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					Acute renal failure
        By H P Shum
     Intensive care unit

• ARF was first recognized
  in crush injury victims
  during World War II
• Eric Bywater described a
  reversible reduction of
  renal function,
  characterized by an initial
  oliguric phase, followed
  after 1–2 weeks by a
  diuretic phase that
  marked the onset of
  complete renal recovery
                  BMJ 1941: 427–32
• Pre-renal ARF is
characterized by decreased
renal perfusion in the absence
of injury to the renal
parenchyma                          • In ATN, renal dysfunction persists
• Prompt reversal of the            even after reversing the
haemodynamic insult results         haemodynamic insult
in the rapid restoration of renal   • Support with dialysis may be
function                            necessary whilst awaiting the typical
• If renal hypoperfusion            recovery that occurs over days to
sustained, cellular injury occur    weeks
resulted in ATN
 ARF - definition
• Great variation
• Ranged from a slight increased in Cr by
  0.5mg/dl (44umol/l) to needs for dialysis
• Difficulty to compare the prevalence of ARF
  between populations
• Reasonable definition: acute and sustained
  increase in Cr concentration of 0.5mg/dl
  (44mol/L) if the baseline is less than
  2.5mg/dl (221 mol/L), or an increase in Cr
  concentration of more than 20% if the
  baseline is more than 2.5mg/dl (221 mol/L)
Epidemiology of acute renal failure: a prospective, multicenter, community-based study.
Madrid Acute Renal Failure Study Group
Liano F et al. Kidney Int 1996 Sep;50(3):811-8
                               • Definite of ARF
                                      •Cr >177 with N baseline
                                      • >=50% Cr in those with CRF (Cr
                               • 13 tertiary care hospitals
                               • 9 months in duration
                               • N=748 cases of ARF

                        66% total
Hospital-Acquired Renal Insufficiency
Nash K et al. Am J Kidney Dis 2002; 39: 930–36

 • 4622 admited to medical and surgical ward
 • Tertiary care hospital
 • 7.2% with baseline Cr >105umol/l

  Pre-renal ARF
• complicate any disease characterized by
  either “true hypovolemia”or a reduction in the
  “effective circulating volume”
• Hypovolemia  fall in SBP  activation of
  SNS and RAAS  decreased renal perfusion
   renal flow flow and GFR were maintained
  by autoregulation
• If the hypovolemia cannot be adequately
  corrected in short time, kidney autoregulation
  mechanism will fail and renal perfusion and
  GFR decreased progressively
   NSAID in pre renal ARF
• In normal situation,
  PGI2 and PGE2 do not
  play very significant
  role in renal
• However, it become
  important for
  preservation of renal
  perfusion and GFR
  during reduced
  effective circulating
Is COX-2 inhibitor less
nephrotoxic than nonselective
COX inhibitor ?
•   Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a
    Low-Salt Diet
                                                                          Ann Intern Med. 2000;133:1-9
•   Randomized, three period, single dose cross-over study
•   N =45, placebo vs vioxx vs indocid
•   Inulin clearance was determinated every 30min after dosing for total 6 hr
    Is COX-2 inhibitor less
    nephrotoxic than nonselective
    COX inhibitor ?

•   Celecoxib vs diclofenac and
    omeprazole in reducing the risk of
    recurrent ulcer bleeding in patients
    with arthritis
                N Engl J Med 2002;347:2104-10
•   Aim at learning the effect of
    celecoxibs 200mg bd vs. diclofenac
    + losec on GIB in patient with
•   Duration 6 mo
•   N = 287
  ACEI and renal impairment

