Colloids Can Cause Renal Failure

1. Colloids Can Cause Renal Failure MFM James Dept of Anaesthesia University of Cape Town

2. Colloids and ARF • Colloids are frequently given in resuscitation • A goal of therapy is the maintenance of renal function • Are the colloids potentially harmful to the kidney under certain circumstances?

3. Colloids and ARF • First description after infusion of Dextran 40 Mailloux et al, N.Engl.J Med., 1967 Matheson et al, Surg.Gynecol.Obstet., 1970 • Subsequently described with • Gelatin • 10% HES • 20% mannitol • 20% albumin • High MS HES

4. Possible Mechanisms • Accumulation of low MW fractions in tubules (direct toxicity) • Osmotic nephrosis-like lesions (vacuolization of proximal tubular cells) • Hyperoncotic renal failure Ragaller et al, J.Am.Soc.Nephrol. 2001

5. Low MW Fractions • Precipitation of particles in tubules • Tubular accumulation of particles • Tubular obstruction responsive to diuretic therapy • Possible tubular uptake and direct toxicity • Only described with dextrans

6. Osmotic Nephrosis-Like Lesions • Reported with all colloids, including albumin • Associated with characteristic tubular lesions • Functional significance?

7. Tubule Osmoticnephrosis-like lesion Normal Tubule Pathology • Also shown with • Mannitol • Hypertonic glucose • Cyclosporin A • Functional significance questionable • Inconsistent relationship to ARF

8. Hyperoncotic Renal Failure • Glomerular filtration of hyperoncotic molecules causes hyperviscous urine, stasis and tubular obstruction Chinitz et al, J Lab Clin Med, 1971 • Effective filtration pressure depends on the balance of hydrostatic and osmotic pressures:GFR= Kf [(Pcap- Pbow)-(plas - bow)] Moran & Kapsner, NEJM, 1987

9. Hyperoncotic Renal Failure • GFR= Kf [(Pcap- Pbow)-(plas - bow)] • bow = 0 • GFR= Kf [(Pcap- Pbow)-plas] • If Pcap is low and plas is high, glomerular filtration will cease

10. Hyperoncotic Renal Failure • Occurs with all hyperoncotic colloids • Inadequate crystalloid administration • Occurs in dehydrated patients given large volumes of hyperoncotic solutions • Most likely with poorly-filtered, osmotically-active particles

11. P P H Hyperoncotic Renal FailureDextran Moran & Kapsner, N Engl. J. Med, 1987

12. H P P Hyperoncotic Renal FailureDextran Day 7 Day 9 Day 11 Day 13 Moran & Kapsner, N Engl. J. Med, 1987

13. D D D Hyperoncotic Renal FailureAlbumin in Cirrhosis Rozich & Paul, Am J Med., 1989

14. Hyperoncotic Renal FailureGelatin • ABF grafting with 200ml blood loss • 2L gelatin given for low urine output and to keep CVP > 8mmHg • Minimal crystalloid given • Postoperatively 20% albumin given • Anuric renal failure • ? Contribution from gelatin Hussain & Drew, BMJ, 1989

15. Renal InjuryGelatin • The small gelatin molecules are excreted through the glomeruli • They form part of the ultrafiltrate and a small portion is reabsorbed whereas the major part is excreted in the urine Hussain & Drew, BMJ, 1989

16. Morphological findings following gelatin administration Kief H, Bibl Haemat, 1969 • Gelatin molecules are excreted through the glomeruli. • A small portion of the ultrafiltrate is reabsorbed whereas the major part is excreted in the urine • Reabsorption occurs via vacuoles which are surrounded by a simple membrane. The presence of gelatin could be demonstrated by fluorescence

17. ARF and HESAssumptions • Renal toxicity of HES is now well recognised Peron et al, Clin Nephrol, 2001 • Administration of even low doses of HES causes tubular lesions in patients predisposed to renal insufficiency De Labarthe et al, Am J Med, 2001 What is the Evidence?

