Acute Renal Failure

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Acute Renal Failure

• Matthew L. Paden, MD
• Pediatric Critical Care
• Emory University
• Childrens Healthcare of Atlanta at Egleston

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Structure and Function of the Kidney

• Primary unit of the kidney is the nephron
• 1 million nephrons per kidney
• Composed of a glomerulus and a tubule
• Kidneys receive 20 of cardiac output

Renal Lecture Required Picture 1
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Renal blood flow

• Aorta ? Renal artery ? interlobar arteries ?
  interlobular arteries ? afferent arterioles ?
  glomerulus ? efferent arterioles
• In the cortex ? peritubular capillaries
• In the juxtamedullary region ?vasa recta
• Back to the heart through the interlobular ?
  intralobar ? renal veins

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Glomerular Filtration Rate

• Determined by the hydrostatic and oncotic
  pressure within the nephron
• Hydrostatic pressure in the glomerulus is higher
  than in the tubule, so you get a net outflow of
  filtrate into the tubule
• Oncotic pressure in the glomerulus is the result
  of non-filterable proteins
• Greater oncotic pressure as you progress through
  the glomerulus
• GFR Kf (hydrostatic oncotic pressure)

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Renal Lecture Required Picture 2
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Glomerular Filtration Rate

• The capillary endothelium is surrounded by a
  basement membrane and podocytes
• Foot processes of the podocytes form filtration
  slits that
• Allow for ultrafiltrate passage
• Limit filtration of large negatively charged
  particles
• Less than 5,000 daltons freely filtered
• Large particles (albumin 69,000 daltons) not
  filtered

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Tubular Function

• Proximal
• Most of reabsorption occurs here
• Fluid is isotonic with plasma
• 66-70 of sodium presented is reabsorbed
• Glucose and amino acids are completely reabsorbed

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Tubule Function

• Loop of Henle
• Urine concentration and dilution via changes in
  oncotic pressure in the vasa recta
• Descending tubule permeable to water,
  impermeable to sodium
• Ascending tubule actively reabsorbs sodium,
  impermeable to water

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Tubular Function

• Medullary thick ascending limb critical for
  urinary dilution and most often damaged in ARF
• ADH stimulates Na re-absorption in this area
• Most sensitive to ischemia
• Low oxygen tension, high oxygen consumption
• Lasix use here inhibits the Na-K-2Cl ATPase which
  in the face of ARF, may decrease oxygen
  consumption and ameliorate the severity of the ARF

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Tubular Function

• All of those studies done in an in vitro model
• In vivo, if you drop oxygen concentration even
  sub-atmospheric you do not get tubular damage
  even with increased tubular workload
• In vivo models exist where you do see that
  damage, but appears to need a second hit

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Tubule Function

• Distal Tubule
• Re-absorption of another 12 of NaCl
• Proximal segment impermeable to water
• Distal segment is the cortical collecting duct
  and secretes K and HCO3

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Tubular Function

• Collecting Duct
• Aldosterone acts here to increase Na reuptake and
  K wasting
• ADH enhances water re-absorption
• Urea re-absorption to maintain the medullary
  interstitial concentration gradient

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Acute Renal Failure - Definitions

• Renal failure is defined as the cessation of
  kidney function with or without changes in urine
  volume
• Anuria UOP lt 0.5 cc/kg/hour
• Oliguria UOP more than 1 cc/kg/hour
• Less than?

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Acute Renal Failure - Definitions

• 70 Non-oliguric , 30 Oliguric
• Non-oliguric associated with better prognosis and
  outcome
• Overall, the critical issue is maintenance of
  adequate urine output and prevention of further
  renal injury.
• Are we converting non-oliguric to oliguric with
  our hemofilters?

