Online Clearance Monitoring

Haemodialysis

Contents

1. Foreword 4

2. Dialysis dose 5 2.1 Standard methods of determination of the dialysis dose 5 2.1.1 Urea Reduction Ratio (URR) 5 2.1.2 Kt/V 5 Clearance K Effective treatment time t Urea distribution volume V 2.1.2.1 Determination of Kt/V using blood samples 7 Formal urea kinetic modelling Single-pool Kt/V (Daugirdas formula) Single-pool variable-volume Kt/V Double-pool Kt/V (dpKt/V) and its approximation: Equilibrated Kt/V (eKt/V) 2.2 The clinical relevance of dialysis dose 10 2.3 Recommendations for dialysis dose and the frequency 11 of measurement of delivered dose

3. Online Clearance Monitoring – OCM® 12 3.1 The method of OCM® operation 12 3.2 OCM® in ONLINEplus Haemodiafiltration treatments 17

4. Optimisation of dialysis efficiency 18 4.1 Blood flow 18 4.2 Dialysis time 19 4.3 Dialyser (Membrane surface area, low flux/high flux) 20 4.4 Dialysate flow rate 20

5. Measurement of plasma sodium with OCM® 22

6. Frequently Asked Questions about OCM® 24

7. References 26

3 1. Foreword

Online Clearance Monitoring (OCM®) is a standard feature of the Fresenius Medical Care Therapy System 5008 that provides an automatic intradialytic measurement of the effective in-vivo urea clearance K, the total cleared blood water volume Kt, the delivered dose of dialysis Kt/V and the plasma sodium concentration of the patient.

With the OCM® it is possible to easily monitor these essential parameters without additional costs during regular ONLINE Haemodiafiltration in either pre- or post-dilution mode, and during haemodialysis treatments.

The OCM® helps physicians and nursing staff to ensure and document on a regular basis that the renal replacement therapy meets the recommended or required quality standards without the need for additional laboratory tests or expenses.

This user brochure provides clinical and technical background information on the OCM®, describes its operation and gives recommendations for the application of the OCM®.

4 2. Dialysis dose

Similar to the term “dose”, that defines the specific Ultrafiltration leads to a very efficient transfer of urea quantity of a medical product or drug required for the from the blood into the dialysate, but this does not treatment of a patient, the dialysis dose can be defined result in a direct reduction of the urea concentration in as the quantity of dialysis treatment delivered for a the blood. This removal of urea is not accounted for in given period of time. In general the dialysis dose is the URR method. The greater the UF volume removed measured by the comparison between the baseline and during dialysis, the more inaccurate the results of final concentration of a defined substance in the blood dialysis dose calculation based on URR (2,3). of the patient. The more efficient the dialysis session, the greater the reduction of this given substance is. 2.1.2 Kt/V In theory, it is possible to determine how efficient any substance which is present in the blood has been removed during dialysis. Even though different methods Clearance Dialysis time (Manufacturer) (Nephrologist) have been developed to measure the dialysis dose, K x t changes in urea concentration are monitored in order to determine the dialysis dose in standard practice. V

Distribution volume 2.1 Standard methods of determination (Patient) of the dialysis dose 41: The variables of the Kt/V formula

2.1.1 Urea Reduction Ratio (URR) The formula Kt/V, which is the most commonly used A simple and commonly-used method of determining index of the adequacy of the dialysis treatment, is the dose of dialysis is the calculation of the Urea Reduc- a mathematical representation involving the blood tion Ratio (URR). This involves a direct comparison of volume which has been completely cleared of urea pre- and postdialytic urea concentrations and shows during a specified dialysis and the urea distribution the percentage reduction of the urea concentration volume of the patient requiring detoxification. 41 during dialysis treatment (1).

The variables of the Kt/V formula:

Cpost URR = 100 ( 1 - ) Clearance K Cpre

Cpost: postdialytic urea concentration/Cpre: predialytic urea concentration As well as being used as a diagnostic parameter in renal function tests, the term “clearance” is also used in renal replacement therapy. The primary parameter In view of the simplicity of the method, URR is frequently used to determine the volume of blood which has used to determine the dose of dialysis, despite the fact been purified during treatment is the effective in-vivo

2 that the method has an in-built analytical weakness clearance Keff (mL/min) 4 . Clearance is defined as which may cause inaccurate results. In contrast to other the (hypothetical) volume of blood which has been methods, the URR method does not take into account totally “cleared” of a given substance each minute; that urea is also removed from the blood by ultrafiltration. clearance is thus expressed as mL/min.

5 In-vivo must be differentiated from effects of the corpuscular blood constituents (mainly in-vitro clearance: the erythrocytes), the dissolved plasma proteins, and the adsorption of plasma proteins on the dialysis mem- In-vitro clearance represents the purely diffusive clearance brane (the “secondary membrane”) considerably alters achieved by a dialyser tested under defined conditions the diffusion properties of the dialysis membrane even (as specified in standard EN 1283) using standardised under otherwise comparable circumstances. aqueous solutions. The EN 1283 standard requires that measurements be conducted at a predefined dialysis In-vivo clearance is thus inevitably lower than the stan- fluid flow rate without any ultrafiltration (that is, without dardised in-vitro clearance, but does reflect the actual a convective clearance component). Only on the basis conditions of the treatment and is thus of central impor- of these non-patient-specific laboratory measurements tance for the determination of dialysis efficiency. is it possible to compare clearance values and thus the relative efficiency of individual dialysers. In-vitro clear-

ance, i. e. the efficacy of a dialyser under laboratory CB in – CB out K = QB conditions, is thus primarily determined by the design CB in features of the dialyser as well as the membrane char-

K = clearance (mL/min), QB = effective blood flow (mL/min), CB in = concentration acteristics. of inflowing blood, CB out = concentration of outflowing blood

In-vitro clearances of dialysers, on the other hand, are measured under the actual dialysis treatment conditions Effective dialysis time t involving the patient, generally by means of analysis of the blood prior to and after passing the dialyser: the term Effective dialysis time t is the actual duration of diffusive “whole blood clearance” is thus used in this context. blood detoxification (time of dialysis fluid flow in the In-vivo clearances are substantially different from in-vitro dialyser with the blood pump operating). Interruptions clearances as, during the dialysis of whole blood, the to the dialysis treatment for therapeutic or technical

In-vivo Clearance K influenced by: dialyser, effective blood (water) flow (considering haematocrit), ultrafiltration, recirculation, dialysis fluid flow Effective dialysis time t sometimes reduced due to alarms and bypass conditions or premature termination of the treatment

Urea distribution volume V 42: The dose of dialysis Kt/V is a result of the effective dependent on body size and composition, in-vivo urea clearance K, the effective dialysis time t and weight, age and gender of the patient the urea distribution volume V.

