Kinetics of dialysis

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					Dialysis Adequacy
   Historical background of hemodialysis duration
   Measure of dialysis adequacy
   Major problems with short (high speed) dialysis
       Increased mortality
       Intradialytic hypotension
       Poor blood pressure control
       Poor blood access results
   Need to change paradigm
       Duration and frequency of dialysis should be
                         In the beginning

       In the 1960s, chronic HD sessions, as developed in
        Seattle, Washington, were long procedures
         In-center: 20 – 40 hours/week on Kiil dialyzer. No blood pressure
          meds needed in 22 of 24 patients
            Pendras JP, Erickson RV. Ann Intern Med. 1966; 64(2):293-311.
         8 – 10 hours thrice weekly at home. No blood pressure meds in
          29 of 33 patients,
            Eschbach JW Jr, Barnett BM, Cole JJ, Daly S, Scribner BH. Ann Intern Med 1967;

       No hypotensive episodes mentioned
      Adequate dialysis in
              the 1960’s
Pendras JP, Erickson RV. Hemodialysis: a successful therapy
   for chronic uremia. Ann Intern Med. 1966; 64(2): 293-311.

      Defined as the absence of clinical
       symptoms and signs of uremia
Major symptoms and signs indicating inadequate
dialysis if no other etiology could be determined

   Gastrointestinal and nutrition
     Nausea,vomiting, anorexia, dysgeusia,
   Neurological
     Motorneuropathy, restless leg syndrome,
     burning feet syndrome, insomnia,
     depression, pruritus, decreased nerve
     conduction velocity, sleep apnea
                                   Twardowski Z. Acta Med Pol, 1974;
                                           15: 227-243 and 245-254.
Major symptoms and signs indicating inadequate
dialysis if no other etiology could be determined

   Cardiovascular
     hypertension, arrhythmia related to electrolyte
        disturbances, pericarditis
   Hemodialysis disequilibrium
       headaches during or immediately after dialysis
   Intradialytic and postdialytic hypovolemia
       During dialysis: cramps, hypotension, backache, crash. After
        dialysis: dizziness, hangover (thirst, headache, fatigue)

                                                    Twardowski Z. Acta Med Pol, 1974;
                                                            15: 227-243 and 245-254.
Why have clinical symptoms and signs
been rejected as an adequacy index?
   Symptoms and signs may have other etiology
   Increased Kt/V does not influence the majority of these
   Increasing time or duration of dialysis favorably
    influences these symptoms
   Instead of rejecting Kt/V as a measure of dialysis
    adequacy, clinical symptoms and signs have been
  In the 1970s, it was considered as obvious
that absence of uremic symptoms predicted
           low mortality and hospitalizations

                       How is it now?
Relative Risk of Death and First Hospitalization by
Quintile Scores for Physical Component Summary
   Adjusted relative risk

                            2,0        1.93
                                                                      Death      Hospitalizations
                            1,6                                  1.36
                            1,4      1.56         1.46                               1.17
                            1,2                                1.33
                            1,0                                               1.14
                                     <25          26-32         33-38           39-46        >46
                                            Physical component summary score
                                  Mapes D, et al. Health-related quality of life as a predictor of mortality
                                      and hospitalizations: The DOPPS. Kidney Int. 2003; 64:339-349
Short hemodialysis is not a new fad
   “Shortening the time of dialysis has always been
    an aim of physicians”.
       Rotellar E, et al: Why dialyze more than 6 hours a
        week? ASAIO Trans1985; 31:538-545.
        Early attempts to shorten dialysis
               duration in the USA

