Acute Kidney Injury

Mohammad Rudiansyah

Division of Nephrology and Hypertension - Department of Internal Medicine

Medical Faculty of Lambung Mangkurat University – Ulin Hospital
 OBJECTIVES
1. Definition and Classification of AKI

2. Epidemiology of AKI

3. Etiology of AKI

4. Pathophysiology of AKI

5. Biomarker of AKI

6. Management of AKI
Definitions and
Classification
 Definitions

Acute Renal Failure

Acute Kidney Injury

 Definition

Rapid (hours to weeks) decline in GFR and retention
of waste products.

Lack a uniform definition  Classic laboratory
definition

↑ of creatinine of >0.5 mg/dl in <72hrs

↑ in more than 50% over baseline Cr.

↓ in calculated Cr Cl by more than 50%.

Any ↓ in renal function that requires dialysis

Cr > 1.5 x, urine output <0.5ml/kg/hr

Cr ↑ ≥ 1.0 mg/dl/2d
 Definitions

“ More than 35 different definitions of
ARF”. Mehta R, et al. Acute Renal Failure Definitions and
Classification: Time for Change? J Am Soc Nephrol 2003, 14:2178-
2187.

“ There are 58 definition of ARF based on

serum creatinine and 33 criteria based on
urine output”. Ricci et al: The RIFLE criteria and mortality in
acute kidney injury: A systematic review. Kidney International (2008)
73, 538–546
 Alternative ARF definitions
from several published studies
Issues in Design of Clinical Trials
in ARF

Heterogeneity of patient population

Effect of co-morbidty and illness on
outcome

Large variations in clinical practice

Lack of a standardized definition of ARF

Metha et al, J Am Soc Nephrol 2002

 Diagnosis of AKI is
Often Delayed

Elevation in serum creatinine is the current gold

standard, but this is problematic

Normal serum creatinine varies widely with age,
gender, diet, muscle mass, muscle metabolism,
medications, hydration status

In AKI, serum creatinine can take several days
to reach a new steady state
 Factors that affect serum creatinine concentration
Factor Effect on Mechanism
serum
creatinine
Kidney Increase Decreased GFR (increase is blunted by increased
Disease tubular secretion of creatinine and by reduced
creatinine generation)

Reduced Decrease Reduced creatinine generation (common in children,

muscle mass women, and older and malnourished patients)

Ingestion of Increase Transient increase in creatinine generation (increase

cooked meat may be blunted by transient increase in GFR)

Cimetidine, Increase Inhibition of tubular creatinine secretion

trimethoprim

Ketoacidosis Increase Positive interference with picric acid assay for

creatinine
 Definition
Risk, Injury, Failure, Loss, & End-stage Kidney (RIFLE)
classification
Class Glomerular filtration rate criteria Urine output criteria

Risk Serum creatinine × 1.5 or GFR decrease > 25% < 0.5 ml/kg/hr × 6 hrs

Injury Serum creatinine × 2 or GFR decrease > 50% < 0.5 ml/kg/hr × 12 hrs
Serum creatinine × 3, or serum creatinine ≥ 4 < 0.3 ml/kg/hr × 24 hrs,
Failure mg/dl with an acute rise > 0.5 mg/dl or anuria × 12 hrs
Loss Persistent ARF = complete loss of kidney function > 4 weeks

ESKD End-stage kidney disease > 3 months

• ADQI (the acute dialysis quality initiative)  RIFLE system  classifies ARF into:
- 3 categories according to severity and
- 2 categories according to clinical outcomes
• The RIFLE classification is a very sensitive definition of AKI.
 Proposed Diagnostic Criteria for AKI

Diagnostic criteria for acute kidney injury

“ An abrupt (within 48 hours) reduction in kidney function
currently defined as an absolute increase in serum
creatinine of more than or equal to 0.3 mg/dl (>26.4
umol/L), a percentage increase in serum creatinine of
more than or equal to 50% (1.5-fold from baseline), or
reduction in urine output (documented oliguria of less
than 0.5 ml/kg per hour for more than six hours”.

