1. Acute renal failure By H P Shum Intensive care unit PYNEH

2. Introduction • 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 phasethat marked the onset of complete renal recovery BMJ1941: 427–32

3. Pre-renal ARF ischaracterized by decreased renal perfusion in the absence of injury to the renal parenchyma • Prompt reversal of the haemodynamic insultresults in the rapid restoration of renal function • If renal hypoperfusion sustained, cellular injury occur resulted in ATN • In ATN, renal dysfunction persists evenafter reversing the haemodynamic insult • Support with dialysis may be necessary whilstawaiting the typical recovery that occurs overdays to weeks

4. 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 increasein Cr concentration of 0.5mg/dl (44mol/L) if thebaseline 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)

5. 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 <265) • 13 tertiary care hospitals • 9 months in duration • N=748 cases of ARF 66% total

6. 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 164

7. 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

8. NSAID in pre renal ARF • In normal situation, PGI2 and PGE2 do not play very significant role in renal haemodynamic regulation • However, it become important for preservation of renal perfusion and GFR during reduced effective circulating volume

9. Is COX-2 inhibitor less nephrotoxic than nonselective COX inhibitor ? • Effect of Cyclooxygenase-2 Inhibition on Renal Function in ElderlyPersons 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

10. 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 arthritis • Duration 6 mo • N = 287

11. ACEI and renal impairment • A study of the prevalence of significant increases in serum creatinine following angiotension-converting enzyme inhibitor administration J Hum Hypertens. 2005 May;19(5):389-92 • 20644 pts on ACEI with age >40 • Monitor RFT changes within 6 mo after ACEI initiation • 31 (0.15%) had increased Cr from 105umol/l to >220umol/l 325umol/l

12. ACEI and renal impairment • Diarrhoea, vomiting and ACE inhibitors:an important cause of acute renal failure Journal of Human Hypertension (2003) 17, 419–423 • 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 challenge 38%

13. 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

14. ATN • Causes of ATN have great variation among different populations • 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

15. Septicemia related ATN

16. Ischemic ATN • Two components contribute to decreased GFR • Vascular • Intrarenal vasoconstriction • Vascular congestion within outer medulla • activation of tubuloglomerular feedback • Tubular • Tubular obstruction • Transtubular backleak • Interstitial inflammation

17. 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

18. ATN

19. 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, tacrolimus

20. Volume expansion • Essential mx of patients with hypovolemia • Crystalloids vs. colloids vs. albumin ??

21. 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, asciteswere included • Total >2000 pts • No evidence for either improved outcome or increased mortality in patients given albumin

22. 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

23. Colloids versus crystalloids for fluid resuscitation in critically ill patients The Cochrane Database of Systematic ReviewsVolume (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 surgery

24. 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 resuscitation

25. 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 • Presence of other nephrotoxic drugs Ann Int Med 1984; 100: 352-7 AJKD, Vol 39, No 5 (May), 2002: pp 930-936

26. Once versus thrice daily gentamicin in patients with serious infections Prins JM et al. Lancet1993;341: 335–9 N=123 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-analysisof antibiotic therapy, includingaminoglycosides in patients with neutropenicfevers, found no significant differences incure rates or nephrotoxicity with single vsmultiple doses of aminoglycosides Clin Infect Dis1997;24: 810–5

27. 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

28. Radio-contrast induced nephropathy AJKD, Vol 39, No 5 (May), 2002: pp 930-936

30. Prevention of contrast nephropathy • NAC • Hydration • Iso-osmolar contrast media • Theophylline • Fenoldopam

31. Prevention of Radiocontrast NephropathyWith N-Acetylcysteine in patients with Chronic Kidney Disease: A Meta-Analysis ofRandomized, Controlled Trials 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

35. Prevention of contrast media-associated nephropathy: randomized comparisonof 2 hydration regimens in 1620 patients undergoingcoronary 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

37. 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

38. 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 PatientsUndergoing Angiography • 129 pts, DM with impaired RFT (cr about 132 – 308umol/l) • coronary or aortofemoral angiography • All well hydrated IV NS 1L before procedure • CN defined as Cr >44umol/l

40. 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

41. Fenoldopam (DA-1 receptor agonist) • Induce renal vasodilatation • Increase renal blood flow • Increase urine output American Journal of Therapeutics 12, 127–132 (2005)

42. The Prevention of Radiocontrast-Agent–Induced Nephropathy by Hemofiltration 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

44. Results: • 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% (p=0.01)

45. 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 group

46. Low dose dopamine • Thought to restore renal blood flow and GFR • But no evidence that it is beneficial

47. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group • Lancet. 2000 Dec 23-30;356(9248):2139-43 328 pts admited to ICU low-dose dopamine (2 µg kg-1 min-1) vs. placebo End point: peak serum creatinine concentration

48. Survival to ICU discharge (108 vs 105 patients; p=0.61) and survival to hospital discharge (92 vs 97 patients; p=0.66) were similar

49. Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study • Nephrol Dial Transplant. 1997 Dec;12(12):2592-6 Unless the patient had fluid overload, use of loop diuretic can further exacerbate ATN • 92 pts with ARF • All received renal dose of dopamine and mannitol 3 d before • Randomized to torasemide, frusemide, or placebo • 3mg/kg q6h

50. 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