   12 – 16 hr/week with the use of coil dialyzers
        Biochemical control similar to that reported by the
         Seattle group
           Schupak E, Merrill JP. Experience with long-term intermittent
            hemodialysis. Ann Intern Med. 1965; 62(3):509-518.
        Early attempts to shorten dialysis
                duration in Europe
       3 hours every other day or 4 hours thrice weekly for
        an average of 11.2 hours per week
         Excellent biochemical control, hematocrits improved
            Cambi V, et al. Intensive utilisation of a dialysis unit. Proc Eur Dial
             Transplant Assoc. 1973; 10:342-348.
            Cambi V, et al. Short dialysis schedules (SDS)- Finally ready to become a
             routine? Proc Eur Dial Transplant Assoc. 1975; 11:112-120.
         No information on residual renal function.
         Difficulties with blood pressure control
            2 of 53 patients required bilateral nephrectomy
    How could short hemodialysis be
     justified and widely accepted?
   Technical feasibility, economic incentives, and
    medical/scientific justification
       Barth RH. Short hemodialysis: big trouble in a small package.
        In: Friedman EA. (ed.) Death on Hemodialysis: Preventable or
        Inevitable. Dordrecht, The Netherlands, Kluwer Academic
        Publishers, 1994; 143-157.
   Technical feasibility and economic incentive had been
    already shown by the Cambi group but some scientific
    support and some mathematical formula were needed
    to define an adequate dose of dialysis and justify short
    treatment duration
    Medical/scientific justification of
         short hemodialysis
   Godsend for short HD
       Kt/Vurea
           Urea clearance times time divided by urea
            distribution volume
       National Cooperative Dialysis Study
        (NCDS) accepted Kt/Vurea as a single
        measure of dialysis adequacy
                Conclusion of NCDS

   Time of dialysis has little influence on results
    provided that dialyzer clearance is high
       Harter HR. Review of significant findings from the National
        Cooperative Dialysis Study and recommendations. Kidney Int
        Suppl. 1983; 13:S107-12.
   Kt/Vurea should be over 0.95/treatment with
    three times weekly dialysis
       Gotch FA, Sargent JA. A mechanistic analysis of the National
        Cooperative Dialysis Study (NCDS). Kidney Int 1985;
               Shortcomings of NCDS

   The study was conducted for only 52 weeks in the early
   Clinical assessment rejected as a measure of dialysis
    quality; hospitalizations accepted instead
   Residual renal function was not taken into account
    in spite that many patients were of short vintage and must
    have had substantial urine output
   Time of dialysis rejected as a measure of dialysis
    adequacy based on p = 0.06
       Forgotten truth: Absence of evidence is not evidence of
    Consequences of Kt/Vurea concept

   Time of dialysis may be shortened if
    dialysis clearance is proportionately
     Efficient dialyzers
     High blood flow

     High dialysate flow
        Attempts of ultra-short dialysis
       Hemodiafiltration, 115 min three times weekly
         von Albertini B, et al. High-flux hemodiafiltration: under six
          hours/week treatment. ASAIO Trans 1984; 30:227-231.
       Two-hr, 3weekly, 500 ml/min BF, 5 m2 dialyzer
         Rotellar E, et al: Why dialyze more than 6 hours a week?
          ASAIO Trans1985; 31:538-545.
     An editorial posed a question in the title “Are there
      limitations to shortening dialysis treatment?” and did not
      answer affirmatively
        Collins AJ, Keshaviah PR. ASAIO Trans. 1988; 34(1): 1-5.
Dialysis duration in the last quarter of
           the 20th century
   “In contrast to AIDS, the virus of short
    duration dialysis has crossed the ocean
    from the old world and has invaded the
       Wizemann V, Kramer W. Short-term dialysis -
        Long-term complications. Ten years
        experience with short-duration renal
        replacement therapy. Blood Purif. 1987;
Dialysis duration in the last quarter of
           the 20th century
   Even though European dialysis facilities
    were first to introduce short dialysis, most
    centers practiced longer dialysis sessions
    that those in the USA. Japanese centers
    practiced the longest dialysis sessions.
       Goodkin DA, Young EW. DOPPS update.
        Contemporary Dialysis & Nephrology. 2001;
        October, pp 36 – 40.
Are any data that dialysis duration
      influences mortality?

   In the period 1982-1987, hemodialysis mortality in
    the United States was found to be 22% higher than
    in Europe and 40% higher than in Japan, where
    dialysis durations were longer
       Held PJ, et al. Am J Kidney Dis 1990 May;15(5):451-7.