Mehta et al. Crit Care, 2007; 11(2):R31

Epidemiology
 AKI: A Common, Serious Problem

AKI is present in 5% of all hospitalized patients,

and up to 50% of patients in ICUs

The incidence is increasing - globally

Mortality rate 50 - 80% in dialyzed ICU patients–
4 Million die each year of AKI

AKI requiring dialysis is one of the most
important independent predictors of death in
ICU patients

25% of ICU dialysis survivors progress to ESRD
within 3 years
Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243–248.
Brivet FG, Kleinknecht DJ, Loirat P, et al. Acute renal failure in intensive care units — causes, outcomes and prognostic factors of hospital
mortality: a prospective multicenter study. Crit Care Med 1996;24:192–198.
Etiology or Common
Causes of AKI
Etiology/Risk factors
General risk factors

Thadhani R, Pascual M, Bonventre JV. Acute renal failure. NEngl J Med 1996;334:1448–1460.
 Principle causes of AKI
Pre-renal Renal Post-renal

Cause: Hypovolemia Nephritic syndrome Nephrotic syndrome Cause: Obstruction

• Sepsis • Azotemia • Massive proteinuria • BPH
• Shock • Hematuria • Severe edema • Cancer
• Heart Failure • Red cell cast • Hyperlipidemia • Stone
• hypertension • Hyperchlesterolemia
• Mild edema • No hematuria, azotemia
• Mild proteinuria or HTN at onset

MPGN MCD
Acute GN 5%

PIGN MGN • Interstitial nephritis 10%
RPGN FSGS • Tubular necrosis 85%
IgA nephropathy DN (Toxin 35%, Ischemia 50%)
Alport syndrome SLE
Amyloidosis

BUN < 20 May present as polyuria

BUN > 20 Urine is dilute
Urine is concentrated w/ high urine [Na+] &
Urine [Na +] high (> 20 mEq/L) Unconcentrated urine
Urine [Na +] low (< 10 mEq/L) ↑ FENa+
↓ FENa+ Cells/casts  tubular injury
Pathophysiology
 Renal blood supply

the kidneys receive 20-25% of the cardiac output

vascular supply:

renal arteries

interlobar arteries

arcuate arteries

interlobular arteries

afferent arterioles

glomerular capillaries

efferent arterioles

peritubular capillaries
 2 3
4

1 7

8

Cortical
cortex nephrons have
short loops with
abundant
peritubular
capillaries.
medulla
Juxtamedullary
nephrons have
long loops and
the vasa recta
 Blood oxygen pressure and blood supply in the kidney
Medullary ray
Collecting duct
Venous drainage with nephrons
Arterial and
capillary blood
supply
Cortex

Adapted from:
Brezis M et al: Outer
"The Kidney", Stripe

Medulla
Outer
4th Ed.
(Brenner & Rector)
Saunders, 993-1061, Inner
Stripe
1991

O2 consumption
in different organs
O2 consumption/
O2 delivery (%)
Kidney 08% Inner
Medulla
Renal outer medulla 79%
Brain 34%
 Pathophysiology of prerenal AKI
Hypovolemia
RAA-axis
RBF maintained initially
through:
-Local myenteric reflex
-PG synthesis
-Actions of Ag II
Homeostatic goal:
Restore intravascular volume
and blood pressure to maintain
perfusion of essential organs
Decreased cardiac output
Systemic vasodilatation
Baroreceptor activation
Neurohormonal responses
Vasopressin Sympathetic
nervous system
Vasoconstriction
Mesangial cell contraction
Avid salt and water reabsorption
Reducing sweating
Thirst and salt appetite
Prerenal AKI
Dramatic reduction in renal Dramatic reduction in
Blood flow, glomerular filtration, splanchnic, skin, and
urine flow muskuloskeletal blood flow
 Glomerular Hypoperfusion

↓ ECF volume

↓ Effective volume
(CHF, sepsis, cirrhosis)

Glomerular Hemodynamic: Contrast

Vasoconstriction (pre glomerular) CSA
Ampho

NSAID/ COX-2 inhibitor

Contrast

Amphotericin B NSAID ACE-I
ARB

Cyclosporine/ tacrolimus

Hypercalcemia

Efferent vasodilatation

ACE inhibitors/ ARBs
Intrarenal mechanisms for autoregulation of GFR
 Pathophysiology of Acute Tubule Necrosis
Acute renal tubular cell injury

Tubular Intrarenal Endothelial

cell injury inflammation cell injury

Persistent medullary Vasoconstriction and

hypoxia vascular congestion

Reduced glomerular
Backleak Capillary pressure
Obstruction
and plasma flow

Severe reduction in GFR

Brener & Rector; saunders. The Kindey 4th Ed
Inflammation in AKI

Thadhani R, Pascual M, Bonventre JV. Acute renal failure. NEngl J Med 1996;334:1448–1460.
Contribution of ‘back-Leakage’ of glomerular filtrate
and intratubule obstruction to Renal Failure in ATN

Brener & Rector; saunders. The Kindey 4th Ed

 SEPSIS

PERIPHERAL VASODILATION OTHER RENAL INSULTS:

