Acute renal replacement therapy

Vineeta Sood8/18/2009

• 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

Primary therapeutic goals in AKI

• Optimize hemodynamic and volume status• Minimize further renal insult• Correct metabolic abnormalities• Removal of uremic toxins• Permit adequate nutrition

Renal replacement therapy in AKI

• When should RRT be initiated in AKI?

• Which modality is most appropriate ?

• What is the appropriate dose of therapy?

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

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

n BUN pre HD Survival %

Early Late Early Late

PARSONS FM et al. Lancet 1961

33 120-150 >200 75 12

Fischer RP et al. Surg Gynecol Obstet 1966

162 150 >200 43 26

Kleinknecht D et al. ,KI 1972

500 <93 >163 71 58

History of RRT in AKI

Timing of initiating RRT in AKI

Gilium DM, et al: Clinical Nephrology 1986;25: 249-255n= 34

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 P<0.0001

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

1.852.071.97

Timing and dose of CVVH in AKIn=106

Bouman CS ,et al. Critical Care Med 2002;30:2205-2211

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).

Renal replacement therapy in AKI

• When should RRT be initiated in AKI?

• Which modality is most appropriate?

• What is the appropriate dose of therapy?

Modalities of therapy

• Intermittent HD• Continuous therapies

– Continuous hemodialysis– Continuous hemofiltration– Continuous hemodiafiltration

• Hybrid therapies (SLED, extended daily HD)• Peritoneal dialysis

Practical comparison of acute RRT modalities

Fieghen, Nephron Clinical Practice 2009;112:222-229

Reasons for using CRRT

Mehta R and Letteri J Am J Nephrol 1999;19:377-382

ATN Study: Observational Cohart

Palevsky et al, NEJM 2008 July Volume 359:82-84

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

CRRT vs IHD

Swartz RD et al. AJKD 1999 Sept;34(3): 424-32.

•Similarly…

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 11

60 day survival 31.5% 32.6%

Vinsonneau C, et al. Lancet 2006;368(9533):379–85

primary endpoint

Continuous vs IHD in AKI: HEMODIAFE study

Vinsonneau C, et al. Lancet 2006;368(9533):379–85

Results of individual RCT’s comparing CRRT to IHD

In summary, no survival benefit shown in these trials with CRRT

Meta analysis of studies comparing CRRT and IHD in AKI

Rabindranath K et al.cochrane database syst rev 2007 jul (3)

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

Continuous vs. Intermittent Therapy Recovery of Renal Function

Mehta RL et al. KI 2001 Sept ;60(3) 1154-63Manns B et al. Crit Care med 2003Jacka MJ et al. Can J Anesth 2005

* percentage of survivors

CRRT IHD

N survived recovered 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 77 178

95 55

80.2%* 57.9%*

Continuous vs. Intermittent Therapy Recovery of Renal Function

CRRT IHD

N Survived recovered Death or dialysis

N Survived

Recovered

Death or dialysis

Mehtaet al

64 22 16 48 67 34 20 47

Mannet al

178 50 40 138 83 47 30 53

Jacka et al

65 24 21 44 28 14 5 23

total 307 96 77 230 178 95 55 123

80.2%* 74.9%** 57.9%* 69.1%**

Mehta RL et al. KI 2001 Sept ;60(3) 1154-63Manns B et al. Crit Care med 2003Jacka MJ et al. Can J Anesth 2005

*percentage of survivors•** percentage of all pts

• 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

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.

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).

Summary…Other therapies in AKI

• A paucity of data exists concerning the relative benefits of hybrid therapies and acute peritoneal dialysis.

Renal replacement therapy in AKI

• When should RRT be initiated in AKI?

• Which modality is most appropriate?

• What is the appropriate dose of therapy?

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.

• 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

Frequency of HD in AKI

Outcomes

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;346:305-310

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.

Dose of CVVH in AKI(n=425)

Ronco C et al. Lancet .2000 Jul 1;356(9223):26-30..

Dose of CVVH vs CVVHDFn=206

Saudan P et al. KI 2006 Oct;70(7);1312-7.

VA/NIH ATN study(n=1124)

VA/NIH Acute Renal Failure Trial Network et al. NEJM 2008 3;359(1):7-20

no difference in 60 day survivalno difference in renal recovery

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.

Acute Intermittent HD

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

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

CRRT

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

It causes…

• Lower solute clearance and UFR for substantial periods everyday

• Solute is removed using diffusion , convection or both.

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)

Specific techniques

• Slow continuous UF• CAV-H• CVV-HF• CAVHD• CVVHD

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

• 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.

Convection

• Since it mimics mammalian kidney it is thought to be more “physiologic” and provides better removal of middle molecules (500-5000 D) thought to be responsible for uremia

• Enhanced clearance of autologous cytokines- thought to be involved in SIRS

• 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

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.

• 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.

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

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

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.