   Time of dialysis below 5 hrs an important predictor of
    death according to Japanese Dialysis Registry
       Shinzato T, et al. Nephrol Dial Transplant 1997; 12 (5): 884-888.
        Mortality in short dialysis in
   “The proportion of deaths in the Federal
    Republic of Germany was twice as high in
    short dialysis”
       Kramer P, et al. Combined report on regular
        dialysis and transplantation in Europe, XII, 1981.
        Proc Eur Dial Transplant Assoc. 1983;19: 4-59.
    Mortality and dialysis duration in the
           USA in the late 1980s
   Relative mortality risk was about 20% higher in
    patients receiving dialysis duration <3.5 hrs
    compared to those with treatment >3.5 hrs.
    Most shorter treatments were received by
    patients in for-profit units. This indicates that the
    major incentive for short dialysis was financial.
       Held PJ, Levin NW, Bovbjerg RR, Pauly MV, Diamond LH. Mortality and
        duration of hemodialysis treatment. JAMA. 1991; 265(7): 871-875.
       Berger EE, Lowrie EG. Mortality and the length of dialysis. JAMA. 1991;
           Duration of dialysis and
             mortality in Japan
   Analysis of the results in 71,193 patients of
    Japanese HD Registry showed statistically
    significant, gradual decrease of mortality with
    increased dialysis time from 3.5 to 5.5 hours.
    Further decrease in mortality with dialysis
    duration >6 hours, but statistically insignificant
    because of small number of patients in this time
       Shinzato T, Nakai S. Do shorter hemodialyses
        increase the risk of death? In J. Artif Organs. 1999;
     Blood pressure control in the first
    report on shorter dialysis in the USA
   In a group of 22 patients, 8 required
    antihypertensive therapy, 4 required bilateral
    nephrectomy, and two died of cerebral
       Schupak E, Merrill JP. Experience with long-term
        intermittent hemodialysis. Ann Intern Med. 1965;
Sodium retention and hypertension
         in short dialysis
       Exchangeable sodium increases with 14.8 hr/wk
        compared to 18 hr/wk dialysis, and more patients
        require antihypertensive drugs.
       “Problems of hypertension and the side effects of its
        treatment, both medical and surgical, should be
        weighed against the social and economic advantages
        of short dialysis in deciding on the ideal schedule.”
         Sellars L, Robson V, Wilkinson R. Sodium retention and
          hypertension with short dialysis. Br Med J. 1979; 1(6162):
    Intradialytic hypotension (IDH) and
            duration of dialysis
       Intradialytic hypotension (IDH) occurs in 25 to 50% of
        short, thrice weekly hemodialysis treatments in the
        United States.
         Schreiber MJ Jr. Am J Kidney Dis. 2001; 38(Suppl 4):S1-10.
       Dialysis hypotension occurs because a large volume of
        blood water and solutes are removed over a short
        period, exceeding the plasma refilling rate and reduction
        of venous capacity
         Daugirdas JT. Am J Kidney Dis 2001; 38(4 Suppl 4): S11-17.
         Sherman RA. Am J Kidney Dis. 2001; 38(4 Suppl 4): S18-25.
          Lopot et al. Hemodial Int 2000; 4:8-14
DBV (%)
      Recommended maneuvers to
        decrease IDH episodes
   Higher dialysate sodium, calcium, and potassium
   Isolated ultrafiltration followed by dialysis
   Lower dialysate magnesium, high dialysate potassium
   Lower dialysate temperature
   Bicarbonate instead of acetate dialysate
   Predialysis withdrawal of blood pressure medications
   Blood pressure raising drugs, such as ephedrine,
    fludrocortisone, caffeine, and midodrine
   Sodium and ultrafiltration modeling (profiling)
Stiller S,. A critical review of sodium profiling for hemodialysis. Semin Dial. 2001;14(5): 337-347.
          Change in BV response with Na profile
DBV (%)

          Lopot et al. Hemodial Int 2000; 4:8-14
         Does sodium profiling work?
   In most short studies IDH rates decreased
   Long term studies unavailable
   Sodium profiling works if sodium balance is
       Iselin H, Tsinalis D, Brunner FP. Sodium balance-
        neutral sodium profiling does not improve dialysis
        tolerance. Swiss Med Wkly. 2001;131(43-44): 635-
    Consequences of positive sodium
   Chronic fluid volume overload until new equilibrium
    is achieved
   Decreases IDH rates
   Causes volume dependent hypertension
       >80% of patients in the USA are on antihypertensive
       LVH
       Increased cardiovascular mortality
Comorbidities (%) in Euro- DOPPS, Japan,
              and the USA

