This document discusses acute kidney injury (AKI) in intensive care unit patients. It provides definitions and criteria for AKI, including RIFLE and AKIN classifications. Mortality rates increase significantly with more severe AKI, from 5-10% with no renal dysfunction to 26-40% with renal failure. While decreased urine output can indicate decreased kidney function, urine output alone is a less severe marker. Multiple factors influence the relationship between renal blood flow, perfusion pressure, and glomerular filtration rate. Early markers like neutrophil gelatinase-associated lipocalin and cystatin C may help predict AKI and prognosis better than creatinine. Fluid management must balance resuscitation with avoiding overload,

1. Acute kidney Injury in ICU
Gagan Kumar MD
Fellow
Pulmonary & Critical Care

2. Why should we be concerned?
• Increased risk of death
• Marker of severity

3. Outcomes in AKI
• BEST study* (Beginning and Ending Supportive
Therapy for the Kidney)
– The prevalence of AKI requiring renal replacement therapy
(RRT) ~ 4%
– 28 days in-hospital mortality in patients with AKI was ~
60%
• RIFLE criteria
– In-hospital mortality with AKI is in the range of
•
•
•
•
5 to 10% with no renal dysfunction
9 to 27% in patients classified as at risk
11 to 30% with injury
26 to 40% with failure
*Clin J Am Soc Nephrol. 2007 May;2(3):431-9. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes.

4. Definitions – RIFLE criteria

5. AKIN criteria
1. Increase the sensitivity of the RIFLE criteria by
recommending that a smaller change in serum
creatinine (≥26.2 µmol/L) be used as a threshold to
define the presence of AKI and identify patients with
Stage 1 AKI (analogous to RIFLE-Risk)
2. A time constraint of 48 h for the diagnosis of AKI was
proposed.
3. Any patients receiving renal replacement therapy
(RRT) were to now be classified as Stage 3 AKI (RIFLEFailure)
Bagshaw SM, George C, Bellomo R; ANZICS Database Management Committe. A comparison of
the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial
Transplant. 2008 May;23(5):1569-74. Epub 2008 Feb 15.

6. Is ↓UO= renal failure?
• Does ↓UO = ↓GFR?
• May be physiological to preserve body volume
or electrolyte homeostasis.
• Severe tubular dysfunction can lead to
increased urine output despite low GFR.
• Bottom line: urine output alone is less severe
marker if used alone.

7. Normal GFR
GFR = Kf[(PGC-PBS) –(ΠGC-ΠPB)]
Kf = filtration coefficient
ΠPB = zero, since no protein
A higher renal plasma flow will induce a
reduction in filtration fraction (i.e., ratio
of ultrafiltration to renal plasma flow)
with a lesser increase of capillary plasma
protein concentration along the
glomerular capillaries.
When the renal plasma flow is reduced,
the glomerular filtration rate decreases
but with an increase in the filtration
fraction

8. What if renal blood flow increases?

9. What if renal perfusion pressure increases?
• the ultrafiltrate will be
mainly generated on the first
portion of the afferent side
of the capillary network and
to cease when hydraulic and
oncotic pressures become
equal along the glomerular
capillary network
• Therefore the oncotic
pressure becomes the
limiting factor of glomerular
filtration

10. Clinical implication
• When you resuscitate patient with crystalloids
 you are diluting the serum proteins thereby
decreasing the plasma oncotic pressure.
• Hence the urine response you may be seeing
is simply due to decreased oncotic pressure !!!

11. What if renal perfusion pressure
decreases?

12. What happens in chronic kidney
disease?
• Decreased glomerular surface area
• Glomerular hydraulic pressure becomes major
determinant of GFR.

13. Relation between renal blood flow and
GFR
• the renal blood flow is autoregulated, which
means that it remains unchanged when
arterial blood pressure varies
• Mediated by
– Myogenic mechanism: FAST
– Tubuloglomerular feedback: SLOW

14. How long can kidneys suffer low
perfusion?
• Interruption of blood flow x >30min followed
by reperfusion  tubular and microvascular
damage
• But this scenario is not what we encounter.
• This is seen in supra renal aortic surgery
where aorta has to be clamped for some time!

