HEMO

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Rose EA, et al. "Effect of Dialysis Dose and Membrane Flux in Maintenance Hemodialysis". The New England Journal of Medicine. 2002. 347(25):2020-2019.
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Clinical Question

In patients undergoing hemodialysis, does a higher dialysis dose or a high-flux dialyzer membrane reduce all-cause mortality?

Bottom Line

In patients undergoing hemodialysis, neither a higher dialysis dose nor a high-flux dialyzer membrane reduce all-cause mortality.

Major Points

Dialysis dose and size of molecules removed are important factors in patients undergoing maintenance hemodialysis.[1] Expressed as Kt/V, guidelines at the time of this study recommended a single-pool Kt/V of >1.2.[2] The Hemodialysis (HEMO) Study aimed to determine the effect of a higher dialysis dose (target equilibrated Kt/V 1.45) and a high-flux dialyzer membrane on all-cause mortality in patients undergoing thrice-weekly hemodialysis, as compared to standard-dose (target equilibrated Kt/V 1.05) and low-flux membrane.[3]

Patients were randomized in a 2x2 factorial design to receive hemodialysis at a high-dose (n=920) as compared to standard-dose (n=926), or a high-flux membrane (n=921) as compared to low-flux membrane (n=925). There was no difference in all-cause mortality (primary outcome) when comparing between the groups. However, high-flux membrane was associated with a significant improvement in some secondary CV outcomes.

Similarly, the NCDS findings did not show any mortality benefit in patients treated with a higher dialysis dose.[4] The TiME is an ongoing trial which aims to evaluate the effect of longer hemodialysis duration on all-cause mortality.[5] In addition, the MPO and EGE study did not observe any mortality difference between hemodialysis patients assigned to either low-flux or high-flux membranes.[6][7] A Cochrane analysis published in 2012 (33 studies, 3820 patients) noted that high-flux membranes reduced CV mortality (RR 0.83, 95% CI 0.70-0.99) but this benefit needs to be confirmed.[8] However, no significant benefit on all-cause mortality was seen.

Guidelines

KDOQI Clinical Practice Guideline for Hemodialysis Adequacy (2015 update)[9]

  • For thrice-weekly hemodialysis schedule, the target single pool Kt/V (spKt/V) is 1.4 per session with a minimum delivered spKt/V of 1.2 (Class IB)
  • For other hemodialysis schedules, the target Kt/V is 2.3 volumes/week with a minimum delivered dose of 2.1 (not graded)
  • For intermittent hemodialysis, either high- or low-flux biocompatible hemodialysis membranes are recommended (Class IB)

Design

  • Multicenter, 2x2 factorial, randomized, controlled trial
  • N=1,846
    • high-dose (n=920) vs. standard-dose (n=926)
    • high-flux (n=921) vs. low-flux (n=925)
  • Setting: 15 centers (72 dialysis units) in Canada and the United States
  • Enrollment: 1995-2000
  • Mean follow-up: 2.84 years
  • Analysis: Intention-to-treat
  • Primary outcome: all-cause mortality

Population

Inclusion Criteria

  • age 18-80 years
  • undergoing thrice weekly hemodialysis
  • has been on hemodialysis for ≥3 months

Exclusion Criteria

  • residual urea clearance >1.5 mL/minute per 35 liters of urea
  • serum albumin <2.6 g/dL
  • inability to achieve equilibrated Kt/V of >1.30 within 4.5 hours during two of three consecutive monitored dialysis sessions in the high-dose group
  • obesity (97% of randomized patients were <100 kg)

Baseline Characteristics

From the high-dose group (n=920)

  • Demographics: Age 57 years, females 56%, African-American 61%,
  • Clinical measurements: BP 152/82 mm Hg
  • Medical history: Diabetes 44%, cardiac disease 79%
  • Laboratory measurements: Serum creatinine: 10.3 mg/dL, serum albumin 3.6 g/dL, total cholesterol 174 mg/dL
  • Dialysis and CKD-related history:
    • Dialysis duration: 4 years
    • Equilibrated Kt/V: 1.43
    • Residual urea clearance >0: 34%
    • Weight after dialysis: 69 kg
    • Body water volume after dialysis: 35L
    • High-flux membrane: 61%
    • Equilibrated normalized protein catabolic rate: 1.03 g/kg/day

Interventions

  • Eligible patients were randomized in 1:1 ratio with 2x2 factorial design to receive:
    • Dose randomization:
      • High-dose - Equilibrated Kt/V 1.45, urea-reduction ratio of 75% or a single-pool Kt/V of 1.65
      • Standard-dose -Equilibrated Kt/V 1.05, urea-reduction ratio of 65% or a single-pool Kt/V 1.25
    • Flux randomization:
      • High-flux - Ultrafiltration coefficient >14 ml/hour/mm Hg and mean beta2-microglobulin clearance >20 ml/min
      • Low-flux - Mean beta2-microglobulin clearance <10 ml/min

Outcomes

Comparisons are presented as high-dose vs. standard-dose, followed by high-flux vs. low-flux. P-values are listed where available.