VSM relaxation due to: Nephrotoxic antibiotics
Increased NO release Rhabdomyolysis
Activation of K-ATP channels Radiocontrast
Jaundice
INTRARENAL CONSTRICTION
Increased endothelial
Endothelin MICROVASCULAR INJURY
Thromboxane Congestion
Leukotrienes Inflammation
Thrombosis

ISCHEMIC RENAL INJURY CYTOTOXIC RENAL INJURY

ACUTE TUBULE NECROSIS

Brener & Rector; saunders. The Kindey 4th Ed
 Biomarkers for Early
Prediction of Acute Kidney
Injury
Biomarkers

Late detections
 Potential Roles of Biomarkers in AKI

Early
Detection Prognosis
Differential
• Severity of AKI
Defined Timing & Diagnosis
Single Insult • Need for RRT
• CPB • Location
• Contrast (proximal vs distal tubule) • Duration of AKI
• DGF • Etiology • Response to
• Trauma (toxin, ischemia, sepsis) Treatment
• Chemotherapy
• ATN vs Pre-renal • Length of stay

Underfined Timing & • Acute vs Chronic • Mortality

Multiple Insults
• Sepsis
• ARDS
• Critical Illness

Parikh CR. AKI: better biomarkers and beyond. Kidney I 2008; 73:801-803
 Scenario to decrease mortality with early diagnosis

Current Clinical Scenario WITH Early Biomarkers

SEPSIS SEPSIS

CPB CPB

Normal Elevated Early

Creatinine Creatinine Detection
TRAUMA TRAUMA

Acute Kidney Acute

Kidney Kidney
Kidney CONTRAST Insult
CONTRAST Insult Injury MORTALITY Injury

MORTALITY
ARDS Failed ARDS
Intervention
Opportunity
Early for Early
TOXINS TOXINS Detection
Intervention

Scenario A Scenario B

Parikh CR. AKI: better biomarkers and beyond. Kidney I 2008; 73:801-803
 Potential Biomarkers in AKI
(Human Data)

Early
Detection Prognosis

Cystatin C
Differential IL – 18
IL – 18 Diagnosis
CPB (1) ICU (9) (+) Mortality in ARDS (3)
DSF (2) Duration of AKI (1)
ICU (10) (-)
ARDS (3)
IL – 18
ATN vs other (13) Cystatin C
NGAL Tubular Need for RRT (16)
CPB (4.5) Enzymes
PCI (6) ICU (11) KIM – 1
DSF (7) ATN vs other (14) NGAL
D+HUS (8) Duration of AKI (1)
KIM - 1 Na+ / H+
DSF (12)
Exchanger
ATN vs other (15)

Parikh CR. AKI: better biomarkers and beyond. Kidney I 2008; 73:801-803
 Promising Biomarkers for AKI
Marker Sample Timing Commercial test?
NGAL Plasma Early Biosite

Cystatin C Plasma Intermediate Dade- Behring

NGAL Urine Early Abott

IL-18 Urine Intermediate None

KIM-1 Urine Intermediate None

Nguyen and Devarajan, Pediatric Nephrol, 2007
Management
 Management Principles

Determine exact diagnosis

Remove offending agent/Treat causes

Prevent complications (i.e. hyperkalemia)

Reverse oliguria/Improve renal blood flow (correction of
intravascular volume)

Careful volume and electrolyte management

Remove nephrotoxins, dose-adjust medications

Provide nutrition (low K, low P)
 Prevention
Prevention in high risk people
Beneficial
• Low osmolality contrast media
Likely to be beneficial
• Fluids • Lipid formulations of amphotericin B • N-Acetylcysteine
• Non-ionic iso-osmolar contrast media • Single dose aminoglycosides
Unknown effectiveness
• Sodium bicarbonate based fluids
Unlikely to be beneficial
• Fenoldopam • Mannitol • Prophylactic RRT
• Theophylline/aminophylline
Likely to be ineffective or harmful
• CCBs • Dopamine • Loop diuretics • Natriuretic peptides
 Etiology Treatment

Correct postrenal factor

Correct prerenal factor

Treat underlying sepsis

Stop nephrotoxic drugs
 Volume Control

Must know patient’s fluid status

pre-renal azotemia: fluids can improve condition

ATN: fluids can be harmful, causing fluid-
overload

Must monitor fluid balance carefully

avoids fluid overload

assess efficacy of diuretic therapy

Maintain euvolemia, tissue perfusion,
electrolyte balance
 Volume Control

Crystalloids

use in hypovolemia (shock, dehydration)