18. ARF and HES • Systematic review, English, human: • Keywords • Kidney, kidney function/dysfunction, renal function/dysfunction, volume replacement, HES, dextran, gelatin • 12 studies identified • 3 articles describing renal injury with HES Boldt & Priebe, Anesth. Analg, 2003

19. HES v Gelatin in elderly cardiac surgery patients Boldt , Intensive Care Med, 2003 Total volume of colloid infused Forty consective patients aged > 70 years cardiac surgery with CPB HES 130/0.4 vs Gelatin after induction of anesthesia until POD2 to keep CVP 12-14 mmHg *

20. HES v Gelatin in elderly cardiac surgery patients Boldt , Intens Care Med, 2003 Lysosomal tubular damage Proximal tubular damage Proximal tubular damage Distal tubular damage

21. VISEP Renal Data

22. Criticisms What you should not do: Use hyperoncotic colloids Use inadequate crystalloid support Use high MS HES in large amounts VISEP Study 10% HES 200/0.5 Crystalloid allocation not specified Very large doses of high MS HES Brunkhorst et al, New Engl J Med 2008

23. Reasonable VISEP Conclusions Hyperoncotic colloid administered in a manner not currently recommended will result in renal dysfunction in the critically ill

24. HES v Albumin in Cardiacs • 50 Elderly, low albumin patients for cardiacs • Elevated pre-op creatinine • 2.9L Alb v 3.0L HES • No difference in: • Renal function to 3 mth • Inflammatory response • HES decreased ICAM Boldt et al, Anesth Analg, 2008

25. HES and Renal Failure General critical care • Observational study of 363 patients: • HES 130/0.4 (HES + ) n=168 • No HES (HES - ) n=195 • Risk of renal dysfunction assessed using RIFLE criteria • HES + group more severely ill on admission Boussekey et al., Critical Care, 2010

26. HES and Renal Failure General critical care • SOFA scores and RIFLE classification improved in both groups • No group differences in survival or renal outcomes • Volume expansion with HES 130/0.4 was not associated with AKI Boussekey et al., Critical Care, 2010

27. HES and Renal Failure Animal endotoxic shock • Endotoxic shock induced by Salmonella typhosa infusion to MAP <65 mmHg in 30 adult sheep • Resuscitated with balanced crystalloid, isotonic 6 % HES 130/0.4, or hyperoncotic 10 % HES 200/0.5 • Study endpoints: • Urine output • Plasma creatinine • Urea concentrations Ertmer et al., Anesthesiology, 2010

28. HES and Renal Failure Animal endotoxic shock • Urine output better maintained with crystalloid and HES 130/0.4 than HES 200/0.5 • Creatinine lower in crystalloid and HES 130/0.4 groups than HES 200/0.5 • Electron microscopic score highest in sheep treated with 10 % HES 200/0.5 Ertmer et al., Anesthesiology, 2010

29. HES and Renal FailureOverall evidence • No evidence that tetrastarch has adverse renal effects in high doses • Hyperoncotic colloids may be associated with renal injury • Concern remains in sepsis • “Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients” Dart et al., Cochrane Collaboration, 2010

30. Hyperoncotic Colloids • Renal dysfunction: • Hyperoncotic colloids [OR: 2.48 (1.2-4.9)] • Hyperoncotic albumin [OR: 5.99 (2.7-13.1)] • ICU death • Hyperoncotic albumin [OR: 2.79 (1.4-5.5)] Schortgen et al, Intens Care Med, 2008

31. Trauma Trial • First, randomised, controlled, double blind study of crystalloid v colloid • 0.9% saline v HES 130/0.4 in saline • End points • Fluid volumes for resuscitation • GIT dysfunction • Renal function James et al, unpublished data, 2009

32. What is the Evidence? • Clear evidence that high dose hyperoncotic colloids can cause renal failure • Inadequate crystalloid provision is probably a significant risk factor • No evidence that colloid molecules per se are nephrotoxic