Hemodialysis method

A dialysis method based upon urea kinetic analysis is provided. An objective of the method is to provide guaranteed dose hemodialysis by optimization of each dialysis treatment. The method does not rely upon dialysis treatments equal in time. The method includes determining a preferred post-dialysis urea concentration for a patient and predicting a time endpoint for the dialysis. Computer automation makes the method advantageous in a large, busy dialysis center.

BACKGROUND OF THE INVENTION 
This invention relates to the field of hemodialysis. 
The life expectancy of patients with irreversible renal failure can be 
prolonged by hemodialysis using an extracorporeal circuit including a 
dialyzer (or artificial kidney). As there is no specific measurable toxin 
in the blood of such patients, the provision of a "dose" of treatment has 
been, for the most part, trial and error. A physician bases the dialysis 
prescription often empirically, or if on some concept, on for instance, 
the effect on patient well-being or on blood levels of waste such as 
creatinine or urea. Currently, the hemodialysis procedure for patients 
with end stage renal failure involves treatment three times per week for 
three to six hours, with the majority of patients in North America being 
dialyzed for four hours or less. 
The lack of understanding of the pathogenesis of uremia has made it 
difficult, and continues to make it difficult, to clearly define an 
adequate dialysis prescription. Because of a dispute over which uremic 
toxins were important and because of the clear need for a quantifiable 
approach for the dialysis prescription, the National Cooperative Dialysis 
Study (NCDS) was undertaken in the 1970's and has been a source of 
continual review since its publication in the 1980's. 
At any point in time during dialysis, the blood concentration of urea 
depends on its rate of generation, its volume of distribution, the 
residual renal function, the clearance of the dialyzer, and the elapsed 
dialysis time. The clearance of the dialyzer will depend upon the nature 
of the membrane, the effective membrane surface area, the blood flow rate, 
and the dialysate flow rate. 
The normalized dose of dialysis can be defined for urea by the 
dimensionless parameter Kt/V, where K is the clearance of urea by the 
dialyzer (ml/min), where t is time (min.), and where V is the volume of 
distribution of urea (ml). Current methods of calculating Kt/V (urea) are 
complex and require accurate measurement of the dialyzer urea clearance 
and subsequent calculation of the volume of distribution of urea. The only 
accurate way of determining the dialyzer urea clearance and volume of urea 
distribution is to collect the total dialysate and assay the urea content, 
and the logistic problems of this approach prevent its general use. 
One study involving a mechanistic analysis of the NCDS data has indicated 
that the probability of uremic manifestations is high (57%) and constant 
over the treatment range 0.4.ltoreq.Kt/V (urea).ltoreq.0.8, and that over 
the treatment range 0.9&lt;Kt/V (urea)&lt;1.5, there is a sharp decrease in 
morbidity to a constant 13%. Other studies have confirmed that a Kt/V 
(urea) of 1 or more should be targeted. 
However, each dialysis is not equal. Patients may not receive the 
prescribed Kt/V (urea) for various reasons including decrease in blood 
pressure and decreased blood flow rates. 
Work by Jindal and co-workers utilizes the equation Kt/V=0.04 PRU-1.2, and 
has indicated that a percent reduction in blood urea concentration (PRU) 
of approximately 55 during hemodialysis is necessary to obtain a Kt/V 
(urea) of 1. More recently, Daugirdas has argued that the PRU may result 
in Kt/V (urea) values substantially above or below the target Kt/V, and 
suggested the formula Kt/V=-ln (R-0.03-UF/W), where R is the 
post/predialysis plasma urea ratio, where 0.03 is a constant that allows 
for urea generation during dialysis, where UF is the prescribed 
ultrafiltration volume (1) over dialysis, and where W is the prescribed 
post-dialysis weight (kg). 