15. How long can kidneys suffer low
perfusion?
• Prolonged period of renal hypo-perfusion
does not always results in renal histological
damage and renal failure.
• Reduced renal blood flow by 80% x 2 hrs no
kidney damage

16. In five sheep: renal blood flow (RBF) was reduced by 25, 50 and 75%, respectively, by
acute vascular occlusion for 30 min at weekly intervals.
In another six sheep: RBF was reduced by 80% for 2 h.
Release of occlusion induced brief hyperemia before all measured variables returned
to normal within 8 h and remained normal for the following 72 h.
At autopsy, the kidneys were histopathologically normal

18. • Rats with LPS infusion
to reduce blood flow by
50%
• Decrease in cortical
PO2 from
6852mHg
• Rats with mechanical
reduction of blood flow
to 50%  anuria
• No decrease in PO2
seen
• Fluid resuscitation in
LPS rats with
normalized blood flow
• No decrease in
cortical Po2

19. Conclusions
• Severe transient hypoperfusion is able to reduce
GFR and urine output but is not sufficient to
induce persistent AKI.
• Superimposition of renal hypoperfusion episodes
in relation to other insults, such as sepsis or
ischemia may induce renal failure
• It is expected that preventing a decrease of renal
blood flow may prevent or limit the occurrence of
AKI in ICU patients

20. E. coli induced hyperdynamic sepsis in sheep

21. • Review of all studies in
literature do not show a
correlation between TRPF
and GFR, implying
uncoupling between
perfusion(TRPF) and
function (GFR), such that
‘for a given decrease in
decreased perfusion,
there is an unpredictable
and much greater loss in
function’.

22. Possible explanations for uncoupling
between RBF and GFR.
1. Raised bowman’s space
pressure secondary to tubular
obstruction
2. Failure of active reabsorption
of ultrafiltrate
3. Back-leak of tubular
ultrafiltrate into the
interstitium and circulation
4. Tubulo-glomerular feedbackinduced afferent arteriolar
vasoconstriction
5. Decreased efferent arteriolar
tone

23. Intra renal blood flow distribution
• normal kidneys receive ~20% of cardiac output
• medulla receives less than 10% of renal blood flow
• In contrast to the cortical microcirculation, the medulla
microcirculation appears to be poorly autoregulated,
i.e., pressure-dependent.
– Regulation of diuretics and natriuresis and, therefore, the
response of the kidney to the body fluid composition and
volume status
– in mammalians kidneys, the ability of the medulla
circulation to regulate its own blood flow depends largely
on the body volume status

24. • With changes in
RPP, the only
detectable change
in intra-renal
perfusion occurs
in the inner
medulla

25. • In contrast, both renal cortical and
medulla are well autoregulated in
hydropenic rats.
• Because the descending vasa recta
provide blood flow to the medulla
emerge from efferent arterioles of
juxtamedullary glomerules, these
data suggest that changes in
resistance in the postglomerular
circulation of juxtamedullary
nephrons might be responsible for
the lack of autoregulation of
medullary blood flow in volume
expended animals

26. Pressure induced diuresis
• Increase in renal medullary blood flow
– decreases the outer-inner medullar osmotic gradient
– increases renal interstitial hydrostatic pressure
• which both impair the ability to concentrate urine
and participate in the natriuresis response to
hypertension in well-hydrated mammalians.
• In hydropenic animals, this response is blunted
preventing further loss of water and sodium

27. Hypothesis for developing AKI in sepsis
• Increased vascular response of the renal
microcirculation to vasoconstrictors  elicit
intense renal vasoconstriction  induces AKI
• Endogenous vasoconstrictors, including
angiotensin II
– decrease GFR due to decrease in renal blood flow
– blunt the natriuresis response after the renal
perfusion pressure has been restored
• Endotoxemia also can increase urine output and
water clearance despite decrease in GFR due to
tubular aquaporin-2 dysfunction

29. Tubulo-glomerular feedback
• Higher [NaCl] in tubular fluids in macula densa 
adenosine release  increase of the glomerular
afferent arteriole vascular tone  decreases GFR
– Operates for few seconds to minutes
– It resets in 30-60 min
– Prevents rapid loss of water and electrolytes in condition of
tubular dysfunction
• Na+ absorption network has the major renal oxygen
consumption.
• So decrease in GFR  lesser amount of Na reaching
distal tubules  decreased oxygen consumption.

30. • In ischemic kidneys:
– Diversion of oxygen consumption from Na+
reabsorption to other oxygen-consuming
pathways illustrated by an increase of the ratio
oxygen consumption/Na Reabsorp +

31. Postcardiac surgery patients with (n = 12) and without (n = 37) acute kidney injury were compared with
respect to renal blood flow, glomerular filtration, RVO2, and renal oxygenation.
In the acute kidney injury group, GFR (-57%), renal blood flow (-40%), filtration fraction (-26%), and
sodium resorption (-59%) were lower, renal vascular resistance (52%) and renal oxygen extraction (68%)
were higher, whereas there was no difference in renal oxygen consumption between groups.
Renal oxygen consumption for one unit of reabsorbed sodium was 2.4 times higher in acute kidney
injury