6 reasons are considered in the effective dialysis time The following examples should help explain the

42. The effective dialysis time is, in most cases, use of the Kt/V concept: shorter than the total duration of treatment provided. Assuming Kt is 20 litres, this means that 20 L of blood In an observational study, Segura et al. have demon- have left the dialyser after being cleared of urea. How- strated that the mean prescribed duration of dialysis ever, this information does not yet tell us which dialysis is generally not achieved in practice. Thus, over the dose the patient has received. In the case of a patient period of 1 year, the loss of time and therefore of with a urea distribution volume V of 30 L, a cleared efficiency per patient was equivalent to that of 7 whole blood volume of 20 L has quite a different meaning dialysis sessions (4). than in the case of a patient with a urea distribution volume of 40 L. If Kt/V is equal to 1, this means that the volume of blood which has been completely cleared Urea distribution volume V of urea in the dialyser is exactly equivalent to the urea distribution volume of the patient. In a patient with a The urea distribution volume V is equivalent to the total distribution volume of 40 L, Kt must be equal to 40 L body fluid, consisting of the proportion of water in blood so that the result of the formula Kt/V is also 1. If the Kt (7 %) as well as the interstitial (31 %) and intracellular value is only 20 L, the Kt/V value would be 0.5. volume compartments (60 %). Upon commencement of dialysis, urea is homogeneously distributed throughout Even if Kt/V is equal to 1, this does not mean that the the body; hence, more than 90 % of the urea which total body fluid or the total urea distribution volume accumulates in the human body is not present in blood, of the patient is free of urea, but only that, using the but in the interstitial and intracellular volume compart- example above, 40 L blood have left the dialyser after ments. Thus, only with continuous diffusion of urea being freed of urea. If Kt/V is 1.0, a urea concentration from these compartments into the blood and further of approximately 36 – 37 %, relative to the baseline transport into the extracorporeal circulation is the value, remains after dialysis. largest proportion of urea present in the body made available for dialysis. 2.1.2.1 Determination of Kt/V The larger the blood volume (high blood flow rate) which using blood samples reaches the dialyser during a treatment session and the longer the duration of the time-dependent diffusion There are various methods which can be used to de- from the interstitial and intercellular compartments into termine Kt/V in practice. These differ in terms of the the blood (adequate treatment time), the more efficient underlying mathematical models used to predict and the dialysis treatment will be. determine urea kinetics (in other words, the changes in the blood urea concentration of the patient over time). A major advantage of the Kt/V equation is the fact that Some methods involve very complex calculations and it takes into account the individual body weight of the require appropriate software programmes. dialysis patient. Patients with the same Kt/V are detoxified to the same extent even if they have markedly different body weights. Dialysis treatments can thus be compared in terms of the elimination effect using the Kt/V method.

7 Formal urea kinetic modelling Single-pool Kt/V (Daugirdas formula)

The most complex, but at the same time most precise The best alternative to the urea kinetic modelling method of determination of Kt/V is the so-called for- method, also based on analysis of blood samples, mal urea kinetic modelling (5,6). This requires accurate is provided by the formula for the calculation of Kt/V measurement of: developed by J.T. Daugirdas (8).

• urea or BUN (Blood Urea Nitrogen): concentrations prior to and after the first dialysis session of the week, Single-pool variable volume Kt/V and urea or BUN concentrations prior to the second dialysis session of the week (assuming three treat- Most widely used at present is the following formula ments are provided per week) for calculating Kt/V: • the body weight of the patient prior to and after the first dialysis session of the week • the actual effective treatment time (not the prescribed Kt/Vsp = -ln (R – 0.008 x t) + (4 – 3.5 x R) x Uf/W duration of dialysis and not the time from connection to and disconnection from the dialysis machine) ln: natural logarithm, R: ratio of postdialytic ÷ predialytic BUN, t: effective dialysis time in hours, Uf: ultrafiltration volume in litres, • the effective urea clearance of the dialyser as measured W: weight of the patient after dialysis in kg. at the dialysis centre (not the value for in-vitro clearance quoted by the manufacturer). This mathematical model, which uses the natural loga- Urea kinetic modelling is a reproducible method which rithm to calculate Kt/V, provides sufficiently accurate not only allows calculation of the dialysis dose Kt/V, results over the full range of standard Kt/V values (9,10). but also of the parameter nPCR (normalised Protein In addition, the Daugirdas formula takes into account Catabolic Rate), an important marker of the nutritional the change in patient volume caused by ultrafiltration status of the patient. Moreover, urea kinetic modelling and its contribution to convective urea elimination. allows the exact calculation of the patient-specific urea distribution volume so that the individual dialysis pre-

scription can be given on the basis of measured data. ECV+ ICV blood ICV: Intracellular volume

The main disadvantage of the urea kinetic modelling [mg/dl] ECV: Extracellular volume method is the logistical aspect. Some parameters, such as the effective clearance achieved by a dialyser, are Equilibrated Kt/V (eKt/V) difficult to measure in clinical practice and the effort concentration ECV+ “Rebound” ICV blood required to obtain and process the necessary data BUN Single pool variable ECV+ can be considerable in large dialysis centres. volume Kt/V (spKt/V) ICV blood

More recently, a two point urea kinetic model has been Time [min] End of treatment validated which is based on only two measurements 43: Blood urea nitrogen concentration at the beginning (1), at the end (2) of urea or BUN instead of three, prior to and after the and 60 minutes after the end (3) of a HD treatment dialysis session and which supplies precise results with a marked reduction of logistical effort (7).

8 Double-pool Kt/V (dpKt/V) and its approximation: with low urea concentrations but having higher rates equilibrated Kt/V (eKt/V) of blood perfusion. Organs with low blood perfusion therefore also constitute a further urea reservoir. In the As in the case of the other (not discussed here) single- initial 30 minutes after completion of dialysis, the pool models, the Daugirdas formula considers the concentration equilibration again leads to a rebound, body, for the purposes of mathematical modelling as thus an increase in blood urea concentration. a single unified fluid pool, and does not take into account the differences in rates of urea transfer The extent of total urea rebound can differ greatly between the three fluid compartments blood plas- between individual patients. In a study conducted by ma, extracellular space and intracellular space. This Leblanc et al. (15), the mean rebound, the percentage difference in the transfer rate of urea is described as increase in postdialytic urea concentration 30 minutes the double-pool effect. after dialysis, in comparison with that immediately after completion of dialysis, was 17 %. With increasing efficiency of the dialyser, it is possible that urea is eliminated more rapidly from the blood than If this rebound effect is taken into account in the cal- it can diffuse from the cells into the blood. Due to this culation of the dialysis dose, the resultant Kt/V value is relative delay of urea movement from cells into blood, referred to as equilibrated Kt/V (abbreviated to eKt/V). the intracellular compartment becomes a non-equilib- On average, equilibrated single-pool Kt/V (eKt/V) is 0.2 rated reservoir for urea, and this aspect is not taken into lower than non-equilibrated single-pool Kt/V (17,18). account in the single-pool models for urea kinetics (9,12,13). Hence, on completion of a dialysis treatment, the intra- In order to obtain an exact value for equilibrated Kt/V, cellular urea concentration is greater than in blood the BUN concentration should ideally be measured 30 plasma, and the diffusion of urea from cells into blood minutes after completion of dialysis, but this is, un- nevertheless continues for approximately 30 – 60 fortunately, not practicable in routine practices of out- minutes after the end of treatment43. This phenom- patient haemodialysis centres. In order to overcome enon is called urea rebound (14,15). If this intracellular this problem, various formulae have been developed urea pool is large on completion of dialysis and is not which, after a third blood (urea) sample has been taken taken into account, the effective dialysis dose Kt/V will during the dialysis session (usually after 70 minutes be overestimated. This effect is particularly marked if dialysis), allow the postdialytic equilibrated urea con- high performance dialysers are used in combination centration to be approximatively calculated (16,19). The with a short duration of dialysis (16). additional effort required to obtain a third blood (urea) sample has meant that this method has not been In addition to the relative delay of transfer of urea widely accepted. between the various body compartments, the marked differences in blood perfusion of organs also contribute Daugirdas has also developed a formula which allows to the rebound effect. It should be borne in mind that the results of calculation of single-pool Kt/V to be extra-