Increasing numbers of nephrologists are using various methodologies for 
calculating Kt/V (urea) as a basis for the dialysis prescription. However, 
at present, few renal units are using any form of urea kinetics to aid in 
the dialysis prescription, and a recent study shows that even in a 
dialysis unit using urea kinetic modelling on a regular basis, the 
prescribed dose of dialysis Kt/V is frequently not achieved. 
Furthermore, in this current time of economic restraint, there is pressure 
upon health care teams to consider cost efficiency in therapeutic 
strategies. To the nephrologist, this may mean shortening dialysis time by 
using a device "more efficient" in removing uremic toxins. 
As illustrated by U.S. Pat. Nos. 4,231,366 to Schael and 4,897,184 to 
Shouldice et al, computer automation of hemodialysis has been considered 
in which sensor signals are inputted to a control circuit, condition 
control is effected, conditions are monitored to be within a predetermined 
limit, and a failure to be within the limit is signalled. Schael uses this 
automated approach to maintain patient blood flow within predetermined 
limits, due to the effect of blood flow on time for dialysis. However, 
computer automation has not been employed to predict a time endpoint for 
dialysis. 
Accordingly, there is a need for an improved hemodialysis method based upon 
urea kinetics. Advantageously, the method would provide guaranteed dose 
hemodialysis, that is, would target the optimization of each dialysis 
treatment and no longer rely upon dialysis treatments equal in time as in 
the Schael approach. Beneficially, the improved hemodialysis method would 
provide cost savings. Preferably, the method would be automated and could 
predict a time endpoint for dialysis. If so, better scheduling of patients 
would result. 
SUMMARY OF THE INVENTION 
It is accordingly an object of the present invention to provide an improved 
method for hemodialysis based upon urea kinetic analysis. 
It is a further object to provide a hemodialysis method in which 
optimization of each dialysis treatment is targeted, and which would no 
longer rely upon dialysis treatments equal in time. 
It is a still further object to provide a dialysis method which will 
provide cost savings. 
It is an even further object to provide an automated dialysis method that 
will predict a time endpoint for dialysis. 
Additional objects, advantages and novel features of the present invention 
are set forth in the description that follows, and in part will become 
apparent to those skilled in the art upon examination of the following 
description or may be learned by practice of the invention. The objects 
and advantages of the invention may be realized and attained by means of 
instrumentalities and combinations particularly pointed out in the 
appended claims. 
To achieve the foregoing objects and in accordance with the purpose of the 
present invention, as embodied and broadly described herein, there is 
provided an improved dialysis method based upon urea kinetic analysis. 
The method requires measuring urea concentration, suitably the blood urea 
concentration of the dialysis patient. Urea concentration may also be 
measured on the dialysate side. Typically, at least three measurements of 
urea concentration are made. An initial measurement is suitably made 
immediately after beginning dialysis. 
A preferred post-dialysis urea concentration is determined. A value for 
Kt/V (urea) in the range of about 0.8 to 1.4 is appropriate for the 
determination, where K is the dialyzer urea clearance (mls/minutes), where 
t is time (minutes) and where V is volume of distribution for urea (mls). 
The Kt/V (urea) value is typically selected by the physician. 
An essential feature of the method is that a time endpoint for dialysis is 
predicted. The endpoint prediction is based upon the preferred 
post-dialysis urea concentration and measured urea concentration values. 
Urea concentration is measured at about the predicted time endpoint, and 
the urea concentration value obtained is compared with the preferred 
post-dialysis urea concentration. If appropriate, dialysis should be 
terminated. 
In the detailed description of the invention that follows, there is 
essentially described only a preferred embodiment of this invention, 
simply by way of illustration of the best mode contemplated of carrying 
out this invention. As will be realized, this invention is capable of 
other and different embodiments, and its several details are capable of 
modification in various respects, all without departing from the 
invention. Accordingly, the detailed description is to be regarded as 
illustrative in nature, and not as restrictive.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention is an improved hemodialysis method based upon urea 
kinetics. Advantageously, the method, which may be called guaranteed dose 
hemodialysis (GDHD), targets the optimization of each dialysis treatment, 
and no longer relies upon dialysis treatments equal in time. Beneficially, 
the improved hemodialysis method of the present invention provides cost 
savings. Preferably, the method uses computer automation to predict a time 
endpoint for dialysis. As will become clear, the improved hemodialysis 
method of the present invention provides for better scheduling of 
patients. 