• A study of the prevalence of
  significant increases in serum             325umol/l
  creatinine following
  enzyme inhibitor administration
    J Hum Hypertens. 2005 May;19(5):389-92
• 20644 pts on ACEI with age
• Monitor RFT changes within 6
  mo after ACEI initiation
• 31 (0.15%) had increased Cr
  from 105umol/l to >220umol/l
            ACEI and renal impairment
•    Diarrhoea, vomiting and ACE
     inhibitors: an important cause
     of acute renal failure
    Journal of Human Hypertension (2003) 17, 419–
•    3 cases of ARF, Cr upto
     1000umol/l, on ACEI
     associated with GE symptom
•    3 months, retrospective cohort
     survey of patients admited to
     medical wards
•    0.3% on ACEI with diarrhea
     developed ARF, Cr upto
     290umol/l, all response to fluid
Key points
• Pre-renal ARF is a common cause of ARF
• Early restoration of haemodynamic can
  decrease chance of progression to ischemic
  ATN which takes longer time for full recovery
• NSAID and ACEI/ ARB can induce pre-renal
  ARF especially in those with depleted volume
  status and impaired RFT
• COX II inhibitor is not a renal safe medication
• Causes of ATN have great variation among different
• Strongly related to environmental and therapeutic exposure

                    The spectrum of acute renal failure in the intensive care unit compared with
                    that seen in other settings
                    Kidney Int Suppl 1998; 66: S16–24
Septicemia related ATN
Ischemic ATN
• Two components contribute to decreased
  – Vascular
     • Intrarenal vasoconstriction
     • Vascular congestion within outer medulla
     • activation of tubuloglomerular feedback
  – Tubular
     • Tubular obstruction
     • Transtubular backleak
     • Interstitial inflammation
Tubular changes in ATN
• ischemic and reperfusion
• loss of polarity
• loss of brush border
• redistribution of integrin
and Na/K ATPase
• tubular cell death
• shedding of viable and
non-viable cell
• tubular obstruction
• further reduction of GFR
Prevention and Tx of ARF

• Medications that affect autoregulation
  of renal blood flow should be used with
  care eg NSAID / ACEI / ARB
• Avoid use of nephrotoxic agents
• Check dosing of potential nephrotoxic
  drugs eg aminoglycosides, cyclosporin,
Volume expansion
• Essential mx of patients with
• Crystalloids vs. colloids vs. albumin ??
• Patient survival after human albumin
  administration. A meta-analysis of
  randomized, controlled trials
               Ann Intern Med 2001 Aug 7;135(3):149-64

• 55 trials involving surgery or trauma,
  burns, hypoalbuminemia, high-risk
  neonates, ascites were included
• Total >2000 pts
• No evidence for either improved outcome
  or increased mortality in patients given
A Comparison of Albumin and Saline for Fluid
Resuscitation in the Intensive Care Unit
The SAFE Study Investigators. N Engl J Med 2004;350:2247-56
•6997 pts admitted to ICU need fluid resuscitation
•Half given 4% albumin, half with saline
Colloids versus crystalloids for fluid resuscitation in critically ill patients
The Cochrane Database of Systematic Reviews Volume (3), 2005

       •To assess the effects on mortality of colloids compared to
       crystalloids for fluid resuscitation in critically ill patients
       •Albumin vs. crystalloids: 19 RCT, 7576 pts, pooled RR
       was 1.01 (95% CI 0.92 to 1.10)
       •Hydroxyethyl starch vs. crystalloids: 10 RCT, 374 pts,
       pooled RR was 1.16 (95% CI 0.68 to 1.96)
       •Modified gelatin vs. crystalloids: 7 RCT, 346 pts, pooled
       RR was 0.54 (95% CI 0.16 to 1.85)
       •Dextran vs. crystalloids: 9 RCT, 834 pts, pooled relative
       risk was RR 1.24 (95% CI 0.94 to 1.65)
       • no evidence from RCTs that resuscitation with colloids
       reduces the risk of death, compared to resuscitation with
       crystalloids, in patients with trauma, burns or following
Key points
• For volume expansion
  – No significant different between use of
    albumin, colloid and crystalloid
  – Given the cost of albumin, potential
    hypersensitivity reaction and risk of virus
    transmission, crystalloid should in most
    cases a preferred choice for fluid
    Aminoglycoside nephrotoxicity