(20) 70 % of total body water, and thus also urea, is present polated to equilibrated Kt/V . Formula 1 ( artKt/V) is in body organs with a relatively low blood perfusion, applicable if an arterial postdialytic urea value from such as skin and muscles at rest. As these urea-rich an arterio-venous access is available, while formula 2 organs have only a relatively low blood flow, their con- ( venKt/V) should be used if a mixed venous urea value tribution to the total plasma urea which reaches the from a veno-venous access is available: extracorporeal circulation is less than that of organs

9 In 2002, Port et al. published an observational study (1) equilibrated or eKt/V = artKt/Vsp – (0.6 x artKt/Vsp/T) + 0.03

(2) equilibrated or eKt/V = venKt/Vsp – (0.47 x venKt/Vsp/T) + 0.02 of major importance on the effect of delivered dialysis dose on the risk of mortality (31). T: dialysis treatment time in hours, t: dialysis time in minutes

In this retrospective study, the data for 45.967 US pa- The key advantage of these formulae is that only two tients who had commenced chronic haemodialysis blood samples are required for the calculation of the therapy between April 1997 and December 1998 were

equilibrated Kt/V. examined 44.

The following table shows the relationship between Dose Category

single-pool Kt/V (spKt/V) values and equilibrated Kt/V [%] Size of circle reflects number of patients per group

values (eKt/V) relative to the duration of treatment. rates

* death * * * * * Small Table 1: Ratio of single-pool Kt/V (spKt/V) and equilibrated Kt/V (eKt/V) * * as a function of treatment time (t) 2 * Medium

adjusted Small BMI < 23.2 kg/m Medium BMI 23.2 – 27.8 kg/m 2 Large eKt/V Large BMI > 27.8 kg/m 2

spKTt/V 2.0 hrs 2.5 hrs 3.0 hrs 3.5 hrs 4.0 hrs 4.5 hrs 5.0 hrs Annual 1.0 0.73 0.79 0.83 0.86 0.88 0.90 0.91 1.1 0.80 0.87 0.91 0.94 0.97 0.98 1.00 * p<0.05 compared to next lower URR group 1.2 0.87 0.94 0.99 1.02 1.05 1.07 1.09 1.3 0.94 1.02 1.07 1.11 1.14 1.16 1.17 44: Dialysis dose and body mass index are strongly associated with survival 1.4 1.01 1.09 1.15 1.19 1.22 1.24 1.26 in haemodialysis patients. Retrospective analysis of data from 45.967 US 1.5 1.08 1.17 1.23 1.27 1.31 1.33 1.35 hemodialysis patients starting dialysis during April 1997 through December 1998 (adapted from (31)). 1.6 1.15 1.25 1.31 1.36 1.39 1.42 1.44

In order to not mask the relationship between mortality 2.2 The clinical relevance of the risk and dialysis dose by the separate risk factor “body dialysis dose weight of the patient”, patients were initially sorted into three body weight groups – small, medium and large. If dialysis dose is determined, it is possible to prescribe The relationship between mortality risk and dialysis and subsequently monitor the dialysis treatment on the dose was then analysed separately for each of these basis of clinical parameters. A significant correlation body weight groups. The result was confirmed over between the average delivered dialysis dose and patient the whole range of dialysis doses analysed: the higher mortality rates has been demonstrated in many clinical the delivered dialysis dose, the lower the rate of patient studies (1,21–29). All these studies reiterate the fact that mortality. This study also showed that there is no specific the higher the delivered dose of dialysis, the lower the maximum dose above which no further decrease in patient mortality rates. patient mortality can be achieved. This means that during each dialysis treatment, it is advisable to deliver the The NCDS study (30) was the first long-term study which highest dialysis dose possible. investigated the correlation between dialysis dose and therapeutic outcome. The results not only demonstrated Other clinical aspects, such as the erythropoietin (EPO) a statistical relationship between urea elimination and requirement, can also be influenced by the dialysis dose mortality, but also allowed Gotch & Sargent to develop Kt/V. In a study published in 2001, the EPO require- the urea kinetic modelling method and define the Kt/V. ment of two patient groups with different Kt/V values

10 was compared (32). Measured haematocrit was identi- consensus on best practices and dialysis adequacy cal, at 35 ± 1.5 %, in the two investigated groups, A amongst the European nephrological community (67). and B, although group A received dialysis at a low Kt/V <1.2 and group B received dialysis at a high Kt/V >1.4 The respective recommendations regarding dia-

45. While group A (Kt/V<1.2) had an EPO requirement lysis dose are specified as follows: of 183 ± 95 U/kg/week, patient group B with its high Kt/V (>1.4) required only 86 ± 33 U/kg/week. This • The delivered dialysis dose should be regularly study shows that if a sufficiently high dialysis dose is measured and monitored – at least monthly using a delivered, this can have a positive effect on the overall standardised method clinical condition of the patient, which, in turn, is re- • The delivered dialysis dose should be expressed as flected in a reduction of the EPO requirement. equilibrated Kt/V (eKt/V) or as single-pool Kt/V (spKt/V) • The minimum dose per session on a thrice-weekly schedule should be eKt/V ≥ 1.20 (spKt/V ~ 1.4)

Group A The EBPG for Haemodialysis are considered to be the Hct: 35% reference guidelines in Europe and have been adop- [U/kg/week] ted or taken as the basis for the preparation of national

dose Group B Hct: 35% guidelines. EPO

It has become one of the main aims of haemodialysis EPO dose treatment, particularly in the US, to deliver a high Kt/V

45: The influence of a high Kt/V on the weekly EPO-dose (adapted from (32)). dialysis dose. In the US, the average delivered Kt/V dialysis dose continuously increased in the period 1986 to 1999 from 0.9 to today’s figure of greater than 1.4. 2.3 Recommendations for dialysis dose and the frequency of measurement of The prescription of an adequate Kt/V not only repre- delivered dose sents the mathematically standardised specification of a verifiable therapy goal, but is a quality criterion for As a general rule, it is the task of the treating nephro- dialysis therapy itself because of the frequently descri- logist, to prescribe the form and dose of dialysis treat- bed direct correlation between dialysis dose and patient ment, taking into account the specific clinical factors mortality (1, 21 – 29). The regular measurement of delivered of the individual patient. Kt/V is thus an important aspect of medical quality assurance. To date, however, the need to extensively A very comprehensive collection of recommendations sample urea concentrations, and the associated for the prescription of dialysis was first provided by the logistical and financial requirements, has made it US National Kidney Foundation (NKF) in their guide- difficult to conduct close monitoring of dose or even lines on adequate haemodialysis treatment. The DOQI to measure delivered dose in each session. As an auto- guidelines were published in 1997 and subsequently mated procedure, which is not based on a urea/blood updated as the K/DOQI guidelines (Kidney Disease sampling method, the Online Clearance Monitoring Outcomes Quality Initiative) in 2000 (33). The European (OCM®) has made it possible to measure dialysis dose Best Practice Guidelines for Haemodialysis (EBPG Part1) easily without additional expenses during on-going were introduced in 2002 and represent the current dialysis treatments at every session.

11 3. Online Clearance Monitoring – OCM®

concentration essentially determines the total conductivity of the dialysis fluid.

