting on the failure of
the kidneys to excrete nitrogenous wastes and to
maintain electrolyte and acid-base balance.
When one attempts to review the subject of acute renal
failure, one is immediately struck by the confusion in
terminology and wide disparity in the definitions of
terms.
Thadhani R et al. N Engl J Med 1996;334:1448-1460

AKIN Diagnostic Criteria For AKI
A reduction within 48 hours of kidney function, currently
defined as:
1. An absolute increase of serum creatinine of more
than or equal to 0.3 mg/dL
2. A percentage increase of serum creatinine of more
than or equal to 50% (1.5 fold from baseline)
3. A reduction in urine output (documented oliguria of
less than 0.5 mL/Kg/Hour for more than six hours)
Metha RL et al. Crit Care.2007;11:R31

Phases of Post-Ischemic AKI
GFR
Serum Creatinine
Time

AKIN Conceptual Model
for Acute Kidney Injury
Normal
Increased
risk
Damage
↓ GFR
Kidney
failure
Death
Ideal
Biomarker
Creatinine

Coca SG et al. KI 2008;73:1008-1016

AKI: the Growing Threat
BEST Epidemiology Study
(N: ~ 30,000 patients from 54 hospitals in 23 countries)
• 1/3 to 2/3 of patients admitted to the ICU
will develop acute kidney injury (AKI)
• 6% of all critically ill patients will lose
kidney function completely
• 70% of these patients will require dialysis
• 60% will die
Uchino S et al. JAMA 2005;294:813-818

MMWR 2008; 57:0309-312

MMWR 2008; 57:0309-312

Mean Hospital Costs Associated With
Changes In Serum Creatinine
Chertow, G. M. et al. J Am Soc Nephrol 2005;16:3365-3370

Mortality Associated With Change In Serum
Creatinine
Chertow, G. M. et al. J Am Soc Nephrol 2005;16:3365-3370

Natural History of AKI
Cerda, J. et al. Clin J Am Soc Nephrol 2008;3:881-886

Distant Organ Injury Caused By AKI
Scheel PS et al. KI.2008;74:849-851

Classification of the Etiologies of
Acute Kidney Injury
Acute
Kidney
Injury
Prerenal
AKI
Intrinsic
AKI
Postrenal
AKI

Classification of the Etiologies of
Acute Kidney Injury
Acute
Kidney
Injury
Prerenal
AKI
Intrinsic
AKI
Postrenal
AKI
Acute
Tubular
Necrosis
Acute
Interstitial
Nephritis
Acute
GN
Acute
Vascular
Syndromes
Intratubular
Obstruction

Hou SH, et al. Am J Med 1983; 74:243-248
Kaufman J, et al. Am J Kidney Dis 1991; 17:191-198
Epidemiology of AKI

Acute Tubular Necrosis

Urine Microscopy Is Associated with Severity and Worsening
of Acute Kidney Injury in Hospitalized Patients
Perazella MA et al. CJASN 2010;5:402-408

The Urinary Indexes
Schrier, R. W. et al. J. Clin. Invest. 2004;114:5-14

Pathogenesis of Prerenal Azotemia
Volume
Depletion
Angiotensin II
+
Adrenergic nerves
+
Vasopressin
+
Congestive
Heart Failure
Reduced
Renal
Perfusion
Decreased
GFR
Liver
Failure
-
Sepsis
-
Nitric oxide
Prostaglandins

Normal and Impaired Autoregulation of the
Glomerular Filtration Rate during Reduction of
Mean Arterial Pressure
Abuelo J. N Engl J Med 2007;357:797-805

Intrarenal Mechanisms for Autoregulation of the Glomerular
Filtration Rate under Decreased Perfusion Pressure and
Reduction of the Glomerular Filtration Rate by Drugs
Abuelo J. N Engl J Med 2007;357:797-805

AKI in Liver Disease
Pre-renal Azotemia
Hepatorenal Syndrome
Acute Tubular Necrosis
Interstitial Nephritis
Glomerular Syndromes
• IgA nephropathy
• Cryoglobulinemia
• MPGN
• Membranous nephropathy