0.9% NaCl, 0.45%NaCl/D5W\

500-1000 mL of normal saline (NS) over 30
minutes

check BP, HR, UOP after administration

Colloids

use in hypovolemia due to hemorrhage

blood, albumin
 Hypotonic infusion

• 1 L D5%

Increase ICF > ECF Replace Normal

increases ICF > ECF loss (IWL + urine)

ICF ISF Plasma

660 ml 220 ml 110 ml

 Isotonic infusion
• Ringer’s acetate
• Ringer’s lactate
• Normal saline

Replace acute/
increases ECF abnormal loss

ICF ISF Plasma

660 ml 340 ml
 Plasma Expander

500 mL:
• Dextran 40
• HES

750 ml in 1 h
Expand intravascular volume 1050 ml in 2 h

ICF ISF Plasma

Evaluation of intravascular volume
 Guide of Volume Expansion

CVP 8-14 cm H2O

PCWP 12-16 mmHg

Urine output 0.5-1.0ml/kg/hour

Weighing the patient daily

Insensible water loss from the skin and
respiratory tract (500 ml/day)
 Controversial Issues (or not)

There is little evidence that low-dose dopamine is
of benefit in prevention or treatment of ARF

Loop diuretics do not improve outcome in ARF.

May contribute to increased mortality if delays
RRT

Timing of RRT initiation

Early (BUN < 60 – 100) vs late (BUN > 100)
 Diuretics

For use in patients with adequate intravascular
volume

maintain hydration, then start diuretic therapy

Help kidneys to start working again

increase tubular flow, preventing obstruction

Loop diuretics increase RBF

Mannitol reduces cell swelling

Main goal is to maintain UOP
 Diuretics

Loop diuretics

furosemide most commonly used

initial dose: 40-
40-80mg IV bolus

can double dose if no response in few
hours

max dose: ~2000mg/day

continuous infusion:

start 40-
40-80mg IV bolus, then start 10mg
10mg--
20mg/hr and titrate up
 Use of diuretics in acute renal failure

The literature on the use of diuretics in acute renal

failure is conflicting.

One large cohort study demonstrated an association with
the use of diuretics in ARF and mortality

A second larger cohort study did not demonstrate a
significant association between the use of diuretics and
the development of ARF

No suggestion can be made for or against the use of
diuretics in ARF

LEVEL 2C SUGGESTION that the effect of diuretics
on mortality in acute renal failure is unclear.
 Dopamine

Low doses (0.5-2ug/kg/min) can
selectively dilate renal blood vessels

increase RBF, GFR, and UOP

Side Effects:

vasoconstriction at higher doses,
tachycardia, angina

MP:

UOP, BP, COP
 Meta-analysis of low dose dopamine on mortality

Cardiac surgery

Vascular surgery

Other surgery

IV contrast media

Neonates

Miscellaneous

Friedrich et al, Ann Int Med 2005,

142:510-524
 Conservative Measurement
Prevent further ischemic toxic injury

Fluid balance

Careful monitoring of I/O and body weight

Fluid restriction

(usually less than 1 L/day in oliguric ARF)

Total intake < urine output + extrarenal losses

Electrolytes and acid -base balance

hyperkalemia

hyponatremia

Keep serum bicarbonate >15

hyperphosphatemia

Treat hypocalcemia only if symptomatic
 Conservative Measurement

Uremia-nutrition

Restriction protein but maintain caloric
intake

Drug

Review all medication, Stop magnesium-
containing medication

Adjusted dosage for renal failure, Readjust
with improvement of GFR
 Nutrition Implications of ARF

ARF causes anorexia, nausea, vomiting, bleeding

ARF causes rapid nitrogen loss and LBM loss
(hypercatabolism)

ARF causes ↑ gluconeogenesis with insulin
resistance

Dialysis causes loss of AAs and protein

Uremia toxins cause impaired glucose utilization
and protein synthesis
 Nutrient Requirements in ARF

Calories: 25-45 kcals/kg dry weight or REE

Protein: about 10-16 g amino acids lost per day with CRRT

ARF w/o HD (expected to resolve within a few days): 0.6-1
g prot/kg

Acute HD: 1.2-1.4 g/kg; acute PD: 1.2-1.5 g/kg; CRRT:
1.5-2.5 g/kg

CHO: ~60% total calories; limit to 5 mg/kg/min; peripheral
insulin resistance may limit CHO

