1. Acute renal replacement therapy
Vineeta Sood
8/18/2009

2. AKI is a frequent complication of hospitalization and is associated with significant morbidity and mortality
No proven therapies that reverse course of established AKI
management is mainly supportive, with RRT indicated in pts with severe kidney injury.
4% of all acutely ill pts will require RRT

3. Primary therapeutic goals in AKI
Optimize hemodynamic and volume status
Minimize further renal insult
Correct metabolic abnormalities
Removal of uremic toxins
Permit adequate nutrition

4. Renal replacement therapy in AKI
When should RRT be initiated in AKI?
Which modality is most appropriate ?
What is the appropriate dose of therapy?

5. Indications of renal support in AKI
Refractory Volume overload
Hyperkalemia not responding to medical Rx
Metabolic acidosis
Uremic symptoms
Overdose with a dialyzable drug/toxin

6. History of RRT in AKI
1940s and early 1950s : RRT was used to principally treat advanced symptoms of renal failure
1950s : concept of prophylactic dialysis was introduced
1960s and 1970s :studies suggested that improved outcomes were associated with initiation of HD when BUN reached 90 to 100, as compared to waiting until the BUN exceeded 150 to 200 mg/dL

7. History of RRT in AKI n BUN pre HD Survival % Early Late
PARSONS FM et al. Lancet 1961 33
>200 75 12
Fischer RP et al. Surg Gynecol Obstet 1966
162
150 43 26
Kleinknecht D et al. ,KI 1972
500
<93
>163 71 58

8. Timing of initiating RRT in AKI
Gilium DM, et al: Clinical Nephrology 1986;25:
n= 34

9. PICARD STUDY ;n=243,(CJASN,2006)
BUN ≤76mg/dl
(n=122)
BUN ≥76mg/dl (n=121)
Mean BUN (mg/dl)
47.4
114.9
P<0.0001
Mean Cr(mg/dl)
3.4
4.7
Failed organ systems
4(IQR:3-4)
3(IQR:2-4)
p=0.008
sepsis
37%
46%
P=0.14
Initial RRT with CRRT
69%
43%
P<0.001
Survival
day 14
day 28
80%
65%
75%
59%
P=0.09
Adjusted mortality rate
adjusted fr covariates
Adjusted for propensity score
Adjusted for both covariates and propensity
1.85
2.07
1.97

10. Timing and dose of CVVH in AKI n=106
Bouman CS ,et al. Critical Care Med 2002;30:

11. So to Summarize…
optimal timing for initiation of RRT in pts with AKI is not well defined.
It is suggested that initiation of RRT prior to development of symptoms and signs of renal failure due to AKI, such as advanced uremic symptoms (eg, encephalopathy and serositis).

12. Renal replacement therapy in AKI
When should RRT be initiated in AKI?
Which modality is most appropriate?
What is the appropriate dose of therapy?

13. Modalities of therapy Intermittent HD Continuous therapies
Continuous hemodialysis
Continuous hemofiltration
Continuous hemodiafiltration
Hybrid therapies (SLED, extended daily HD)
Peritoneal dialysis

14. Practical comparison of acute RRT modalities
Fieghen, Nephron Clinical Practice 2009;112:

15. Reasons for using CRRT
Mehta R and Letteri J Am J Nephrol 1999;19:

16. ATN Study: Observational Cohart
Palevsky et al, NEJM 2008 July Volume 359:82-84

17. CRRT vs IHD?
A trial by Mehta et al. (K.I. 2001)revealed higher ICU mortality in pts treated with CRRT as compared to IHD (59.5 vs.41.5%).
However , there were apparent baseline imbalances between the groups, whereby pts randomized to CRRT had a greater severity of illness.
After adjustment for these characteristics, there was no increased risk of death with CRRT
Renal recovery did not differ between the groups

18. CRRT vs IHD
Similarly…
Swartz RD et al. AJKD 1999 Sept;34(3):

19. Continuous vs IHD in AKI: HEMODIAFE study n=360
IHD(n=184)
CVVHDF(n=175)
Vasopressers
86%
89%
Mechanical ventilation
95%
98%
sepsis
59%
56%
SAPS II 64 65
Crossovers 6 31
Duration of RRT (days) 11
60 day survival
31.5%
32.6%
primary endpoint
Vinsonneau C, et al. Lancet 2006;368(9533):379–85