The method is now described with reference to an embodiment in which blood 
urea concentration, more specifically, concentration of urea in the plasma 
water, is measured. However, urea concentration could be measured on the 
dialysate side. The urea concentration is more dilute in the dialysate 
fluid than in the plasma water. 
In the method of the present invention, an initial measurement of the urea 
concentration is made, suitably immediately after commencing dialysis of 
the patient. To this end, the patient's blood may be sampled and the urea 
concentration of the blood sample may be measured. This step can be 
achieved through conventional technology. 
In the method of the present invention, it is essential that a preferred 
post-dialysis urea concentration be determined for the patient. The 
determination is advantageously based upon the dimensionless parameter 
Kt/V (urea), which was earlier described in the Background portion of this 
description of the present invention. More specifically, the requisite 
blood urea value may be determined for the patient from the initial blood 
urea concentration and a value for the proportion of blood urea remaining 
(R) calculated based upon Kt/V (urea). In short, the preferred 
post-dialysis blood urea concentration may be calculated as the 
mathematical product of the initial blood urea concentration and R, or 
(1-PRU/100). R equals 1- PRU/100, where PRU, as earlier explained, is the 
percent reduction in blood urea. 
It has been found that the proportion of blood urea remaining (R) is 
beneficially calculated using the formula 
EQU R=1-[(Kt/V+1.2)/4+UGEN+(UF/IDWT)], 
where a value for Kt/V is in the range of about 0.8 to 1.4, with a value 
greater than or equal to about 1.0 being typically advantageous. UGEN is 
suitably a constant of about 0.03 that allows for urea generation during 
dialysis. UF is the volume (liters) of ultrafiltrate to be lost by the 
patient during dialysis. IDWT is the patient ideal weight (Kg). The values 
for Kt/V, UF and IDWT will typically be physician prescribed. Typically, 
it has been found that optimization of dialysis results when R is less 
than 0.45, particularly when R is in the range of about 0.4 to 0.35. 
In the method of the present invention, urea concentration is measured at 
two or more subsequent time intervals, typically at about 60 and 120 
minutes of dialysis. A suitable additional measuring time is at 180 
minutes of dialysis. These urea concentration measurements are made in a 
manner similar to the initial measurement. 
As an essential feature of the method of the present invention, a time 
endpoint for dialysis is predicted. This feature of the present invention 
provides for cost savings compared to the use of dialysis treatments equal 
in time. The predicted time endpoint may result in about 30 to 80 minutes 
of dialysis time being saved. In such case, dialysis cost to the patient 
will be reduced, and the dialysis center is also benefitted because it can 
more efficiently handle the patient load. 
In a preferred embodiment, the prediction of the time endpoint is 
conveniently achieved using a linear relationship between proportion of 
blood urea remaining and time based upon the prior readings of blood urea 
concentration. The linear relationship may be determined by plotting the 
prior readings on a graph having axes of time (minutes) and proportion of 
blood urea remaining. The proportion of blood urea remaining is 
beneficially graphed as a logarithmic equivalent, which may be a natural 
logarithmic equivalent. The time endpoint for dialysis is the time 
coordinate of the intersection of the value of the ratio of the preferred 
post-dialysis blood urea concentration to the initial blood urea 
concentration, with the linear plot. Alternatively, as will be described, 
an algorithm based upon linear regression analysis may be used for 
predicting the time endpoint for dialysis. 
In the method of the present invention, urea concentration is measured at 
about the predicted time endpoint and compared with the preferred 
post-dialysis urea concentration. The urea concentration measurement is 
made in a manner similar to the initial urea measurement, and the 
necessary comparison is made. 