In CWHD(F) watch for CHO in dialysate or replacement
fluids

Fat: 20-35% of total calories; lipid clearance may be impaired
 Vitamins in ARF

Vitamin A: elevated vitamin A levels are known to
occur with RF

Vitamin B – prevent B6 deficiency by giving 10 mg
pyridoxine hydrochloride/day

Folate and B6: supplement when homocysteine
levels are high

Vitamin C: <200 mg/day to prevent ↑ oxalate

Activated vitamin D

Vitamin K: give Vitamin K especially to pts on
antibiotics that suppress gut production of K
 Minerals in RF

Potassium intake – 40 mEq/d, Phosphorus intake –
800 mg/d

↑ potassium, magnesium, and phos occur often due
to ↓ renal clearance and ↑ protein catabolism

CRRT pts can have ↓ K+, phos

Mg deficiency can cause K+ deficiency resistant to
supplementation

Vitamin C, copper, chromium lost with CVVH
Dialysis
 Dialysis

20% - 60% of ARF

Types:

HD

PD

RRT
 Renal Replacement Therapy

Intermittent hemodialysis (IHD)

Continuous veno-venous hemofiltration
(CVVH)

CVV hemodialysis (CVVHD)

CVV hemodiafiltration (CVVHDF)

Slow low efficiency dialysis (SLED)

Peritoneal dialysis (PD)

Slow continuous ultrafiltration (SCUF)
 Indications for RRT in critically ill ARF patients

Renal Replacement Renal Support

Life-threatening indications
Nutrition

Hyperkalemia
Fluid removal in CHF
Acidemia
Cytokine manipulation in sepsis
Pulmonary edema
Cancer chemotherapy

Uremic complications
Treatment of respiratory acidosis

Solute control of ARDS

Fluid removal
Fluid management in multiorgan

Regulation of acid-base and failure
electrolyte status
Proposed Criteria for the Initiation of RRT in
Critically ill Patients

Oliguria (urine output<200 ml/12 hr)

Anuria/extreme oliguria (urine output<50 ml/12 hr)
Hyperkalemia ([K+]>6.5 mmol/liter)
Severe acidemia (pH<7.1)
Azotemia ([urea]>30 mmol/liter)
Clinically significant organ (especially lung) edema
Uremic encephalopathy
Uremic pericarditis
Uremic neuropathy/myopathy
Severe dysnatremia ([Na]>160 or<115 mmol/liter)
Hyperthermia
Drug overdose with dialyzable toxin
( KI 1998, R. Belloma and C. Ronco)
 CRRT

Blood filtered continuously by semi-permeable

membrane

AV: uses patient’s own BP

VV: pump-driven

Lower extracorporeal blood volume (compared to
HD) so better tolerated by hemodynamically
unstable patients

Types: hemofiltration (AVH, CAVH, SCUF),
continuous hemodialysis (CAVHD, CVVHD) and
continuous hemodiafiltration (CAVHDF or CVVHDF)
HD HF

HDF HFD
IHD in ARF and critically ill patients
 IHD vs. CRRT

Randomized trial, observational studies unclear
and limited because of patient populations and
significant cross-over to CRRT.

Meta-analysis unclear because of limitation of
original studies.

LEVEL 2B SUGGESTION of no difference
between the use of IHD vs. CRRT as therapy for
ARF (unclear)
Complications &
prognosis
 Complications

Cardiopulmonary complication

Metabolic complication

Gastrointestinal complication

Neurogenic complication

Hematological complication

Infection
 Prognosis of acute renal failure

Patient Need for

Study object Mortality
number dialysis
Patient with isolated
1347 < 15%
ARF
Patient with ARF who 36%
need dialysis
Patient with ARF in
> 700 72% v 32% 71% v 18%
ICU v non-ICU
Patient associated
with ARF
> 17000 4X 62.8% v 38.5%

Turney JH, Marshall DH, Brownjohn AM, et al. The evolution of acute renal failure, 1956–1988. Q J Med 1990;74:83–104.
Acute renal failure is independently responsible for increased
Liano F, Junco E, Pascual J, et al. The spectrum of acute renal failure in the intensive care unit compared to that seen in other settings.
The Madrid Acute Renal Failure Study Group. Kidney Int Suppl 1998;53:16–24.
mortality, even if dialysis is used.
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.

The exact mechanism that leads to increased risk of death is

uncertain.
Natural History of AKI
 Conclusions

The causes of ARF are classified as pre, intrinsic, and post-
renal

ARF is a life-threatening condition

Many cases can be avoided

Early diagnosis and expert treatment is associated with a
better outcome

Preventive and therapeutic measures are often delayed due
to lack of early biomarkers

ARF requiring specific treatment, especially urinary tract
obstruction and RPGN must not be missed

Urgent treatment is needed for life-threatening
complications