20. Continuous vs IHD in AKI: HEMODIAFE study
Vinsonneau C, et al. Lancet 2006;368(9533):379–85

21. Results of individual RCT’s comparing CRRT to IHD
In summary, no survival benefit shown in these trials with CRRT

22. Meta analysis of studies comparing CRRT and IHD in AKI
Rabindranath K et al.cochrane database syst rev 2007 jul (3)

23. …so type of treatment (IHD vs CRRT) does not impact survival, but does it impact recovery of renal function?

24. Continuous vs. Intermittent Therapy Recovery of Renal Function
CRRT IHD N
survived
recovered
Mehta,et al 64 22 16 67 34 20
Mann,et al
178 50 40 83 47 30
Jacka et al 65 24 21 28 14 5
total
307 96 77 95 55
80.2%*
57.9%*
Mehta RL et al. KI 2001 Sept ;60(3) Manns B et al. Crit Care med 2003
* percentage of survivors
Jacka MJ et al. Can J Anesth 2005

25. Continuous vs. Intermittent Therapy Recovery of Renal Function
CRRT IHD N
Survived
recovered
Death or dialysis
Recovered
Mehtaet al 64 22 16 48 67 34 20 47
Mannet al
178 50 40
138 83 30 53
Jacka et al 65 24 21 44 28 14 5 23
total
307 96 77
230 95 55
123
80.2%*
74.9%**
57.9%*
69.1%**
Mehta RL et al. KI 2001 Sept ;60(3) Manns B et al. Crit Care med 2003
*percentage of survivors
** percentage of all pts
Jacka MJ et al. Can J Anesth 2005

26. So although these studies report better recovery with CRRT these reports only evaluated renal recovery in pts who survived, thereby failing to account for mortality differences b/w groups.
When analysis combined mortality and non recovery of renal function, both groups showed similar recovery of function
Randomized studies have also found no such benefit with CRRT

27. So to Summarize…IHD vs CRRT
The two principal outcomes that have been examined are patient survival and recovery of renal function.
current data suggest that survival and recovery of renal function are similar with both CRRT and IHD.

28. So to Summarize…IHD vs CRRT
Data do not support superiority of any particular mode of RRT in patients with AKI.
However, in selected pts other factors may prevail. (in pts with acute brain injury or fulminant hepatic failure, continuous therapy may be associated with better preservation of cerebral perfusion).

29. Summary…Other therapies in AKI
A paucity of data exists concerning the relative benefits of hybrid therapies and acute peritoneal dialysis.

30. Renal replacement therapy in AKI
When should RRT be initiated in AKI?
Which modality is most appropriate?
What is the appropriate dose of therapy?

31. Dose of RRT….The problems
impact of RRT intensity or dose on pt outcomes is controversial.
Most definitions of acute RRT dose are based on small molecule removal, (as exemplified by urea), while ignoring other crucial aspects of RRT adequacy in AKI, such as volume and electrolyte control.

32. Also, assumptions pertaining to urea kinetic modeling that are applied to ESRD are inappropriate in acute setting.
Finally ,many of the benefits derived from acute RRT may relate to large-molecular-wt solute clearance, which is poorly quantified

33. Frequency of HD in AKI Outcomes Schiffl et al NEJM 2002;346:305-310
Alternate day HD
Daily HD
P value
mortality
46%
28%
0.01
Duration of AKI(days)
16±6
9±2
0.001
Schiffl et al NEJM 2002;346:

34. However…
study was designed to provide a min. Kt/V urea of 1.2 for each Rx session in both arms of the study.
actual delivered dose per session was significantly lower than intended, but similar in both arms of study (mean Kt/V 0.92 vs. 0.94).
It is therefore unclear if the survival benefit demonstrated in this study was mediated by mere provision of an adequate dialysis dose in the daily dialysis arm or by true merits of more intensive therapy.