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Acute Renal Failure - Diagnosis

• Pre-renal
• Decrease in RBF ?constriction of afferent
  arteriole which serves to increase systemic blood
  pressure by reducing the shunt through the
  kidney, but does so at a cost of decreased RBF
• At the same time, efferent arteriole constricts
  to attempt to maintain GFR
• As GFR decreases, amount of filtrate decreases.
  Urea is reabsorbed in the distal tubule, leading
  to increased tubular urea concentration and thus
  greater re-absorption of urea into the blood.
• Creatinine cannot be reabsorbed, thus leading to
  a BUN/Cr ratio of gt 20

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Pre-Renal vs. Renal Failure
Prerenal Renal
BUN/Cr gt20 lt20
FENa lt1 gt2
Renal Failure Index lt1 gt1
UNa lt20 mEq/L gt40 mEq/L
Specific Gravity gt1.020 lt1.010
Uosm gt500 mOsm/L lt350 mOsm/L
Uosm/Posm gt1.3 lt1.3
Renal Lecture Required Picture 3
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Acute Renal Failure - Diagnosis

• Diagnosis
• Ultrasound
• Structural anomalies polycystic, obstruction,
  etc.
• ATN
• poor corticomedullary differentiation
• Increased Doppler resistive index
• (Systolic Peak Diastolic peak) / systolic peak
• Nuclear medicine scans
• DMSA Static - anatomy and scarring
• DTPA/MAG3 Dynamic renal function, urinary
  excretion, and upper tract outflow

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Acute Renal Failure

• Overall, renal vasoconstriction is the major
  cause of the problems in ARF
• Suggested ARF be replaced with vasomotor
  nephropathy
• Insult to tubular epithelium causes release of
  vasoactive agents which cause the constriction
• Angiotensin II, endothelin, NO, adenosine,
  prostaglandins, etc.

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Regulation of Renal Blood Flow

• In adults auto-regulated over a range of MAPs
  80-160
• Developmental changes
• Doubling of RBF in first 2 weeks of life
• Triples by 1 year
• Approaches adult levels by preschool
• Renal blood flow regulation is complex
• No one system accounts for everything..

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Renin-Angiotensin Axis

• For the one millionth time.
• Hypovolemia leads to decreased afferent
  arteriolar pressure which leads to decreased NaCl
  re-absorption which leads to decreased Cl
  presentation to the macula densa which increases
  the amount of renin secreted from the JGA which
  increases conversion angiotensinogen to AGI to
  AGII which increases Aldosterone secretion from
  the adrenal cortex and ADH which leads to
  increased sodium and thus water re-absorption
  from the tubule which increases your blood
  pressurewhew

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Renin Angiotensin Axis
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Renin Angiotensin Axis

• Renins role in pathogenesis of ARF
• Hyperplasia of JGA with increased renin granules
  seen in patients and experimental models of ARF
• Increased plasma renin activity in ARF patients
• Changing intra-renal renin content modifies
  degree of damage
• Feed animals high salt diet (suppress renin
  production) ? renal injury ? less renal injury
  than those fed a low sodium diet

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Renin Angiotensin Axis

• Not the only thing going on though
• You can also ameliorate renal injury by induction
  of solute diuresis with mannitol or loop
  diuretics (neither affect the RAS)
• No change in renal injury in animals given ACE
  inhibitors, competitive antagonist to angiotensin
  II
• Overall, role of RAS in ARF is uncertain

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Prostaglandins

• PGE 2 and PGI
• Very important for renal vasodilation, especially
  in the injured kidney
• Act as a buffer against uncontrolled A2 mediated
  constriction
• If you constrict the afferent arteriole, you will
  decrease GFR
• The RAS and Prostaglandin pathways account for
  60 of RBF auto-regulation

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Adenosine

• Potent renal vasoconstrictor
• Peripheral vasodilator
• Infusion of methylxanthines (adenosine receptor
  blockers) inhibits the decrease in GFR that is
  seen with tubular damage
• Some animal models show that infusion of
  methylxanthines lessen renal injury in ARF

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Adenosine

• But. Likely not a major factor in ARF
• Methylxanthines have lots of other actions
  besides adenosine blockade
• Adenosine is rapidly degraded after production
• Intra-renal adenosine levels diminish very
  rapidly after reperfusion, but the
  vasocontriction remains for a longer period
• Finally, if you block ADA, creating higher tissue
  adenosine levels, and then create ischemia ? you
  actually get an enhancement of renal recovery

