Acute renal failure

1. Acute Renal Failure
Matthew L. Paden, MD
Pediatric Critical Care
Emory University
Children’s 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 < 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 > 20

16. Pre-Renal vs. Renal Failure
Prerenal Renal
BUN/Cr >20 <20
FENa <1% >2%
Renal Failure Index <1% >1%
UNa <20 mEq/L >40 mEq/L
Specific Gravity >1.020 <1.010
Uosm >500 mOsm/L <350 mOsm/L
Uosm/Posm >1.3 <1.3
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
MAP’s 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 pressure……whew…

21. Renin Angiotensin Axis
Renal Lecture Required
Picture #4

22. Renin Angiotensin Axis
 Renin’s 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
completely…at 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 injury…but…
 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. ATP
ADP
AMP
Adenylosuccinate Adenosine
Inosine
IMP Hypoxanthine
Xanthine
Uric Acid
Allantoin
H20 ∙ O2
H20 ∙ O2
H20 ∙ O2
H2O2
H2O2
CO2

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 can’t be good….

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
 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
Advantages Disadvantages

54. Intermittent Hemodialysis
 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
Advantages Disadvantages

55. Continuous Hemofiltration
 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
Advantages Disadvantages

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