Primary Outcomes

All-cause mortality
High-dose vs. standard-dose: 0.162 vs. 0.171 event/patient-year (risk reduction 4%, 95%CI -10 to 16; P=0.53)
High-flux vs. low-flux: 0.162 vs. 0.171 event/pt-yr (risk reduction 8%, 95%CI -5 to 19; P=0.23)

Secondary Outcomes

First hospitalization for cardiac causes or all-cause mortality
High-dose vs. standard-dose: 0.279 vs. 0.290 event/pt-yr (risk reduction 1%, 95%CI -12 to 12; P=0.91)
High-flux vs. low-flux: 0.275 vs. 0.295 event/pt-yr (risk reduction 10%, 95%CI -1 to 20; P=0.08)
First hospitalization due to infection or all-cause mortality
High-dose vs. standard-dose: 0.292 vs. 0.307 event/pt-yr (risk reduction 3%, 95%CI -9 to 14; P=0.6)
High-flux vs. low-flux: 0.287 vs. 0.312 event/pt-yr
First decrease in album (>15%) or all-cause mortality
High-dose vs. standard-dose: 0.245 vs. 0.244 event/pt-yr
High-flux vs. low-flux: 0.238 vs. 0.251 event/pt-yr
Hospitalizations not related to vascular access
High-dose vs. standard-dose: 1.24 vs. 1.3 event/pt-yr (risk reduction 4%, 95%CI -6 to 13; P=0.38)
High-flux vs. low-flux: 1.28 vs. 1.25 event/pt-yr (risk increase by 1%, 95%CI -9 to 11; P=0.87)
CV mortality
High-dose vs. standard-dose: 0.065 vs. 0.066 event/pt-yr
high-flux vs. low-flux: 0.059 vs. 0.072 event/pt-yr (P<0.05)
First hospitalization for fatal or nonfatal cardiac causes
High-dose vs. standard-dose: 0.219 vs. 0.222 event/pt-yr
High-flux vs. low-flux: 0.208 vs. 0.233 event/pt-yr (P<0.05)
Mortality due to infection
High-dose vs. standard-dose: 0.038 vs. 0.038 event/pt-yr
High-flux vs. low-flux: 0.037 vs. 0.04 event/pt-yr
First hospitalization for fatal or nonfatal infection
High-dose vs. standard-dose: 0.209 vs. 0.226 event/pt-yr
High-flux vs. low-flux: 0.209 vs. 0.226 event/pt-yr

Other outcomes

Single-pool Kt/V
High-dose vs. standard-dose: 1.71±0.11 vs. 1.32±0.09
High-flux vs. low-flux: 1.52±0.22 vs. 1.51±0.22
Equilibrated Kt/V
High-dose vs. standard-dose: 1.53±0.09 vs. 1.16±0.08
High-flux vs. low-flux: 1.34±0.21 vs. 1.34±0.21
Urea-reduction ratio
High-dose vs. standard-dose: 75.2±2.5 vs. 66.3±2.5%
High-flux vs. low-flux: 70.9±5.1 vs. 70.6±5.1
Beta2-microglobulin clearance/dialysis session
High-dose vs. standard-dose: 4.0±3.6 vs. 3.5±3.6 L
High-flux vs. low-flux: 6.8±2.3 vs. 0.7±1.5 L

Subgroup Analysis

For the primary outcome:

Gender
Female: favors high-dose (19% lower risk compared to standard-dose)
Male: favors standard-dose (16% lower risk compared to high-dose)
P-value for interaction 0.01
Prior dialysis duration
≤3.7 years: no difference
>3.7 years: favors high-flux (32% lower risk compared to low-flux)
P-value for interaction 0.005

There was no significant interaction for ethnicity, baseline dialysis prescription, BP and comorbidities.

Criticisms

  • The use of Kt/V to define dialysis dose may result in less power to detect differences in patient outcomes[10]

Funding

  • The National Institute of Diabetes and Digestive and Kidney Diseases
  • Baxter Healthcare
  • Fresenius Medical Care
  • R&D Laboratories
  • Ross Laboratories

Further Reading

  1. Renal Data System. USRDS 2001 annual data report: atlas of end-stage renal disease in the United States. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2001
  2. Eknoyan G, Levin N. NKF-K/DOQI clinical practice guidelines: update 2000. Am J Kidney Dis 2001;37:Suppl 1:S5-S6[Erratum, Am J Kidney Dis 2001;38:917.]
  3. Garabed E, et al. Effect of Dialysis Dose and Membrane Flux in Maintenance Hemodialysis. N Engl J Med 2002; 347:2010-2019
  4. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981;305:1176-1181
  5. NIH Health Care Systems Research Collaboratory: UH3 Project: Time to Reduce Mortality in End-Stage Renal Disease (TiME), 2015. Available at: https://www.nihcollaboratory.org/demonstration-projects/Pages/TiME.aspx. Accessed September 06, 2016
  6. Locatelli, F., Martin-Malo, A., Hannedouche, T. et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009; 20: 645–654
  7. Asci, G., Tz, H., Ozkahya, M. et al. The impact of membrane permeability and dialysate purity on cardiovascular outcomes. J Am Soc Nephrol. 2013; 24: 1014–1023
  8. Palmer SC, Rabindranath KS, Craig JC, Roderick PJ, Locatelli F, Strippoli GFM. High-flux versus low-flux membranes for end-stage kidney disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD005016. DOI: 10.1002/14651858.CD005016.pub2.
  9. Daugirdas, JT. et al. KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 Update. Am J Kidney Dis. 2015 Nov;66(5):884-930. doi: 10.1053/j.ajkd.2015.07.015.
  10. Himmelfarb, J. Success and Challenge in Dialysis Therapy. N Engl J Med 2002; 347:2068-2070