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Endothelin

• 21 amino acid peptide that is one of the most
  potent vasoconstrictors in the body
• Can be used as a pressor
• Its role in unclear in normal state
• In ARF, overproduction by cells (both in and
  outside of the kidney) leads to decreased
  afferent flow and thus decreased RBF and GFR
• Endothelin increases mesangial cell contraction
  which reduces glomerular ultrafiltration
• Stimulates ANP release at low doses and can
  increase UOP
• Anti-endothelin antibodies or endothelin receptor
  antagonists decrease ARF in experimental models

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Nitric Oxide

• Produced by multiple iso-enzymes of NOS
• In addition to its role in vasodilation, likely
  has a role in sodium re-absorption
• Give a NOS blocker and you get naturesis
• Important in the overall homeostasis of RBF
• Exact mechanisms not worked out completelyat
  least when Rogers was written.

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Nitric Oxide

• Confusing results
• Ischemic rat kidney model inducing NOS causes
  increasing injury
• Hypoxic tubular cell culture model inducing NOS
  causes increasing injury
• But if you block NOS production, you get
  worsening of renal function and severe
  vasoconstriction

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Nitric Oxide

• So stimulation of NO in the renal vasculature
  will modulate vasoconstriction and lead to lesser
  injurybut
• That same induction of NO in the tubular cells
  will cause increased cytotoxic effects

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Dopamine

• Dopamine receptors in the afferent arteriole
• Dilation of renal vasculature at low doses,
  constriction at higher doses
• Also causes naturesis (? Reason for increased UOP
  after starting)
• Renal dose dopamine controversy.

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Renal Hemodynamics and ARF

• Conclusions.
• Renal vasoconstriction is a well documented cause
  of ARF
• Renal vasodilation does not consistently reduce
  ARF once established
• Although renal hemodynamic factors play a large
  role in initiating ARF, they are not the dominant
  determinants of cell damage

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ARF - Pathophysiology

• Damage is caused mostly by renal perfusion
  problems and tubular dysfunction
• Usual causes
• Hypo-perfusion and ischemia
• Toxin mediated
• Inflammation

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ARF Pathophysiology

• Hypo-perfusion
• Well perfused kidney 90 of blood to cortex
• Ischemia increased blood flow to medulla
• Outcome may be able to be influenced by
  restoration of energy/supply demands
• Lasix example
• Leads to tubular damage

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ARF - Pathophysiology

• Oxidative damage
• Especially during reperfusion injuries
• Main players
• Super-oxide anion, hydroxyl radical highly
  ionizing
• Hydrogen peroxide, hypochlorous acid not as
  reactive, but because of that have a longer half
  life and can travel farther and cause injury
  distal to the site of production

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ARF - Pathophysiology

• Ischemia
• Damage to mitochondrial membrane and change of
  xanthine dehydrogenase (NAD carrier) to xanthine
  oxidase (produces O2 radicals)
• Profound utilization of ATP ? 5-10 minutes of
  ischemia you use 90 of your ATP
• Make lots of adenosine, inosine, hypoxanthine

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ARF - Pathophysiology

• Once you get reperfusion, the hypoxanthine gets
  metabolized to xanthine and uric acid each
  creating one H2O2 and one super-oxide radical
  intermediate
• Reactive oxygen species oxidize cellular proteins
  resulting in
• Change in function/inactivation/activation
• Loss of structural integrity
• Lipid peroxidation (leads to more radical
  formation)
• Direct DNA damage

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ARF Pathophysiology

• Amount of damage depends on ability to replete
  ATP stores
• Continued low ATP leads to disruption of cell
  cytoskeleton, increased intracellular Ca,
  activation of phospholipases and subsequently the
  apoptotic pathways

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ARF Pathophysiology

• Amount of damage depends on ability to replete
  ATP stores
• Continued low ATP leads to disruption of cell
  cytoskeleton, increased intracellular Ca,
  activation of phospholipases and subsequently the
  apoptotic pathways
• This endothelial cell injury sparks an immune
  response.that cant be good.