Although the small, positively-charged sodium ion differs from the non-charged and larger urea molecule, both particles exhibit comparable in-vitro and in-vivo diffusion characteristics across a synthetic dialysis membrane, i. e. their specific diffusion coefficient is almost identical at 37°C (Na+: 1.94 x 10 – 5 cm2/s,

Urea: 2.20 x 10 – 5 cm2/s46 (34) ). Under real dialysis conditions, the difference in clearance is even smaller than the difference of diffusion coefficients since the OCM® screen during a HDF treatment clearance is limited by blood and dialysate flow rates and not by the diffusion process across the dialyser The Online Clearance Monitoring (OCM®) is a stan- membrane. dard feature integrated in the Fresenius Medical Care 5008 Therapy System. It provides automatic intradia- aqueous solutions lytic measurement of the delivered dialysis dose Kt/V,

the effective in-vivo urea clearance, the accumulated [ml/min]

cleared plasma volume Kt and the plasma sodium Coefficients of diffusion at 37°C

learance 2 ® c [cm /s] concentration of the patient. OCM can be applied Na+ Urea -5 -5 during regular ONLINEplus haemodiafiltration treat- 1.94 x 10 2.20 x 10

ments in pre or post dilution mode as well as during Electrolyte Urea clearance [ml/min] standard haemodialysis. 46: OCM® is based on the equivalence of electrolyte and urea clearance (adapted from (34)) The dialysis dose determined by the Online Clearance Monitoring (OCM®) is equivalent to a single-pool Kt/V (spKt/V). By means of indirect determination of ion concentrations in the haemodialysis solution (measurement of conductivity at the inflow and outflow of the dialyser) it 3.1 The method of OCM® operation is technically possible to determine the diffusion profile of sodium ions across the dialysis membrane and thus To achieve the objective of developing a low cost calculate the dialysance or ionic clearance (D). On the method of monitoring clearance, it was necessary to basis of the dialysance of sodium ions, the “diffusibi- move away from the cost-intensive concept of enzy- lity” of urea through the membrane (permeability) and

matic urea analysis. In searching for an alternative, a thus urea clearance can be determined (35) . substance was considered which is present in large quantities in the dialysis fluid and where changes in For accurate measurement of sodium dialysance, concentrations can be measured by the sensors in- conductivity sensor cells have been installed in the stalled within the dialysis machine – namely ionised inflow and outflow lines of the dialyser to measure the sodium. Sodium ions represent the largest proportion conductivity of the dialysis fluid (prior to the dialyser) of freely mobile electrolytes in the dialysis fluid and their and in the dialysate (after the dialyser) (36).

12 Blood outflow Dialysis fluid inflow This short-term increase in the conductivity of the dialysis fluid prior to entering the dialyser is subsequently Fistula Cb out Cd in Conductivity cell “in” reduced by diffusion of a portion of the sodium ions Dialyser across the dialysis membrane into the blood of the QB QD patient during the passage through the dialyser. The Conductivity cell “out” Cd out dynamic input conductivity signal (pulse) at the dialyser Cb in inflow is continuously monitored by the conductivity Blood pump Blood inflow Dialysate outflow sensor installed at that position: the signal at the outflow

47: The diagram shows the location of the 2 conductivity cells of the OCM® of the dialyser is registered by an equivalent sensor positioned there. The relative areas under the curves for the two recorded conductivity signals reflect the In order to achieve a detectable diffusion of sodium diffusion of sodium ions across the dialyser membrane. ions across the membrane, the otherwise moderate The lower the value of outflow conductivity compared diffusion gradient of sodium between the blood and to inflow conductivity, the greater the amount of sodium dialysis fluid sides of the dialyser must be temporarily that has diffused from the haemodialysis solution into increased. the blood compartment as a result of the diffusion gradient or, in other words, the more permeable the For this purpose, the dialysis machine induces a short dialysis membrane for sodium is (45). term pulse to increase (or decrease) the sodium concentration in the dialysis fluid, thereby resulting in an As urea – as postulated above – has a diffusion profile increase in diffusion of sodium ions into the blood similar to that of the sodium ion, urea clearance can be compartment or in the reverse direction48. Assu- determined (using appropriate correction factors) irre- ming that the conductivity pulse does not exceed the spective of the actual concentration of urea in the blood. specified conductivity limits, alternate pulses increase and decrease conductivity to ensure that the sodium Steil et al. were able to demonstrate in 1993 that the balance remains as neutral as possible (37 – 44). dialysance is directly proportional to urea clearance (35). They showed how closely measured ionic clearance correlates with measured urea clearance. In a validation study conducted in 2001, Kuhlmann et al. produced clinical evidence that dialysance also correlates with

conductivity urea clearance in-vivo, and that it can be determined

[mS/cm] Rec. accurately within a very low analytical error range of only ± 5 % by the OCM®49 (39). As a comparison: the Inlet/Outlet analytical error for the determination of urea in the Dialysis Time [secs] laboratory is approx. ± 7 %. In both of the above-men- tioned investigations, it was possible to demonstrate

Inlet conductivity Outlet conductivity that the correlation between electrolyte clearance and the clearance values for urea determined using stan- Recirculation dard methods is almost ideal. The majority of results lie, with sufficient precision, on the line of identity and 48: Online Clearance Monitoring is operating with a short-term dynamic conductivity pulse the correlation value r is close to the ideal value of 1 (if all values for ionic clearance and laboratory data

13 clearance were exactly identical, all results would be ports recirculating sodium ions to the dialyser which, on the ideal line). The majority of values are within an depending on the concentration in the blood, will diffuse error range of only ± 5 – 6 %. back into the dialysate. Consequently this results in a less favourable ratio of the areas under the conductivity Through further improvements of the Online Clearance curves, and thus to a reduction in clearance equivalent Monitoring® method, Goldau et al. reported in a further to the contribution made by recirculation. Although it is series of analysis in 2002 an improved level of precision not possible to produce actual figures for recirculation of below the 5 % error limit (45). from the OCM®, the effect is taken into account in the calculation of effective in-vivo clearance.

The OCM® determines clearance “online” during the entire treatment period, i. e. with no time lapse and at predefined measurement intervals. The number of

[ml/min] measurement cycles to be performed during the treatment can be pre-selected within certain limits (see 5008

learance ®

c Operator’s Manual). In addition, the OCM is capable

urea of detecting adjustments to blood and/or dialysate flow rates within 1 minute and then immediately recalculates Blood the corresponding new clearance values. This means Error K: ± 5% that the effects of any alteration to treatment parameters on actual clearance can be continuously monitored

Electrolyte clearance OCM® [ml/min] during an ongoing session.

49: Correlation of electrolyte clearance measured by the OCM® and blood urea clearance In addition to the urea clearance K, the data for the current effective dialysis time t are obtained from the Fresenius Medical Care Therapy System 5008 and are The precision of the conductivity monitoring is deter- included in the calculation of the dialysis dose. The mined, among other factors, by the stability of the plasma effective dialysis time t is defined as the time in which sodium concentration during measurement. The less physical dialytic processes between the blood of the variation in the plasma sodium concentration of the patient and the dialysis fluid occur. The time of any patient during the measurement cycle, the more pre- interruption of treatment for technical or therapeutic cise the result is. For this reason, the time interval of reasons and the duration of preparation and reinfusion conductivity variation is kept as short as possible in procedures are not included: only the “true” dialysis the OCM® technique. time (diffusion time) is taken into account.