•   Precise contribution of
    aminoglycosides to renal failure
    to difficult to assess in seriously
    ill pts who had other
    predispositions to renal failure
•   Risk factors included:
      – High dosage
      – Prolong or repeated courses
      – Old age
      – Female sex
      – Underlying renal impairment
      – Hypovolemia
      – Liver impairment
                                          AJKD, Vol 39, No 5 (May), 2002: pp 930-936
      – Presence of other
          nephrotoxic drugs
          Ann Int Med 1984; 100: 352-7
Once versus thrice daily gentamicin in patients with serious infections
Prins JM et al. Lancet 1993; 341: 335–9

  4 mg/kg/d (OD) vs. 1.33 mg/kg 3x/d (MD)
  Mean duration of tx 7d

                                            In conclusion:
                                            A once-daily dosing regimen of gentamicin is at
                                            least as effective as and is less nephrotoxic than
                                            more frequent dosing

                                            A meta-analysis of antibiotic therapy, including
                                            aminoglycosides in patients with neutropenic
                                            fevers, found no significant differences in cure
                                            rates or nephrotoxicity with single vs multiple
                                            doses of aminoglycosides
                                                            Clin Infect Dis 1997; 24: 810–5
Key points
• Use only in absolutely needed condition
• Once daily dose of aminoglycosides is
  as effective as divided dose with less
  nephrotoxic side effect
• Appropriate dosage adjustment needed
  for those with renal impairment
• Beware on concomitant use of other
  nephrotoxic agents
Radio-contrast induced

                AJKD, Vol 39, No 5 (May), 2002: pp 930-936
Prevention of contrast
•   NAC
•   Hydration
•   Iso-osmolar contrast media
•   Theophylline
•   Fenoldopam
Prevention of Radiocontrast Nephropathy With N-Acetylcysteine in patients
with Chronic Kidney Disease: A Meta-Analysis of Randomized, Controlled
AJKD Vol 43, No 1 (January), 2004: pp 1-9

        8 RCT, 885 pts
        Another 4 RCT in abstract form, 427 pts
        Age >18
        Cr >106umol/l or CrCl < 70ml/min
        RCN defined as Cr  > 44umol/l or > 25% baseline
Prevention of contrast media-associated nephropathy: randomized comparison of 2
hydration regimens in 1620 patients undergoing coronary angioplasty
Mueller C et al. Arch Intern Med. 2002;162: 329-336

                    • N= 1620
                    • Compare NS vs. half half sol
                    • CN defined as Cr >44umol/l
                    from baseline
                    • Monitor RFT 24-48 hr postop
Prevention of Contrast-Induced Nephropathy With Sodium
Bicarbonate: A Randomized Controlled Trial
JAMA Volume 291(19), 19 May 2004, p 2328–2334

•prospective, single-center, RCT
•119 pt
•receive a 154-mEq/L infusion of
either sodium chloride (n = 59) or
sodium bicarbonate (n = 60)
•CN defined as  Cr >25%
baseline in 2 d
Low osmolar contrast media (LOCM, 780
mOsm) vs. iso-osmolar contrast media
(IOCM, 290 mOsm)
 N Engl J Med. 2003;348:491–499

• Prevent nephrotoxicity in High-Risk Patients
  Undergoing Angiography
• 129 pts, DM with impaired RFT (cr about 132 –
• coronary or aortofemoral angiography
• All well hydrated IV NS 1L before procedure
• CN defined as Cr >44umol/l
    Theophylline for prevention of contrast-induced
    nephropathy: a systematic review and meta-analysis
    Arch Intern Med. 2005 May 23;165(10):1087-93