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ARF - Prevention

• Maintenance of blood flow
• Cardiac output, isovolemia, etc
• Avoidance of toxins
• Aminoglycosides, amphoteracin, NSAIDs
• Easy on paper.difficult in practice

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ARF - Prevention

• Lasix
• May have uses early in ARF
• Mannitol
• May work by
• Increasing flow through tubules, preventing
  obstruction
• Osmotic action, decreasing endothelial swelling
• Decreased blood viscosity with increased renal
  perfusion (???)
• Free radical scavenging

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ARF - Prevention

• Renal dose dopamine.
• Endothelin antibodies
• No human trials
• Thyroxine
• More rapid improvement of renal function in
  animals
• Increased uptake of ADP to form ATP or cell
  membrane stabilization as a possible cause

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ARF - Prevention

• ANP
• Improve renal function and decrease renal
  insufficiency
• ? Nesiritide role
• Theophyline
• Adenosine antagonist prevents reduction in GFR.
• Growth Factors
• After ischemic insult, infusion of IGF-I,
  Epidermal GF, Hepatocyte GF improved GFR,
  diminished morphologic injury, diminished
  mortality
• None of these things are well tested..

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ARF Prevention in Specific Cases

• Hemoglobinuria/Myoglobinuria
• Mechanism of toxicity
• Disassociation to ferrihemate, a tubular toxin,
  in acidic urine
• Tubular obstruction
• Inhibition of glomerular flow by PGE inhibition
  or increased renin activation
• Treatments (?)
• Aggressive hydration to increase UOP
• Alkalinization of urine
• Mannitol/Furosemide to increase UOP
• ?Early Hemofiltration

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ARF Prevention in Specific Cases

• Uric Acid Nephropathy
• A thing of the past thanks to Rasburicase?
• Treatments
• Aggressive hydration to drive UOP
• Alkalinization of the urine
• Xanthine oxidase inhibitors

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ARF - Management

• Electrolyte management
• Sodium
• Hyponatremia fluid restriction first, 3 NaCl
  if AMS or seizing
• Potassium
• Calcium/Bicarb/Glucose/Insulin/Kayexalate
• Hemodialysis

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ARF - Management

• Nutrition management
• Initially very catabolic
• Goals
• Adequate calories
• Low protein
• Low K and Phos
• Decreased fluid intake

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Renal Replacement Therapy

• Peritoneal Dialysis
• Acute Intermittent Hemodialysis
• Continuous Hemofiltration
• CAVH
• SCUF
• CVVH, CVVHD
• And others.

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Peritoneal dialysis
Advantages
Disadvantages

• Simple to set up perform
• Easy to use in infants
• Hemodynamic stability
• No anti-coagulation
• Bedside peritoneal access
• Treat severe hypothermia or hyperthermia

• Unreliable ultrafiltration
• Slow fluid solute removal
• Drainage failure leakage
• Catheter obstruction
• Respiratory compromise
• Hyperglycemia
• Peritonitis
• Not good for hyperammonemia or intoxication with
  dialyzable poisons

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Intermittent Hemodialysis
Advantages
Disadvantages

• Maximum solute clearance of 3 modalities
• Best therapy for severe hyperkalemia
• Limited anti-coagulation time
• Bedside vascular access can be used

• Hemodynamic instability
• Hypoxemia
• Rapid fluid and electrolyte shifts
• Complex equipment
• Specialized personnel
• Difficult in small infants

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Continuous Hemofiltration
Advantages
Disadvantages

• Easy to use in PICU
• Rapid electrolyte correction
• Excellent solute clearances
• Rapid acid/base correction
• Controllable fluid balance
• Tolerated by unstable pts.
• Early use of TPN
• Bedside vascular access routine

• Systemic anticoagulation (except citrate)
• Frequent filter clotting
• Vascular access in infants

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Indications for RRT

• Still evolving.Generally accepted
• Oliguria/Anuria
• Hyperammonemia
• Hyperkalemia
• Severe acidemia
• Severe azotemia
• Pulmonary Edema
• Uremic complications
• Severe electrolyte abnormalities
• Drug overdose with a filterable toxin
• Anasarca
• Rhabdomyolysis