                                Euro-DOPPS             Japan             USA

Coronary artery disease              28.7               18.7             48.3

Congestive heart failure             24.1                5.6             43.9

Other cardiac problem                36.2               23.9             34.6

Hypertension                         72.5               56.1             83.7

Peripheral vascular disease          22.0               10.9             24.3

Cerebrovascular disease              13.2               11.8             16.8

Dyspnea                              18.9                2.4             27.5

               Fukuhara S, et al. Health related quality of life among dialysis patients
                  on three continents: The DOPPS. Kidney Int. 2003; 64:1903-1910
                 Prevention of IDH
   The simplest and almost always effective is prolongation
    of dialysis to match ultrafiltration rate with plasma
    refilling rate
   Although obviously logical, this maneuver is not
    recommended by DOQI guidelines and most review
    papers on the subject
       Short dialysis time seems to be a
        sacrosanct element of dialysis prescription
     Fewer IDH episodes and better BP
        control with longer dialysis
   Fishbane SA, Scribner BH. Blood pressure control in dialysis patients.
    Semin Dial. 2002; 15(3):144-145.
   Hörl MP, Hörl WH. Hemodialysis-associated hypertension:
    pathophysiology and therapy. Am J Kidney Dis 2002; 39(2):227-244.
   Locatelli F, Manzoni C. Duration of dialysis session – Was Hegel right?
    Nephrol Dial Transplant. 1999; 14(3):560-563.
   Covic A, et al. Long-hours home haemodialysis - the best renal
    replacement therapy method? QJM 1999; 92(5):251-260.
   McGregor DO, et al. A comparative study of blood pressure control with
    short in-center versus long home hemodialysis. Blood Purif 2001;
   Katzarski KS, et al. Extracellular volume changes and blood pressure
    levels in hemodialysis patients. Hemodial Int. 2003; 7(2): in press.
             Advantages of short dialysis
   For the provider
       Financial
          More shifts
          No benefit for home hemodialysis

   For patients
       Shorter time while tethered to dialyzer
       Shorter time while sitting in chair (in the USA)
        Patients’ position during dialysis
   Most Japanese and many European patients are
    dialyzed in beds in the supine position
   Most US patients are dialyzed while sitting in chairs
       In the early days of hemodialysis in the USA it was
        assumed that patients would feel better psychologically if
        they came to the dialysis unit but were not treated like
        patients, dressed in hospital garbs and lying in beds, but
        rather like visitors sitting in chairs and casually dressed.
A HD patient in the USA
A patient of Dr. Charra
   in Tassin, France
Why patients request short dialysis
   Patients are told that longer dialysis is not better
    than short dialysis
       No benefit - more time wasted
   Sitting in a chair for a long time is uncomfortable
       In the sitting position, there is translocation of body
        fluids to the lower extremities; consequently,
        hypotensive episodes are more likely, especially during
        the second half of HD
Why patients request short dialysis
   Patients want to have taken away this “miserable
    last hour of dialysis”
   It is impossible to take away the last hour of
    dialysis but patients’ pressure is frequently
    successful, HD is shortened and target weight
     Interdialyticblood pressure increases with
      all its consequences
Prescribed blood flow, HD duration, and percent fistula in
 prevalent patients in Japan, Euro-DOPPS, and the USA
         Calculated from DOPPS data kindly
 350     provided by Dr. Phil Held
 250            240               228
          200                                           210
 100                  90,2
  50                                                          19,9
           Japan             Euro-DOPPS            USA
    Blood flow (mL/min)       HD Duration (min)     Fistula (%)
    A-V fistula survival is
markedly higher in Europe
    compared to the USA
Pisoni RL, Young EW, Dykstra DM, Greenwood
RN, Hecking E, Gillespie B, Wolfe RA, Goodkin
   DA, Held PJ. Vascular access use in Europe
        and the United States: Results from the
      DOPPS. Kidney Int. 2002; 61(1):305-316.
     High blood flow rates and A-V
            fistula problems
   Primary A-V wrist fistula providing <300
    mL/min blood flow is sufficient for long
    dialysis but is in jeopardy if short dialysis
    is practiced
       May be deemed unusable and other access
         Allon M, Robbin ML. Increasing arteriovenous
         fistulas in hemodialysis patients: Problems and
         solutions. Kidney Int. 2002; 62(4):1109-1124.
      High blood flow rates and A-V
             fistula problems
   A-V fistula may be damaged by repeated
    attempts to achieve higher blood flows, using
    tourniquets and other maneuvers
   Hypotensive episodes rapidly reduce fistula
    blood flow, predispose to damage of the intima
    by suction of the inflow needle with consequent
          High blood flow and catheter
       High blood flow requires a large internal
        diameter of the catheter
       Large diameter catheter fits the vein too
        tightly and predisposes to damage of the
        vein wall, vein thrombosis and stenosis
        Davenport A. Central venous catheters for hemodialysis: How
         to overcome the problems. Hemodial Int. 2000; 4:78-82.
        The results of the HEMO study
           Eknoyan et al. NEJM. 2002; 347(25):2010-2019.