35. Dose of CVVH in AKI (n=425)
Ronco C et al. Lancet Jul 1;356(9223):

36. Dose of CVVH vs CVVHDF n=206
Saudan P et al. KI 2006 Oct;70(7);

37. VA/NIH ATN study (n=1124)
no difference in 60 day survival no difference in renal recovery
VA/NIH Acute Renal Failure Trial Network et al. NEJM ;359(1):7-20

38. RENAL Study
Randomized Evaluation of Normal vs. Augmented Level (RENAL) Replacement Therapy study
enrolled 1,500 critically ill patients in Australia and New Zealand with AKI at multiple sites.
Preliminary study results have been reported and indicate that CVVHDF at a dose of 40 ml/kg/h did not confer improved 90-day survival as compared to a dose of 25 ml/kg/h.

39. Acute Intermittent HD

40. Techniques for Acute IHD:
Categorized according to HD membrane and mechanism of solute removal
High- flux membranes allow greater convective removal of middle and larger solutes ,but limited data in AKI patients

41. Measures to improve hemodynamic stability during IHD
Maximize UF rate requirement by
Increased frequency of treatment
Increased duration of treatment(then consider SLED or CRRT)
Bicarbonate buffered dialysate
Sodium/UF profiling
? Increase dialysate Calcium
?change modality from HD to HDF
?blood temperature monitoring

42. CRRT

43. CRRT : Advantages
Provides better hemodynamic stability and steady state control of uremia
Consistent solute control avoids the water shifts during IHD that increase brain edema.
However….
Mean operating time for CRRT has been reported at 21.9 hr/d

44. It causes…
Lower solute clearance and UFR for substantial periods everyday
Solute is removed using diffusion , convection or both.

45. Techniques of CRRT
Acute dialysis initiative group has proposed standardized classification based on
Vascular access
A-V or V-V
Method of solute removal
CVVH(convection)
CVVHD(diffusion)
CVVHDF(both)

46. Specific techniques
Slow continuous UF
CAV-H
CVV-HF
CAVHD
CVVHD

47. Continuous Hemofiltration
Describes an almost exclusive convective treatment with highly permeable membrane
Ultrafiltrate produced is replaced by a sterile solution
Patient weight loss results from the difference between UF and reinfusion rates

48. Convection utilizes hydrostatic pressure to effect the translocation of water across semi-permeable membrane while concomitantly dragging solutes with molecular weights that are below the pore size of the membrane.

50. Convection
Since it mimics mammalian kidney it is thought to be more “physiologic” and provides better removal of middle molecules ( D) thought to be responsible for uremia
Enhanced clearance of autologous cytokines- thought to be involved in SIRS

51. An important determinant of Clearance is the site of fluid replacement
Pre dilution
Disadvantages: UF is generated from blood diluted with replacement fluid and thus contains lower conc of uremic solutes
Post dilution(standard method)
Disadvantages : higher UFR can cause hemoconcentration in the filter and increase clotting

52. HemoDialysis (Diffusion)
movement of solutes across a semi-permeable membrane down concentration gradients for the respective solutes.
Larger molecules are poorly removed by this process.

54. Qb and Qd during CRRT are relatively low (100-200ml/min and 1-2 l/hr respectively)
Under these conditions , DUN/BUN is 1.0,indicating complete saturation
Urea Clearance therefore equals Qd and is unaffected by Qb until it decreases to < 50ml/min.
With increasing Qd, there are proportionally decreasing gains in small solute clearance as DUN/BUN progressively decreases.

57. CRRT versus SLED
Observational data from single centers suggest that SLED is a feasible way of providing RRT that is adequate, hemodynamically well tolerated, potentially anticoagulation- free and possibly cost-effective

58. CRRT versus SLED
However,only two small RCTs have compared SLED and CRRT
Kielstein et al. randomized 39 critically ill pts with AKI to receive either 24 h of CVVH or 12 h of SLED.
Using invasive monitoring, these authors found no significant differences in all measured hemodynamic parameters (MAP, SVR, CO) with comparable removal of creatinine and urea.
Kielstein et al AJKD 2004; 43: 342–349

59. CRRT versus SLED
Another study randomized 16 pts to receive 3 sessions with either CVVH or SLED and showed that fluid removal and hemodynamic parameters were similar in both groups
further studies that utilize patient relevant outcomes are reqd to define precise role of SLED, compared to CRRT in hemodynamically unstable pts with AKI.