32. • Oxygen consumption to absorptive work mismatch is
not well understood and may result from:
– higher production of reactive oxygen species by infiltrative
immune cells
– high level of NO, which regulates the renal oxygen
consumption
• This may partially explain why strategies designed to
inhibit renal oxygen consumption (e.g., loops diuretics)
have failed to improve the prognosis of patients
suffering from AKI

33. Distant effects of renal
ischemia/reperfusion injury
J Am Soc Nephrol 14: 1549–1558, 2003

34. Acute renal failure leads to dysregulation
of lung salt and water channels
Kidney International, Vol. 63 (2003), pp. 600–606

35. Summary
• Decrease urine output can mirror a decrease
in creatinine clearance.
• Although a decrease in renal blood flow
and/or a decrease in renal perfusion pressure
is a major determinant of GFR, plasma oncotic
pressure appears to be central in the
glomerular hydrodynamic forces.
• Colloids increase the oncotic pressure and
may reduce filtration rate

36. Summary
• Fluid administration may be found inappropriate
and even harmful in numerous situations due to
the inconstant relationship between renal blood
flow or renal perfusion pressure and
diuresis/natriuresis due to complex
neurohormonal control.
• systemic inflammation can induce natriuresis and
diuresis changes due to functional changes
unrelated to hypoperfusion, histological, or
tubular damage

37. How to identify early AKI ?
• Is creatinine good enough?
• Use it with Urine output
• What about prediction equations: MDRD or
Cockroft & Gault.
– In critical care where creatinine is changing
rapidly, these formulas cannot be used to predict
GFR.
– Cannot be used in oliguric/anuric patients.
– These are used only for steady states

38. Is FeNa
useful?
Crit Care Med. 2007 Jun;35(6):1592-8.

39. Is FeNa useful?
• Although a low UNa or FeNa (e.g., FeNa <1%) suggest a
preserved renal tubular reabsorptive capacity, there is
NO evidence for a correlation between urinary
biochemical modifications and tissue damage.
• Control of urinary Na+ excretion results from a complex
neurohumoral regulation and is influenced by
• fluid resuscitation
• arterial pressure
• infusion of diuretics

40. How do I predict renal prognosis?
• FeNa and FeUrea are not helpful
• Neutrophil Gelatinase associated lipocalin (NGAL)

41. Neutrophil Gelatinase associated
lipocalin (NGAL)
• Plasma NGAL had an area under the ROC curve of 0.71
(95% confidence interval (CI), 0.55-0.88) for predicting
AKI progression and of 0.78 (95% CI, 0.61-0.95) for
need for renal replacement therapy
• Area under the ROC curve of 0.82 (95% CI, 0.7-0.95) for
predicting the use of renal replacement therapy
• Urine NGAL remains low in patients admitted in the
emergency department with prerenal azotemia versus
AKI

42. Cystatin-C
• 13 kD endogenous cysteine-proteinase
inhibitor that is produced by all cells.
• Freely filtered across the glomerulus and, in
contrast to creatinine, it is not secreted by
renal epithelial cells.
• Rises earlier than creatinine in ICU patients
with AKI
Kidney Int. 2004 Sep;66(3):1115-22.

43. Conclusions
• These urinary markers have been poorly studied among
critically ill patients.
• Recent reviews of experimental and human sepsis have
highlighted the paucity of available studies and their
design heterogeneity regarding urinary findings in septic
AKI
• there is no evidence that these urinary biochemical
findings can predict the response to hemodynamic
optimization in terms of renal injury and renal function

44. How should we assess renal perfusion
in ICU patient?
• Doppler-based determination of resistive
index
• Problems
– Need data with respect to GFR, Crclearance, FeNa
and oxygen consumption
– Need baseline data before the insult
– Difficult technically and in obese persons

45. Can We Predict Which Patient in the
ICU Will Develop AKI ?
• There are risk factors but no prediction score.
– Age
– Sepsis
– Cardiac surgery
– Infusion of contrast
– Diabetes
– Rhabdomyolysis
– Preexisting renal disease
– Hypovolemia and shock

46. How do we protect kidneys?
• Improve Renal perfusion
1. Volume status – fluid resuscitation
2. Pressors

47. Fluids
• How much?
• What type?

48. FACTT trial
• Selected patients with acute lung injury, conservative fluid
management may not be detrimental to kidney function.
• Fluid balance over 7 days was -136 ml in the conservative
group versus +6,992 ml in the liberal fluid strategy group
• Not associated with an increase in the frequency of RRT,
which occurred in 10% of the conservative-strategy group and
14% of the liberal-strategy group