   No major benefit of spKt/Vurea above 1.3 in
    thrice-weekly dialysis, except in woman
   Higher Kt/Vurea was achieved mainly by
    increasing K
       The average blood flow was 311 mL/min in the low
        dose group and 375 mL/min in the high dose group.
       The average dialysis duration was 190 min in the low
        dose group and 219 min in the high dose group
        Importance of dialysis frequency
           higher than thrice weekly
   Sudden and cardiac death highest on Monday and Tuesday
    in HD but not in CAPD
       Bleyer AJ; Russell GB; Satko SG. Kidney Int 1999; 55:1553

   QOD, 4, 5, 6, and 7 times weekly HD decrease fluctuations
    in pre and post dialysis fluid volumes and solute
       Decrease interdialytic and intradialytic symptoms
            IDH, cramps, and postdialysis hangover
       Improve mental health, energy, social functioning, physical activity,
        vitality, blood pressure control with decreased use of
        antihypertensive drugs, and hematocrit with decreased use of
    Reasons that patients do better on quotidian HD with
         the same overall weekly dialysis duration

   Alleviation of hemodialysis “unphysiology”
        Kjellstrand CM, et al. The "unphysiology" of dialysis: A major cause of
         dialysis side effects? Kidney Int 1975; 7: S30-S34.
   Less swings in concentrations of all solutes (lower
    time average deviation)
             Urea, creatinine, uric acid, etc.
   Maintenance of concentrations within normal limits
             Potassium, phosphorus, calcium, pH, bicarbonate
   Less swings in hydration/ECV
             Lower interdialytic weight gains
             Elimination of hypervolemia/hypovolemia
                Weekly substance concentrations in routine HD
                   Weekly fluctuations in routine hemodialysis

                 NO NORMAL RANGE OF ECV, K, Bicarb, P, Ca, pH

Concentration   Weekly substance concentrations in daily HD
                    Weekly fluctuations in daily hemodialysis

                   NORMAL RANGE OF ECV, K, Bicarb, P, Ca, pH

      Call for change of paradigm
   Kt/V should be abandoned as the most
    important measure of dialysis quality
   Clinical symptoms and signs should be
    accepted instead
   Blood flow should range from 200 to 300 ml/min
   High performance dialyzers should continue to
    be used
         Call for change of paradigm
   Time and frequency of dialysis must be adjusted to residual
    urine output and tolerance of ultrafiltration. Ultrafiltration
    rate should range from 0.5%-1.5% of body weight/hr
   Dialysis frequency and duration should permit the
    achievement of blood pressure control without
    antihypertensive medications in 90%-95% of patients
   Anuric patients should not have dialysis shorter than five
    hours in thrice weekly schedule.
   More frequent dialysis is preferred in anuric patients, but
    weekly dialysis time should not drop below 15 hrs
                              Festina lente
                 [hasten slowly (deliberately)]
                Motto of Gaius Julius Caesar
            Octavian Augustus (63BC - 14AD)
The first and greatest Emperor (27BC - 14AD)

                This Latin motto should be
                 written on a wall of every
                        hemodialysis room

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