With this comparatively short (but still sufficiently long) On the basis of the two measured parameters – urea measurement of dialysate conductivity at the dialyser clearance and effective dialysis time – the OCM® outflow, not only the sodium dialysance of the dialyser, calculates the cumulative water volume contained but also the negative effects of total recirculation (fis- within the blood K x t (in litres) which has been cleared tula recirculation plus cardiopulmonary recirculation) of urea, which is equivalent to that proportion of the

can be determined48. Even after the conductivity pulse circulating blood from which all urea has been re- in the dialysate has faded out, recirculating blood trans- moved during dialysis: K x t = x (L).

14 In order that the Kt/V value can be determined by di- vision of the result for K x t by the urea distribution volume V, the operator must enter an appropriate value for the urea distribution volume V of the individual dialysis patient.

Effective clearance: Effective dialysis time: accurately known precisely known from from OCM® (±6%) the 5008 K x t

V Normally unknown

V from anthropometric data (Watson,Hume-Weyers ...),large deviations 411: A calculator to estimate the urea distribution volume V according to lead to an approximate Kt/V anthropometric formulae is integrated in the OCM® V from a previous Urea Kinetic Modelling procedure (DCTool), leads to the best results for Kt/V (± 0.1 Kt/V) V from other methods, e.g. bioimpedance

410: To calculate the Kt/V the OCM® measures K and the 5008 Therapy It is not only possible to derive the V of a patient by System measures the exact effective dialysis time t; the user has to enter the patient’s V calculation, but this parameter can also be precisely measured. In clinical routine, the bioimpedance spectroscopy technique or the urea kinetic modelling The easiest method of estimating urea distribution method described in section 2 above can be used. volume V is to use the anthropometric formulae de- Once this measured value is available, it can be directly veloped by Watson (48), Hume-Weyers (49) and Mellits- entered into the data-entry menu of the OCM®: the Cheek (70), the latter being especially adapted for information necessary for the anthropometric formulae children below the age of 16. All formulae can be (age, gender, etc.) is then, of course, no longer required. selected in the OCM® menu of the 5008. The Watson formula calculates the V of a patient on the basis of The anthropometric formulae allow V to be simply and body weight, height, age and gender411. quickly estimated, but the results represent only a standardised mean value for the population as a whole. Deviations attributable to individual factors, such as an Male above-average proportion of fat or muscle tissue, are V = 2.447 - 0.09516 x age + 0.1074 x height + 0.3362 x weight urea not accounted for. In some cases, there may be marked Female differences between the value for V calculated using V = -2.097 + 0.1069 x height + 0.2466 x weight urea the Watson formula and the measured value for V.

Kloppenburg et al. have demonstrated, in a compara- The Hume-Weyers formula requires information on tive study, that the results for urea distribution volume body weight, height and the gender of the patient; in- V calculated using the anthropometric Watson formula formation on age is not required. For information on the regularly exceed the measured V of the same patient Mellits-Cheek formula please refer to the FAQ section. by 26 % (50). Thus, if the value for V obtained using the Watson formula is used instead of a measured value for calculation of Kt/V, the achieved Kt/V is frequently underestimated.

15 In order to determine an exact value for spKt/V using urea profile of a haemodialysis patient based on two the OCM®, it is always preferable to enter the measured blood samples (pre and postdialytic) using the sing- urea distribution volume rather than an anthropomet- le-pool variable volume method (7). Important data rically-derived V. relevant to the dialysis and nutritional status of the patient, such as urea distribution volume, Kt/V and protein catabolic rate (PCR) are derived from this. The DCTool programme differs from the standard urea kinetic programmes in that, instead of calculating theo- retical clearance on the basis of blood and dialysate flow rates, the effective in-vivo clearance – averaged for the treatment as a whole – as measured by the OCM® is used for modelling.

For the determination of the urea distribution volume of a patient using the DCTool, the basic patient data and information on treatment regimen needs to be entered. Then one dialysis treatment is selected and the related main treatment and OCM® data (i. e. the average effective in-vivo clearance) together with the 412: DCTool is a urea kinetic modelling software to precisely calculate pre- and postdialytic urea values from blood samples, the urea distribution volume of the patient are entered in the DCTool programme. With this information, the DCTool conducts an urea kinetic analysis With the software “Dose Calculation Tool” (DCTool), and determines a precise value for the urea distribution Fresenius Medical Care provides the OCM® user volume V; apart from other very interesting dose and with an uncomplicated and precise instrument for nutritional parameters. Once this assessed value for V the accurate calculation of patient-specific urea dis- is available, it can be entered directly into the OCM® tribution volume V using treatment and laboratory template, saved on the PatientCard and is hence avail- data. The DCTool is a urea kinetic modelling (UKM) able for subsequent treatments. This enables the OCM® software programme based on 2 point urea kinetic to calculate an exact value for spKt/V with an error < 0.1 modelling. The programme determines the weekly for each routine dialysis session conducted over a lon-

The conventional procedure today Aspects 5008 with OCM® option

Blood samples (expensive) Kt/V ≥ 1.2... 1.8 Dialysate; K and t (no additional costs) Once a month/quarterly Frequency In every session Retrospective Control Continuous, online Staff, syringes, lab time, cost and energy Effort None 6 – 8 % Accuracy of K 6 % Inconvenient Handling Automatic Unpractical and uncommon Quality assurance Standard!

413: OCM® offers many advantages in comparison with the conventional method for the Kt/V measurement

16 ger time period (up to 6 months for stable patients) (66). It is possible to convert this single-pool Kt/V determined by the OCM® to an eKt/V (≈ double pool Kt/V) using the formulae provided in section 2.1. Alternatively, eKt/V values are also shown in the table 1 on page 10. In order to ensure that the V value is appropriately updated, it is advisable to repeat urea kinetic model- 414: The OCM® display: The blue line indicates the urea clearance, the cumulating Kt/V is displayed by the red line, the Goal-Kt/V is visualised as a ling calculations with DCTool within the framework of green line. routine laboratory tests every 6 – 12 weeks.

In clinical studies in which 40 treatments and 151 treat- haemodialysis in the removal of middle molecules. In ments were analysed, it was shown that the DCTool- selected European countries, up to 30 – 40 % of the method provided the optimum value for the urea distri- dialysis population is treated with ONLINE HDF, the bution volume of a patient (51,52,66) and that the results average however being around 10 % (61). agree well with the total body water measured with bioimpedance spectroscopy. Several studies have demonstrated clinical advantages of the ONLINE HDF treatment modality such as

® The use of the OCM functionality and DCTool in an increased dose of dialysis, a reduced risk of ß2- combination makes it possible to determine the exact microglobulin-associated amyloidosis (62,63), a positive value for spKt/V during each routine dialysis. influence on the treatment of anaemia (64) and improved intradialytic cardiovascular stability (65). The The parameters relevant to therapy monitoring, includ- results of two recent studies even demonstrate that ing the OCM® measurement results, are displayed patients treated with ONLINE HDF had a significant in a clear overview with a multi-coloured diagram on 35 % reduction of mortality risk compared to patients the touch screen of the 5008 Therapy System. The treated with standard haemodialysis (68,69). clearance K is displayed during the course of the treatment as a blue line in the “OCM® diagram” graphic, The precision of the OCM® clearance measurement so are the current and absolute values for K, Kt/V or under ONLINE HDF conditions has been validated Kt and Goal-Kt/V. In addition, the cumulative Kt/V (red in-vitro and in clinical experiments by Canaud et al. line) or Kt (black line) are visualised in relation to the set (Hôpital Lapeyronie, Montpellier, France; publication in Kt/V target (green line). KI pending (71)). In these investigations, an error range of 6 % for the clearance measurement of the OCM® system during ONLINEplus HDF was reported. 3.2 OCM® in ONLINEplus Haemodiafiltra- tion treatments With the introduction of Online Clearance Monitoring in ONLINEplus Haemodiafiltration it is possible to easily ONLINE Haemodiafiltration (HDF) with its numerous monitor the dose of dialysis during highly efficient, positive effects on uraemia-related cardiovascular risk convective treatments. factors, is acknowledged as the most effective dialysis treatment modality that comes closest to the elimination profile of the natural kidney. In particular, HDF shows superior clearances in comparison to standard