Revised Diagnostic Criteria
for Hepatorenal Syndrome
Cirrhosis with ascites
Serum creatinine >1.5 mg/dl
No improvement of serum creatinine after at least 2 days with
diuretic withdrawal and volume expansion with albumin (1 g/kg/day
up to 100 g/day)
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria
>500 mg/day, hematuria (>50 RBC/hpf) and/or abnormal renal
ultrasound
Salerno F, et al. Gut 2007; 56: 1310-1318

Forms of Hepatorenal Syndrome
Type 1: Doubling of serum creatinine to a level
of >2.5 mg/dL or a reduction in creatinine
clearance by 50% or more to a value of < 20
mL/min over a duration of < 2 weeks
Type 2: Moderate and stable reduction in renal
function

Survival in Type 1 and Type 2
Hepatorenal Syndrome
Gines P, et al. Lancet 2003; 362: 1819-827

Treatment of Hepatorenal Syndrome
Liver transplantation
Vasoconstrictors:
‣ Terlipressin
‣Norepinephrine
‣Midodrine / Octreotide
Transjugular intrahepatic portosystemic shunting (TIPS)
Renal replacement therapy as bridge therapy
Extracorporeal liver assist device (ELAD)

Abdominal Compartment Syndrome
• Definitions
‣Intra-abdominal hypertension:
intra-abdominal pressure ≥12 mm Hg; or
abdominal perfusion pressure (MAP-IAP)

Systemic Effects
Renal Effects
Decreased APP and
Mesenteric venous outflow
j tlntracinal Pressure rt
~~:~~~~~~
Elevated Diaphragm
1' Intrathoracic pressure
1' PIP
1' Dead space
1' PaC02
.t.Pa02
( Cardiovascular I
Hypovolemia
.t. Venous return
tCVP
1'PAOP
1'SVR
.t.CO
.
(vi, cycle) ) pe USion J------1--'
Bowel ischemiaflnflammation
Bacterial translocation
Cytokine release
Capillary leak & edema
Portal blood flow
Clinical Effects
Oliguria
Decreased G FR
Proteinuria
worsening of ischemic injury
Diuretic resistance
Proposed Mechanisms
of Renal Dysfunction
Increased renal vein pressure
lrculatlon
Microvascular congestion
Renal vascular resistance
Increased Catecholamines
Increased Angiotensin II
Proinflammatory cytokines
Increased lntracapsular pressure
(in ischemic injury)

Abdominal Compartment Syndrome
• Clinical settings
‣ Trauma patients following massive volume resuscitation
‣ Post liver transplant
‣ Mechanical limitations to the abdominal wall:
Tight surgical closure
Burn injuries
‣ Bowel obstruction
‣ Pancreatitis
• Diagnosis
‣ Measurement of intra-abdominal pressure via transduction of bladder
pressure
• Treatment
‣ Abdominal decompression

Acute Tubular Necrosis

Acute Tubular Necrosis
• Ischemic
‣ prolonged prerenal azotemia
‣ hypotension
‣ hypovolemic shock
‣ cardiopulmonary arrest
‣ cardiopulmonary bypass
• Sepsis
• Crystal
‣ Antivirals
‣ MTX
‣ Sulfas
‣ Quinolones
• Nephrotoxic
‣ drug-induced
radiocontrast agents
aminoglycosides
amphotericin B
cisplatinum
acetaminophen
‣ pigment nephropathy
hemoglobin
myoglobin

Pathogenesis of Ischemic ARF
Ischemia
Endothelial Injury
Tubular Injury
Disruption of Cytoskeleton
Activation of Vasoconstrictors
Impaired Vasodilation
Increased Leukocyte Adhesion
Inflammation
Loss of Cell Polarity
Apoptosis
&
Necrosis
Capillary Obstruction
&
Continued Ischemia
Desquamation of Cells
Tubular Obstruction
&
Backleak