49. Fluid resuscitation in AKI
• Although fluid
resuscitation and
optimization of renal
perfusion pressure are
central to the prevention
and treatment of AKI,
excessive fluid
resuscitation may be
harmful in some
critically ill patients

50. Problems with fluid overload
• Aggressive fluid resuscitation  increases renal blood
flow  but can be ineffective in restoring renal
microvascular oxygenation due to hemodilution with
no increase in blood-oxygen carriage capacities.
• Positive fluid balance can deteriorate cell oxygenation
and prolong mechanical ventilation.
• Fluid overload may lead to central venous congestion
and decrease of renal perfusion pressure, which will
promote the development of AKI in patients with acute
heart failure or sepsis

51. Which is
better –
crystalloids
or colloids ?

52. • Hyperosmotic colloids can be associated with
development of renal dysfunction
Schortgen F et al. Effects of hydroxyethylstarch and gelatin on renal function in severe
sepsis: a multicentre randomised study. Lancet 2001;357:911–916.

53. Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe
sepsis. N Engl J Med 2008;358:125–139

54. SAFE study
• No differences between
the groups in
– Patients who required RRT
(1.3% and 1.2%)
– the mean number of days
of RRT (0.5 ±2.3 and 0.4 ±
2.0; P =0.41)
– number of days of
mechanical ventilation (4.5
± 6.1 and 4.3 ± 5.7; P =
0.74).
N Engl J Med. 2004 May 27;350(22):2247-56

55. • Fuid resuscitation with
crystalloids or gelatin is
associated with a lower
incidence of AKI than
resuscitation with artificial
hyperoncotic colloids
• Dextran in 3% of patients
and starches in 98% of
patients (adjusted odds
ratio, 2.48) or
• Hyperoncotic albumin
(adjusted odds ratio, 5.99)
Schortgen F, Girou E, Deye N, Brochard L. The risk
associated with hyperoncotic colloids in patients with
shock. Intensive Care Med 2008;34:2157–2168.

56. Recommendations*
• Consider fluid resuscitation with crystalloids to be as
effective and safe as fluid resuscitation with
hypooncotic colloids (gelatins and 4% albumin)
• Based on current knowledge, hyperoncotic solutions
(dextrans, hydroxyethyl starches, or 20–25%
albumin) not be used for routine fluid resuscitation
because they carry a risk for renal dysfunction.
*An Official ATS/ERS/ESICM/SCCM/SRLF Statement:Prevention and Management of
Acute Renal Failure in the ICU Patient. Am J Respir Crit Care Med Vol 181. pp 1128–
1155, 2010

57. Role of vasoactive drugs
• Titrate to what ?
• What pressors should I use?
• Don’t the vasopressors cause renal afferents
to vasoconstrict and worsen renal blood flow?

58. How much MAP is sufficient ?
• Unknown whether the current
recommendation to maintain a mean arterial
pressure (MAP) at or above 65 mm Hg in
patients who are critically ill is adequate for
preventing AKI.
• It is likely that some patients—especially
those with history of hypertension and the
elderly—may require higher MAP to maintain
adequate renal perfusion.

59. • Twenty-eight patients with a
diagnosis of septic shock who
required fluid resuscitation and
pressor agents
• to achieve and maintain a mean
arterial pressure of 65 mm Hg.
• Then they were randomized in
two groups:
– In the first group (control group,
n 14), mean arterial pressure
was maintained at 65 mm Hg
– in the second group (n 14),
mean arterial pressure was
increased to 85 mm Hg by
increasing the dose of
norepinephrine

61. • Increasing the CI to a supra normal level > 4.5 (cardiac-index group)
• Increasing mixed venous oxygen saturation to a normal level (oxygen-saturation
group)

62. Conclusions
• Higher MAP is associated with increased cardiac
output but no difference in urine output or
creatinine clearance
• Normalization of mixed venous oxygen saturation or
by increasing oxygen delivery to supranormal levels
does not decrease rate of AKI
• Resuscitation should be titrated to end points of
oxygen metabolism and organ function.

63. Does type of vasopressor has any
role?
• You would expect NE to cause afferent vessel
vasoconstriction and decrease renal blood
flow.

64. Does NE infusion improves renal
perfusion?

66. • Twelve post-cardiac
surgery patients with NEdependent vasodilatory
shock and AKI were
studied
• 2–6 days after surgery.
• NE infusion rate was
randomly and
sequentially titrated to
target MAPs of 60, 75 and
90 mmHg.

