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Acute Renal Failure

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Acute Renal Failure Matthew L. Paden, MD Pediatric Critical Care Emory University Children s Healthcare of Atlanta at Egleston Structure and Function of the Kidney ... – PowerPoint PPT presentation

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Title: Acute Renal Failure


1
Acute Renal Failure
  • Matthew L. Paden, MD
  • Pediatric Critical Care
  • Emory University
  • Childrens Healthcare of Atlanta at Egleston

2
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
3
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

4
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)

5
Renal Lecture Required Picture 2
6
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

7
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

8
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

9
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

10
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

11
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

12
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

13
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?

14
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?

15
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

16
Pre-Renal vs. Renal Failure
Renal Lecture Required Picture 3
17
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

18
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.

19
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..

20
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

21
Renin Angiotensin Axis
Renal Lecture Required Picture 4
22
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

23
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

24
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

25
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

26
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

27
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

28
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.

29
Obligatory Incomprehensible Pathway for Jim 1
30
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

31
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

32
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.

33
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

34
ARF - Pathophysiology
  • Damage is caused mostly by renal perfusion
    problems and tubular dysfunction
  • Usual causes
  • Hypo-perfusion and ischemia
  • Toxin mediated
  • Inflammation

35
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

36
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

37
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

38
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39
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

40
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

41
Obligatory Incomprehensible Pathway for Jim 2
42
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.

43
(No Transcript)
44
ARF - Prevention
  • Maintenance of blood flow
  • Cardiac output, isovolemia, etc
  • Avoidance of toxins
  • Aminoglycosides, amphoteracin, NSAIDs
  • Easy on paper.difficult in practice

45
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

46
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

47
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..

48
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

49
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

50
ARF - Management
  • Electrolyte management
  • Sodium
  • Hyponatremia fluid restriction first, 3 NaCl
    if AMS or seizing
  • Potassium
  • Calcium/Bicarb/Glucose/Insulin/Kayexalate
  • Hemodialysis

51
ARF - Management
  • Nutrition management
  • Initially very catabolic
  • Goals
  • Adequate calories
  • Low protein
  • Low K and Phos
  • Decreased fluid intake

52
Renal Replacement Therapy
  • Peritoneal Dialysis
  • Acute Intermittent Hemodialysis
  • Continuous Hemofiltration
  • CAVH
  • SCUF
  • CVVH, CVVHD
  • And others.

53
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

54
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

55
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

56
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
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