Risk Factors for
Contrast-Induced Nephropathy
• Patient Related
‣ Preexisting renal insufficiency
‣ Diabetes mellitus
‣ Intravascular volume depletion
‣ Reduced cardiac output
‣ Concomitant nephrotoxins
• Procedure related
‣ Increased dose of radiocontrast
‣ Multiple procedures within 72 hours
‣ Intra-arterial administration
‣ Type of radiocontrast

Prevention of
Contrast-Induced Nephropathy
• Identify high risk patients
• Volume expand with isotonic sodium chloride or sodium
bicarbonate
‣ Optimal fluid composition and timing and rate of fluid
administration remain uncertain
• Use low osmolar or iso-osmolar contrast in high-risk population
• N-acetylcysteine
‣ Although data are inconclusive, NAC is inexpensive and safe
• Discontinue NSAIDs and vasoconstrictors

A Risk Score To Predict Contrast-Induced
Nephropathy
http://www.zunis.org/Contrast-Induced%20Nephropathy%20Calculator2.htm

Major Categories and Commonly Reported Causes of
Rhabdomyolysis
• Genetic:
‣ Disorders of glycolysis
‣ Disorders of lipid metabolism
‣ Mitochondrial disorders
• Trauma
• Exertion
• Muscle hypoxia:
‣ Arterial occlusion
‣ Prolonged immobilization
• Metabolic and electrolyte disorders:
‣ Hypokalemia
‣ Hypocalcemia
‣ Hypophosphatemia
‣ Hyperosmolar states
‣ DKA
• Infections:
‣ Influenza A & B
‣ Legionella
‣ HIV
‣ EBV
‣ Coxsackievirus
‣ Clostridum
‣ Streptococci
‣ Staphylococcus aureous
• Body temperature changes
• Drugs and toxins
‣ Statins
‣ Fibrates
‣ ETOH
‣ Heroin, Cocaine
• Idiopathic
Bosch X et al. N Engl J Med 2009;361:62-72

Prevention of Myoglobinuric AKI
• Standard management recommendations
‣Aggressive intravenous fluids
‣Bicarbonate
‣Mannitol

Acute Interstitial Nephritis
• Fever
• Rash
• Eosinophilia
• Sterile pyuria
• Eosinophiluria
• White cells casts
• Tubular dysfunction

Acute Interstitial Nephritis
• Drug-induced:
‣ penicillins
‣ cephalosporins
‣ sulfonamides
‣ rifampin
‣ phenytoin
‣ furosemide
‣ proton pump inhibitors
‣ NSAIDs
• Malignancy
• Idiopathic
• Infection-related:
‣ bacterial
‣ viral
‣ rickettsial
‣ tuberculosis
• Systemic diseases:
‣ SLE
‣ sarcoidosis
‣ Sjögren’s syndrome
‣ tubulointerstitial nephritis
and uveitis

Acute Interstitial Nephritis:
Treatment
Discontinue offending drug
Treat underlying infection
Treat systemic illness
Glucocorticoid therapy:
recommended in patients who fail to respond to
more conservative therapy
no RCTs have been reported

Acute Vascular Syndromes
• Macrovascular
‣ Renal artery
thromboembolism
‣ Renal artery dissection
‣ Renal vein thrombosis
• Microvascular
‣ Atheroembolic disease

Atheroembolic Disease
• Risk factors
‣ Atherosclerosis
‣CAD
‣AAA
‣PVD
‣ Hypertension
‣ Hypercholesterolemia
‣ Diabetes Mellitus
• Precipitating factors
‣ Arterial catheterization
‣ Arteriography
‣ Vascular surgery
‣ Anticoagulation
‣ Thrombolytic therapy

Kidney
Skin
Acute, subacute, and chronic renal failure
Severe uncontrolled hypertension
Renal infarction
Livedo reticularis
Blue toe syndrome
Ulceration and gangrene
Purpura
Gastrointestinal syst em
Abdominal pain
Gastrointestinal bleeding
Bowel ischaemia, infarction, and obstruction
Pancreatitis, cholecystitis, and abnormal liver tests
Splenic infarcts
H eart
Myocardial ischaemia
Myocardial infarction
Central n ervou s system
Transient ischaemic attacks
Eye
Amaurosis fugax
Altered mental status
Cerebral infarction
Spinal cord infarction
Retinal emboli (Hollenhorst plaques)
Systemic sign s
Fever
Weight loss
Malaise
Myalgia
Anorexia