Adenosine antagonist (adenosine is an important mediator of CN)
9 RCT, 585 pts
Overall pooled OR 0.4 favor theophylline use
     Fenoldopam (DA-1 receptor agonist)
• Induce renal vasodilatation
• Increase renal blood flow
• Increase urine output

                                American Journal of Therapeutics 12, 127–132 (2005)
The Prevention of Radiocontrast-Agent–Induced Nephropathy by
N Engl J Med 2003;349:1333-40
         •114 pt
         • all with Cr >177umol/l
         •CVVH vs. NS 1ml/kg/h
         •4-8 hr before cardiac procedure, 18-24hr after after
         • CN defined as increased Cr >25% baseline
• CN in CVVH:NS gp = 5% : 50% (p<0.001)
• needs for subsequent dialysis support in CVVH : NS =
3% : 25% (p<0.001)
• In-hospital mortality in CVVH : NS = 2% : 14% (p=0.02)
• Cumulative 1-yr mortality in CVVH : NS = 10% : 30%
Key points
• Consider other imaging technique
• Hydration is most important
• NS is better than half half solution and
  NaHCO3 may be better than NS but need
  larger study to provide firm support
• NAC/ theophylline/ IOCM is more useful in
  those with significant risk factors
• CVVH may be useful in extremely high risk
Low dose dopamine
• Thought to restore renal blood flow and
• But no evidence that it is beneficial
  Low-dose dopamine in
  patients with early renal
  dysfunction: a placebo-
  controlled randomised trial.
  Australian and New Zealand
  Intensive Care Society
  (ANZICS) Clinical Trials
  Lancet. 2000 Dec 23-

328 pts admited to ICU
low-dose dopamine (2 µg kg-1 min-
1) vs. placebo

End point: peak serum creatinine
Survival to ICU discharge (108 vs 105 patients; p=0.61) and
survival to hospital discharge (92 vs 97 patients; p=0.66) were
   Loop diuretics in the
   management of acute
   renal failure: a
   prospective, double-blind,
   randomized study
   Nephrol Dial Transplant.
   1997 Dec;12(12):2592-6

Unless the patient had
 •92 pts with ARF
                     use of
fluid overload, dose of
 •All received renal
loop diuretic can 3 d
 dopamine and mannitol
further exacerbate
 •Randomized to
 torasemide, frusemide, or
•3mg/kg q6h
Key points
• Renal dose of dopamine do not have
  any role in ARF Mx
• Although, use of loop diuretic in ARF
  can increase u/o, it use is very limited
  in most of the cases of ARF
Acute renal failure in the intensive care unit: A systematic review of the impact of
dialytic modality on mortality and renal recovery
Am J Kidney Dis 2002; 40: 875–85

  RR of death for IHD (6 RCT)             RR of death for IHD (12 non-RCT)
                                        RR of dialysis dependency with IHD
RR of renal death with IHD

      IHD is not an inferior treatment as compared with CVVH
Hemofiltration and Peritoneal Dialysis in Infection-Associated Acute Renal
Failure in Vietnam
N Engl J Med 2002; 347 : 895– 902

•70 Pts with malaria or sepsis
related ARF
•Randomized to PD (70L/d) vs.
CVVH (25L/d)
•Mortality 47% in PD vs. 15%
•Acidosis corrected more
rapidly with CVVH
•Fast renal recovery with
                                                     Hours after randomization
Key points
• IHD and CVVH are treatment choice for
  ARF, choose should be based on local
• Better to avoid use of PD for ARF due
  to infection except when other
  modalities not a/v or contraindicated
The End
Cochrane Injuries Group Albumin
Human albumin use in critically ill
patients. Systematic review of
randomised controlled trials
BMJ. 1998 Jul 25;317(7153):235-40

   •Compare use of albumin vs.
   crystalloids in critically ill pts
   •30 RCT, 1419 pts
   •Pooled risk of death with
   albumin use is 6%
   •Every 17 critically ill pt use
   albumin, one additional death

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