17 4. Optimisation of dialysis efficiency

The efficiency of each haemodialysis treatment is determined by the following four parameters:

• the effective extracorporeal blood flow • the actual dialysis time • the effective urea clearance achieved by the dialyser • the dialysate flow rate

It is essential to achieve the appropriate balance of these parameters in order to ensure that adequate dialysis treatment is provided and also to ensure that the resources available are economically utilised.

4.1 Blood flow – under standard conditions of dialysis lead to an increase in the urea clearance of approximately 15 %.

Dialysate flow 500 mL/min When prescribing the required blood flow, and particularly when increasing blood flow, the individual vascular access of each patient must be considered.

[mL/min] The fistula blood flow rate (average flow rate in radio- cephalic fistula is approximately 500 – 900 mL/min) learance c should always markedly exceed that of the extracor-

Urea poreal blood flow rate in the dialyser, otherwise there is the risk that recirculation, which compromises efficiency, may be induced. Recirculation occurs when Blood flow [mL/min] blood that has already been cleared of toxins flows, counter to the natural direction of flow in the fistula, 415: Urea clearance of Fresenius Medical Care FX 60 dialyser at different blood flow rates out of the venous cannula directly into the arterial cannula and mixes with non-purified blood. Recirc- ulating blood has only a low toxin load prior to its The extent of urea clearance achieved during dialysis repeated passage through the dialyser. As a result, is determined largely by the effective blood flow rate. the toxin removal per time unit is reduced and dialysis Increasing the blood flow rate is thus a very effective efficiency decreases. method of increasing dialysis efficiency (53). Figure 15 illustrates that in the blood flow rate range 0 – 600 There are, however, various devices available, such as mL/min, the increase in urea clearance is proportional the Blood Temperature Monitor (BTM), obtainable to the increase in blood flow rate. Under the specified as an optional extra to the 5008 Therapy System, conditions, e. g. with the Fresenius Medical Care FX 60 which can automatically measure recirculation at a dialyser, an increase in blood flow rate from 200 mL/min pre-selected blood flow rate. In case of a signifi- to 400 mL/min results in an increase in urea clearance cant drop in the measured clearance values (≥ 20 %) by 65 %, while an increase in blood flow rate from during the same treatment or compared to the 150 mL/min to 300 mL/min results in an improvement previous one stored on the 5008 PatientCard, a of 82 %. But even moderate increases in blood flow BTM recirculation measurement can be automati- rate by 50 mL/min – from 250 mL/min to 300 mL/min cally initiated by the OCM®.

18 Since the OCM® conducts the clearance measure- 4.2 Dialysis time ment on the dialysate side only, the accuracy of K is not influenced by deviations in the blood flow rate. In As the dialysis time t is a direct variable in the Kt/V the case of blood or dialysate flow changes in between formula, it is important to ensure that a sufficiently long two subsequent measurements, the OCM® is able to effective dialysis time is delivered to ensure provision of account for these changes by using a mathematical an adequate dialysis dose. It is essential to prescribe estimate for K under the new conditions. a sufficiently long treatment time which, by avoiding all interruptions caused by alarms or other delays, should, as far as possible, also represent the effective dialysis time.

The DOQI guidelines, for example, take into account the discrepancy between prescribed and effective treatment time, which frequently occurs as a result of undesirable interruptions in the dialysis treatment, by recommending prescription of a slightly increased Kt/V value of 1.3 if a Kt/V of 1.2 is to be achieved (33). In a study published in 2001, J. Leon et al. investigated the dialysis prescriptions for 721 dialysis patients (54). They found that in 15 % of patients the dialysis prescription was too low to achieve the minimum dose of Kt/V 1.2 as recommended in the DOQI guidelines. They also concluded that in this patient group, a prolongation of treatment by up to 30 minutes (depending on patient) would have resulted in the delivery of an adequate dialysis dose in 75 % of the cases.

This result shows that even a moderate prolongation of treatment time can be an essential factor in ensur- ing delivery of an adequate dialysis dose. Individual prolongation of treatment time should thus seriously be taken into consideration, despite the difficulties of incorporating this in shift schedules and the unwilling- ness of patients to an increase in the dialysis time.

19 4.3 Dialyser 4.4 Dialysate flow rate (Membrane surface area, low flux/high flux) It is the concentration gradient between the blood and

240 dialysate which mainly determines the diffusion rate during haemodialysis. The larger the flow of fresh, toxin- 230 free dialysis fluid through the dialyser, the larger the 220 removal of toxins by diffusion is (55). 210 [mL/min]

200 Blood flow QB: 300 mL/min

learance QD: 500 mL/min c 190 QB: 300 mL/min

Urea QD: 500 mL/min 180 [mL/min]

170 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2 2,4 FX 60 Effective dialyser surface [m2] learance

FX-class high flux range c FX-class low flux range urea 416: Urea clearance of Fresenius Medical Care low and high flux dialysers as function of the effective surface vitro In Dialysate flow [mL/min]

417: Urea clearance of a FX 60 dialyser as function of blood and dialysate The dialyser itself plays an important role in the effi- flow. The higher the blood flow the higher is the positive effect of increasing the dialysis fluid flow on urea clearance ciency of dialysis treatment. The use of a dialyser with the highest possible urea clearance is required for optimisation of the dialysis treatment. As a representative In many dialysis centres, a dialysis fluid flow rate of of other low molecular weight substances, urea is one 500 mL/min is used by default in haemodialysis treat- of the most important marker substances in dialysis. ments, although optimal solute clearances would already be achieved at lower dialysis fluid flow rates. As The urea clearance is not only determined by the active shown in figure 17, at a dialysate flow rate equal to the surface area of the membrane, but also by the membrane blood flow rate, approximately 90 % of the maximum permeability (high or low flux) and the construction of solute clearance is already achieved. Thus, much the dialyser itself. Figure 16 shows the increase in urea higher dialysis fluid flow rates would not significantly clearance under the given conditions (blood flow rate: contribute to increases in clearances and are therefore 300 mL/min, dialysate flow rate: 500 mL/min) in relation not necessary from an economical point of view. to an increase in the effective membrane surface area. Under identical conditions, urea clearance is improved The 5008 Therapy System offers the AutoFlow func- by changing from low flux to high flux dialysers. To uti- tion, which automatically adjusts the dialysis fluid flow lise a given dialyser to its full capacity, it is important rate in order to derive an optimal ratio between blood to consider the relationship between effective surface flow rate and dialysis fluid flow rate. Any potential effects area and the achievable blood flow (see instructions on low molecular (e. g. urea) clearance can however be for use: re-commended blood flow range). monitored with OCM®, thus providing another very meaningful function for further treatment optimisation, e. g. by means of increased blood flow and/or perform- ing ONLINE HDF.