Atheroembolic Disease:
Laboratory Features
• Serum chemistries
‣ ⇑BUN and creatinine
‣ ⇑Amylase
‣ ⇑CPK
‣ ⇑LFTs
• Hematology
‣ Leukocytosis
‣ Eosinophilia
‣ Anemia
‣ Thrombocytopenia
• Serologic
‣ ⇑ESR
‣ ⇓Serum complement
• Urine
‣ Eosinophiluria
‣ Proteinuria (may be in the
nephrotic range)
‣ Hematuria
‣ Pyuria

Atheroembolic Disease:
Avoid anticoagulation
Treatment
Avoid vascular interventions
ACE inhibitors / angiotensin receptor blockers
Statin therapy
Nutrition support
Dialysis for management of volume status and
uremia
Role of steroid therapy is uncertain

Prevention and Treatment of AKI
• Volume expansion
• Avoid hypotension
• Prevent sepsis
• Discontinue nephrotoxins
• Nutrition

Pharmacological Interventions in Acute Kidney Injury
Drug
Biological
rationale
Animal
experiments
Uncontrolled
human data
Small
RCT
Large
RCT
Loop diuretics Present Favorable Favorable Negative N/A
Low-dose dopamine Present Favorable Favorable Variable Negative
Mannitol Present Favorable Favorable N/A N/A
The only FDA
Ca antagonist Present Favorable Favorable Variable N/A
Theophylline Present Favorable Favorable Positive N/A
approved treatment for
Prostaglandins Present Favorable Favorable N/A N/A
established AKI
Natriuretic peptide Present Favorable Favorable Negative N/A
α-receptor antagonist Present N/A N/A Positive N/A
is dialysis
Endothelin antagonist Present Favorable N/A N/A N/A
Thromboxane antagonist Present Favorable N/A N/A N/A
Thyroxine Present Favorable N/A Negative N/A
Saline Present Favorable Favorable Positive N/A
NAC Present Favorable N/A Positive N/A
Non-ionic media Present Favorable Favorable Positive positive
C. Ronco and R.Bellomo Nephron Clinical Practice 93:C13, 2003

Diuretic Therapy in ATN
Mehta RL, et al. JAMA 2002; 288:2547-2553

Renal Replacement Therapy
in AKI
• Timing:
‣Medically intractable volume overload, acidemia,
hyperkalemia
‣Overt uremic manifestations
• Modality:
‣Continuous: CVVH, CVVHD, CVVHDF
‣Intermittent: IHD
‣Hybrids: SLED
• Dosing: Is more merrier

Current data do not suggest a benefit of
CRRT as compared with IHD with regard
to either survival or recovery of renal function.
There are no data comparing outcomes
with the "hybrid" modalities with
either CRRT or IHD. There is increasing
evidence that higher dosages of RRT in
AKI are associated with improved outcomes;
however, results have not been
consistent across all studies. Two large
multicenter, randomized trials to address
this issue are ongoing.

Dose of RRT in AKI:
The ATN Study
The RENAL Study
P=0.47
Palevsky PM, et al. N Engl J Med 2008; 359:7-20
Bellomo R, et al.
N Engl J Med 2009;361:1627-1638

The BEST Kidney (Beginning and Ending Supporting Therapy for
the Kidney) study
• The development of ARF in the ICU is a
relatively common occurrence
• Of those patients who develop ARF in the
ICU, the majority require renal
replacement therapy
• Chronic kidney disease is a major risk
factor for the development of ARF

The BEST Kidney (Beginning and Ending Supporting Therapy for
the Kidney) study
• Dependence on chronic dialysis is a common
outcome following ARF in the ICU
• CRRT is the most commonly applied renal
replacement modality for ARF in the ICU
• Despite significant improvements in both
dialysis technology and critical care medicine,
hospital mortality in this population remains
high.

Thank you for your attention
mfrubin@partners.org