If the comparison reveals that the preferred post-dialysis blood urea 
concentration has been obtained or substantially obtained or has been 
exceeded, with a deviation of about +/-10% generally being within the 
objective, dialysis should be terminated. On the other hand, if the 
comparison reveals that further dialysis is appropriate, then a revised 
time endpoint for dialysis should be predicted, and the urea concentration 
at that revised endpoint compared with the preferred post-dialysis blood 
urea concentration. 
If desired or appropriate for enhanced accuracy of the method, third and 
even subsequent measuring times can be predicted prior to predicting the 
time endpoint. The prediction may be made by using the prior measurements 
of urea concentration either to graphically determine a linear 
relationship between proportion of urea remaining and time, or to conduct 
a linear regression analysis. Further measurements of urea concentration 
are thereafter made, and the results are used to predict a time endpoint 
for dialysis. 
The method of the present invention is well suited for a large, busy 
dialysis center. Patient identifying information, the desired values for 
Kt/V, UF and IDWT for the particular patient, urea concentration measuring 
times, and urea concentration data may be beneficially inputted to a 
computer system equipped with appropriate software. 
Referring to the FIGURE, a suitable computer system includes a conventional 
microprocessor 12 and a conventional programmable memory 14, which 
operatively intercommunicate. In a preferred automated approach, urea 
concentration data may be automatically inputted to the microprocessor by 
conventional equipment 16 for analyzing urea-containing fluid samples, so 
that the method provides for measuring the removal of urea on-line during 
dialysis. 
Based on the inputted data, the computer microprocessor advantageously 
determines the preferred post-dialysis urea concentration and predicts a 
time endpoint for dialysis, or may predict a third and even subsequent 
urea concentration measuring times and then predict a time endpoint based 
upon the urea concentration measurements. In any event, microprocessor 12 
generates a signal indicative of the preferred post-dialysis urea 
concentration or a signal indicative of a time, and communicates the same 
to programmable memory 14. The programmable memory receives and stores the 
signals. 
An algorithm for predicting a time endpoint for dialysis may be stored in 
memory 14. A suitable algorithm is based upon a linear regression of the 
curve for the decreasing urea concentration during dialysis. For four 
blood urea concentrations, the algorithm may be as follows: 
1. Take four urea concentrations (representing four different sampling 
times): c.sub.0, c.sub.1, c.sub.2 and c.sub.3. 
2. Non-dimensionalize each concentration by dividing each c.sub.n by 
c.sub.0 to yield C.sub.n (or the proportion of blood urea remaining). 
3. Also non-dimensionalize the preferred post-dialysis blood urea 
concentration (c.sub.ep) by dividing c.sub.ep by c.sub.0, so that if 
c.sub.ep is 5 and c.sub.0 is 40, then C.sub.ep =5/40=0.125. 
4 Determine the linear constant using the equation for a regression slope 
for a line through the origin, which equation is b=[sum of (X.sub.n 
.times.ln C.sub.n)]/(sum of X.sub.n.sup.2) 
a) Compute the sum of the square of each time X.sub.n (minutes) at which 
the samples were taken, that is, the sum of X.sub.0.sup.2, X.sub.1.sup.2, 
X.sub.2.sup.2 and X.sub.3.sup.2, so that if the samples were taken at 0, 
60, 120 and 180 minutes, then 0.sup.2 +60.sup.2 +120.sup.2 +180.sup.2 
=50,400. 
b) Calculate the sum of the product of time (X.sub.n) and ln C.sub.n 
(natural logarithmic value of the proportion of urea remaining) at the 
respective time, for the four samples, that is, if the urea concentrations 
of the four samples are 40, 30, 20 and 10, then [0.times.ln 
(40/40)]+[60.times.ln (30/40)]+[120.times.ln (20/40)]+[180.times.ln 
(10/40)]=-349.97. 
c) Solve the foregoing equation for b using the illustrative values of a) 
and b) above, such that b=-349.97/50,400=-0.00694. 