67. Vasopressin
• Binding to the V2-receptors in the inner
medullary collecting ducts activates the UTA1 molecules
•  increases the urea permeability of
collecting duct
•  increase the ability to concentrate urine

68. Vasopressin
• Increase of plasma
vasopressin concentration
(independently of any
increase of systemic arterial
pressure) also influences
the pressure-natriuresis/
diuresis relationship in
decreasing the medullary
blood flow through
receptor V1a
Crit Care Med. 2004 Sep;32(9):1891-8.

69. • Vasopressin may reduce the progression to severe AKI only in a
prespecified subgroup of patients with less severe septic shock
(norepinephrine dose ,15 mg/minute)
• No difference was observed in the need for RRT in any subgroup.
Holmes CL, Mehta S, Granton JT, Storms MM, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl
JMed2008;358:877–887.

70. What about dopamine? Low dose?
7 sheep
6 h of placebo (saline solution) or
drugs (MD-NE at 0.4 micro g/kg/min or LDD
at 2 micro g/kg/min),
Outcomes: cardiac output (CO), and flow to
vital organs, lactate, creatinine, and
creatinine clearances
Chest. 2004 Jun;125(6):2260-7.Increasing renal blood flow: low-dose dopamine or medium-dose norepinephrine.

72. In patients with or at risk for AKI, low-dose dopamine may increase diuresis on the first
day of use but it does not protect against the development of AKI

73. Dobutamine
• Not been shown consistently to improve renal
blood flow.

74. Fenoldopam
• Short-acting dopamine receptor-1 agonist
• Fenoldopam did not affect the need for RRT
and survival at 21 days.
• In secondary analysis, however, fenoldopam
reduced the need for RRT and the incidence of
death in patients without diabetes and in
postoperative patients who have undergone
cardiothoracic surgery

77. Anything else?
• Angiotensin II
• In the absence of angiotensin II, volume
expansion with no increase in MAP induces
natriuresis, whereas the increase in MAP by
angiotensin II infusion did not induce a
natriuresis response

78. Summary
• Norepinephrine and vasopressin may induce, in septic
states, an increase of renal blood flow through a
combined
– increase of renal perfusion pressure (i.e., prerenal mechanism)
and
– an increase of renal vascular conductance (i.e., intrarenal
mechanism)
• Increase of renal blood flow does not necessarily
translate into GFR increase
• Current clinical data are insufficient to conclude that one
vasoactive agent is superior to another in preventing
development of AKI

79. Renal support
• Introduce early
• Traditional thresholds used in stable patients may not be
appropriate in ICU patients with AKI
– impact of renal failure on other failing organs such as the lungs (ARDS,
pulmonary edema) and brain (encephalopathy) should be considered
in the timing of RRT
– the increased catabolism associated with critical illness and the need
to administer adequate nutritional protein will lead to increased urea
generation
– Often difficult to limit fluid intake in these patients, in part due to the
administration of intravenous medications (antibiotics, vasopressors,
etc.)
– patients who are critically ill may be more sensitive to metabolic
derangements, and swings in their acidbase and electrolyte status may
be poorly tolerated.

80. Program to Improve Care in Acute
Renal Disease (PICARD) study
• Timing: early vs. late
• Odds ratio for adverse outcome of 1.97 (95%
confidence interval *CI+ 1.21– 3.20) was
associated with late start of RRT (BUN ,76
mg/dl versus BUN .76 mg/dl)
Clin J Am Soc Nephrol 1: 915–919, 2006

81. RRT dose
• Acute Renal Failure Trial Network study: no
difference between CVVHD(22ml/kg/hr) and
IHD (>3.9Kt/Vd/Wk) – OR 0.92 (0.73-1.16)
• Randomized Evaluation of Normal versus
Augmented Level [RENAL] Replacement
Therapy Study: CVVHD @ 25 and 40ml/kg/hr.
– OR for mortality 1.00 (0.81-1.23)

83. Recommendations
• Timing
– In patients who are critically ill with AKF we suggest initiating RRT
before the development of extreme metabolic derangements or other
life-threatening events.
• Intensity
– For IHD and SLED, we recommend clearances at least equal to
minimum requirements for chronic renal failure (3.6 Kt/Vd/wk)
– For CRRT (CVVH or CVVHD), we recommend clearance rates for small
solutes of 20 m/kg/h (actual delivered dose).
– Higher doses of CRRT cannot be generally recommended and should
only be considered by teams that can administer them safely
*An Official ATS/ERS/ESICM/SCCM/SRLF Statement:Prevention and Management of Acute Renal
Failure in the ICU Patient. Am J Respir Crit Care Med Vol 181. pp 1128–1155, 2010

84. Comments & Questions