20 The prerequisite for an effective dialysis treatment is an appropriate balance between blood flow rate, dialysate flow rate, treatment time and the dialyser used.

For this purpose, Fresenius Medical Care has developed appropriate software in the form of the Clearance Cal- culation Tool (CCT), which makes it possible to compare the efficacy of Fresenius Medical Care dialysers under diverse predefined treatment conditions.

418: The CCT Clearance Calculation Tool is a software for the planning of haemodialysis treatments. CCT allows a clearance estimation of any Fresenius Medical Care dialyser over the full range of treatment conditions

21 5. Measurement of plasma sodium with the OCM®

In addition to the delivered dialysis dose, the OCM® also Various studies have demonstrated that restriction of measures the level of plasma sodium of the patient. sodium intake has a favourable effect on long term This information is a useful aid in the appropriate blood pressure control in dialysis patients; low sodium therapeutic adjustment of the sodium concentration content in the dialysate, provided this is tolerated by of the dialysis fluid to the individual plasma sodium the patient, can assist in dietary control of sodium in- level of the patient. take (57 – 59). Krautzig et al. have demonstrated that with low sodium intake, it is possible to reduce, or even dis- In a clinically stable haemodialysis patient, there is continue, the use of anti-hypertensive medication (60). physiological equilibrium between the quantity of salt ingested with the nutrition and the quantity of NaCl However, if a dialysate with a non-physiological, low removed during haemodialysis. sodium concentration is used, this can frequently trigger intolerance reactions, such as hypotension, There are two mechanisms of intradialytic removal of tiredness and cramps. NaCl: ultrafiltration (UF) and diffusion. Conversely, the use of a dialysate with a non-physio- The electrolyte composition of the ultrafiltrate removed logical, high concentration of sodium may improve for the purposes of dehydration of the patient is very blood pressure stability during dialysis, but also in- similar to that of blood plasma, the NaCl concentration creases the patient’s thirst and results in a subsequent in the ultrafiltrate varies from patient to patient in the increase in fluid intake by the patient. This, in its approximate range 135 – 140 mmol/L. The quantity of turn, leads to increased overhydration and long-term NaCl removed during ultrafiltration depends directly on hypertension in the patient. Figure 20 summarises the volume of UF removed; the higher the volume of UF, the advantages and disadvantages of high and low the greater the quantity of NaCl removed from the patient. sodium concentrations in the dialysate.

Diffusion is even more effective than ultrafiltration in Acute effects Chronic effects the removal of NaCl, though in this case maintenance + cardiovascular stability Chronic volume overload – of an effective concentration gradient between blood – thirst Na145 hypertension – and dialysate sides is required.

Na138 If the concentration of NaCl available for free diffusion – extracellular dehydration – plasma osmolality in the blood plasma of the patient is higher than in the – disequilibrium Na dialysis fluid, there is a flow of NaCl from blood into – hypotension 130 blood pressure control + dialysis fluid; NaCl is removed from the patient. The 419: Acute and chronic effects of different sodium concentrations in the opposite can, of course, also occur: if the concentra- dialysis fluid tion of NaCl in the dialysis fluid is higher than in blood plasma, it diffuses from the dialysis fluid into the blood and there is dialysis-induced salt-loading. Individual prescription of the sodium concentration of the dialysis fluid always requires achieving a compromise The concentration of sodium in the dialysis fluid thus between long-term beneficial blood pressure control determines whether the sodium balance is positive or (with low dialysis fluid sodium) and the short-term ad- negative during haemodialysis treatment. vantage of better cardiovascular stability during treatment (with high dialysis fluid sodium). Hence, when

22 deciding on the optimum concentration of sodium in factors so that the displayed value for plasma sodium the dialysis fluid, the nephrologist should consider the is equivalent to that obtained by means of flame pho- predialytic plasma sodium, the general status and the tometry assay. cardiovascular stability of the patient. Small absolute differences between the plasma sodium concentration determined by the dialysis machine using this non-invasive method and the results of laboratory analysis can be explained by deviations of the measurement and calibration instruments [mmol/l]

Pat 1 (Dial.-Na: 140 mmol/l) used. Of more clinical relevance, however, is the Pat 2 (Dial.-Na: 140 mmol/l) change in plasma sodium concentration during dialy-

Plasma-Na Pat 3 (Dial.-Na: 142 mmol/l) sis – with its associated effects – relative to predialytic Pat 4 (Dial.-Na: 142 mmol/l) baseline plasma sodium. Using the data for changes in plasma sodium over time registered by the dialysis machine, it can be determined whether the patient 420: Example of a plasma sodium profile of 4 HD patients measured by OCM® is being loaded with sodium from the dialysis fluid (plasma sodium concentration increase) or whether too much sodium is being removed from the blood Figure 20 shows the effects of a haemodialysis treat- (plasma sodium concentration falls), or whether the ment on the plasma sodium concentration in individual sodium concentration of the haemodialysis solution is patients (mean values for 10 treatments are quoted). appropriate for the patient (e. g. a tendency to cons- tant plasma sodium concentrations). Online Clearance While there was little fluctuation in plasma sodium levels Monitoring (OCM®) can assist to appropriately adjust in patients 1 and 2 (the dialysis fluid used for both these the sodium concentration of the haemodialysis solu- patients had a sodium concentration of 140 mmol/L), tion during the ongoing treatment. plasma sodium levels in patients 3 and 4 (here the specified dialysis fluid sodium concentration was 142 The plasma sodium concentration over time is displayed mmol/L) increased by 2.5 – 3 mmol/L during dialysis. as a red line in the UF-Na-Diagram of the 5008. At low

flow conditions (QB ≤ 80 mL/min; QD < 300 mL/min), the plasma sodium concentration is not displayed. The How can the OCM® be used for measurement of accuracy of the value displayed is furthermore strongly plasma sodium? affected by the existence of fistula recirculation.

The OCM® determines sodium concentrations at the dialysate inflow and outflow by monitoring conductivity. The difference between the two values, in relation to the dialysate flow rate, shows the rate of flow of sodium into or out of the patient. Using the value for clearance as measured by the OCM®, the plasma concentration of sodium can be calculated. In this way, the OCM® derives a value for plasma sodium from each clearance 421: The kinetics of the plasma sodium concentration in the course of a HD measurement. The result is adjusted using correction treatment can be displayed by the OCM® (red line)