5. Calculate the predicted time endpoint for dialysis using the linear 
relation Y=bX and Y.sub.ep =ln C.sub.ep, such that when C.sub.ep =0.125 
and b has the illustrative value of 4.c) above, then ln C.sub.ep =-2.079; 
and X.sub.ep =Y.sub.ep /b=-2.079/-0.00694=299 minutes. 
If desired, the computer could activate an audible or visual signal to 
indicate a urea concentration measuring time. In such case, programmable 
memory 14 automatically communicates at the appropriate time with 
microprocessor 12, which in turn, as represented in the FIGURE, may 
activate a signal light 18 to indicate the time. 
The urea concentration at about the predicted time endpoint for dialysis is 
compared by the microprocessor with the preferred post-dialysis urea 
concentration. If desired, the computer could cause an audible or visual 
signal to be given to indicate, if appropriate, termination of dialysis. 
In such case, microprocessor 12 may activate a signal light 20, which may 
be green, to indicate termination of dialysis. 
In the event the comparison reveals that further dialysis is appropriate, 
the microprocessor beneficially may predict a revised time endpoint for 
dialysis, and thereafter compare the urea concentration at the revised 
time endpoint with the preferred post-dialysis blood urea concentration. 
Beneficially, microprocessor 12 communicates with a conventional printer 
22, which provides a paper record in the form of, for instance, a graph of 
proportion of blood urea remaining and time. A paper record would assist 
the physician in evaluation of the patient. 
In a highly automated embodiment of the method of the present invention, 
computer control of urea-containing fluid sampling may be provided. In 
such case, signals indicative of selected measuring times such as 0 time, 
60 minutes and 120 minutes, are stored in programmable memory 14. At a 
selected time, the programmable memory automatically communicates with the 
microprocessor, which in turn activates a fluid sampling device 24. Thus, 
a technician would need only to commence and terminate dialysis, and input 
necessary data. 
Accordingly, by the method of the present invention, optimization of each 
dialysis treatment is targeted, rather than targeting dialysis treatments 
equal in time. The improved hemodialysis method provides cost savings and 
provides for better scheduling of patients. While the method has been 
described primarily with reference to blood side measurements and values, 
urea could be also measured on the dialysate side. 
EXAMPLE 
A blood sample of a patient is taken immediately after commencing dialysis, 
and a blood urea concentration of 17.4 mmol/L found and inputted to 
microprocessor 12. Physician-prescribed values for the patient are 1.0 for 
the Kt/V, 3 liter for the volume of ultrafiltrate to be lost during 
dialysis, and 72 kg for the ideal weight. These values are likewise 
inputted to microprocessor 12, which uses these values and a value of 0.03 
mmol for UGEN, in the formula 
EQU R=1-(Kt/V+1.2)/4+UGEN+(UF/IDWT)], 
to calculate a value of 0.38 for the proportion of blood urea remaining. 
Thereafter, the computer calculates a preferred post-dialysis blood urea 
concentration of 6.6 mmol (the mathematical product of 17.4 mmol and 
0.38). 
Thereafter, blood samples are taken at 60 min and 120 min, and blood urea 
concentrations of 12.2 mmol and 9.0 mmol are found. These values of blood 
urea concentration and time are inputted to microprocessor 12, which 
predicts a time endpoint for the dialysis. 
A blood sample is taken at the predicted time endpoint, and the blood urea 
concentration at such time is found to be 6.8 mmol. This value is inputted 
to microprocessor 12, which compares the value to the preferred value of 
6.6. Microprocessor 12 activates green signal light 20 to indicate that 
dialysis may be terminated. 
Having described the invention in detail and by reference to a preferred 
embodiment thereof, it will be apparent that modifications and variations 
are possible without departing from the scope of the invention defined in 
the appended claims. Several changes or modifications have been briefly 
mentioned for purposes of illustration.