23 6. Frequently Asked Questions about the OCM®

1. Is Kt/V as measured by the OCM® a single-pool or of a blood flow change between 2 measurements). If an double-pool Kt/V? estimated Hct which deviates from the actual Hct of the patient is entered in the OCM® template, this will have The Kt/V value determined by the OCM® is a single-pool little effect on the accuracy of the value for clearance Kt/V (spKt/V). It is possible to convert the single-pool calculated by the OCM®. If, for example, the entered Kt/V determined by the OCM® to an eKt/V (≈ equilibrated value for Hct is 10 % higher or lower than the actual or double pool Kt/V) using the formulae provided in value for Hct, there is only a 2 – 3 % change in the re- Section 2.1.2.1 Alternatively, eKt/V values are also sult for clearance. If no value for Hct is entered prior to shown in the table on page 10. commencement of treatment, the OCM® automatically assumes a hypothetical value of 35 %. In case a 5008 2. In a comparison conducted at a dialysis centre, it Blood Volume Monitor (BVM) is used simultaneously was observed that the OCM® Kt/V was 10 % lower than with the OCM®, the continuously measured Hct value can the Kt/V measured on the blood side: what is the cause be automatically transferred from the BVM to the OCM®. of this discrepancy? 4. Why is the clearance measured by the OCM® frequen- Such a difference is frequently seen if the value for urea tly lower than clearance measured on the blood side? distribution volume V used for Kt/V calculation by the OCM® has been estimated using the Watson formula. This occurs if a simplified method of whole blood The anthropometric Watson formula tends to overesti- clearance measurement is performed on the blood

mate the urea distribution volume in dialysis patients. As side, where the full blood flow value QB is used the precisely measured result for K x t determined by for blood side calculation of clearance, while the the OCM® is then divided by an incorrectly high value OCM® correctly uses the effective flow of water for V, this results in an underestimation of the delivered contained within the blood (= plasma water + intra- dialysis dose (Kt/V). This problem can be avoided if the cellular water). The effective flow of water contained value for V is determined more precisely using a bioim- within the blood is equivalent to the effective blood pedance spectroscopy (BIS) technique or urea kinetic flow x 0.87. The factor 0.87 takes into account the modelling (e.g. with the aid of DCTool) – see Section characteristic composition of human blood. If the 3 – and this value being entered into the OCM® and effective flow of water contained within the blood is not stored on the PatientCard for future use. used for blood side calculation of clearance, there can be an inappropriate overestimation of urea clearance 3. What is the significance of haematocrit for the calcu- by up to 25 % compared with the effective clearance lation of clearance and plasma sodium concentrations? which is accurately measured by the OCM®. What alternative is there if no recent value for haematocrit is available for a patient? Could an estimated value 5. Could the accuracy of OCM® measurements be im- for haematocrit result in an inaccurate result for Kt/V? paired if equipment is not disinfected between each dialysis treatment? The haematocrit is required to calculate the effective flow of water contained within the blood (= plasmawa- In theory, throughout dialysis deposits may occur on ter + intracellular water) and subsequently the effective the conductivity sensors of the OCM® just as in any of Kt/V (Comment: Hct does not have any influence on K, the other components of the hydraulic system of a since only dialysate-side quantities are used to deter- dialysis machine. To avoid this problem, it is mandatory mine it. Rather, it enters the estimation formula in case to disinfect the equipment after each dialysis session.

24 The risk of an inaccurate clearance measurement is For girls with a height > 110.8 cm: thus excluded. V = -10.313 + 0.252 x body weight (kg) + 0.154 x height (cm) 6. Does the accuracy of the OCM® depend on the membrane material used in the dialyser? In order to obtain a precise value for V in children, a bioimpedance measurement or urea kinetic modelling No evidence has been found to date that the accuracy (e. g. with DCTool) is preferable. of the clearance measurement by the OCM® is influenced by the type of dialyser membrane used. 9. How does one take into account an amputation when calculating urea distribution volume? 7. Can OCM® measurement be started during on-going dialysis treatment? Urea distribution volume V in amputated dialysis patients should not be estimated using anthropometric In principle, the OCM® can be started at any time during formulae (such as the Watson formula), but should be on-going treatment. If, however, more than 80 minutes determined by a bioimpedance measurement or urea have passed since treatment was started without a suc- kinetic modelling (DCTool). cessful OCM® measurement performed, the system will not calculate Kt and Kt/V. It would not be worthwhile ex- 10. Can OCM® also be used during ONLINE HDF? trapolating backwards, as there may have been marked changes in clearance since the initiation of treatment. OCM® can be used during regular ONLINEplus Haemo- dialfitration treatments in either post- or predilution mode 8. Is it possible to calculate the urea distribution volume but due to the missing dialysate flow in the dialyser not of children using the Watson formula? in ONLINE-HF nor in Single-Needle modes.

The Mellits-Cheek formula rather than the Watson formula should be used for anthropometric estimation of V in children:

For boys with a height < 132.7 cm: V = -1.927 + 0.465 x body weight (kg) + 0.045 x height (cm)

For boys with a height > 132.7 cm: V = -21.993 + 0.465 x body weight (kg) + 0.209 x height (cm)

For girls with a height < 110.8 cm: V = 0.076 + 0.507 x body weight (kg) + 0.013 x height (cm)

25 7. References

1. Owen W, Lew N, Liu Y, Lowrie E, Lazarus J: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329: 1001-1006 2. Sherman R, Cody R, Rogers M, Solanchick J: Accuracy of the urea reduction ratio in predicting dialysis delivery. Kidney Int 1995; 47: 319-321 3. Depner T: Estimation of Kt/V from the URR for varying levels of dialytic weight loss: A bedside graphic aid. Semin Dial 1993; 6:242 4. Segura L, Doleson M, Pastre F, Gaffet J, Granolleras C, Oules R, Fourcade J, Shaldon S: Dialysis time: what you prescribe is what you get? (WYPIWYG). EDTNA ERCA J. 1998; 24(1): 43-4 5. Gotch F, Sargent J: A mechanistic analysis of the National Cooperative Dialysis Study. Kidney Int 1985; 28: 524-534 6. Sargent J, Gotch F: Principles and biophisics of dialysis, in Maher J (ed): Replacement of renal function by dialysis (ed 3). Boston, MA, Kluwer Academic, 1989: 87-143 7. Depner T, Cheer A: Modeling urea kinetics with two versus three BUN measurements. A critical comparison. ASAIO Trans 1989; 35: 499-502 8. Daugirdas J: Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol 1993; 4: 1205-1213 9. Flaningan M, Fangman J, Lim V: Quantitating hemodialysis: A comparison of three kinetic models. Am J Kidney Dis 1991; 17: 295-302 10. Bankhead M, Toto R, Star R: Accuracy of urea removal estimated by kinetic models. Kidney Int 1995; 48:785-793 11. Daugirdas J, Smye S: Effect of a two compartment distribution on apparent urea distribution volume. Kidney Int 1997; 51: 1270-1273. 12. Star R, Hootkins J, Thompson J et al.: Variability and stability of two pool urea mass transfer coefficient. J Am Soc Nephrol 1992; 3: 395 (abstr) 13. Cappello A, Grandi F, Lamberti C, Santoro A: Comparative evaluation of different methods to estimate urea distribution volume and generation rate. Int J Artif Organs 1994; 17: 322-330 14. Pedrini L, Zereik S, Rasmy S: Causes, kinetics and clinical implications of post-hemodialysis urea rebound. Kidney Int 1988; 34: 817-824 15. Leblanc M, Charbonneau R, Lalumiere G, Cartier P, Deziel C: Postdialysis urea rebound: determinants and influence on dialysis delivery in chronic hemodialysis patients. Am J Kidney Dis 1996; 27: 253-261 16. Smye S, Dunderdale S, Brownridge G, Will E: Estimation of treatment dose in high-efficiency hemodialysis. Rev Enferm 1994; 67: 24-29 17. Spiegel D, Baker P, Babcock S, Contiguglia R, Klein M: Hemodialysis urea rebound: The effect of increasing dialysis efficiency. Am J Kidney Dis 1995; 25: 26-29 18. HEMO Study Group, Daugirdas J, Depner T, Gotch F, Greene T, Keshaviah P, Levin N, Schulman G: Comparison of methods to predict equilibrated Kt/V in the Hemo pilot study. Kidney Int 1997; 52: 1395-1405 19. 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