Methods and apparatuses for determining a patient's daily loss of iron

Abstract

A method for determining or approximating a patient's daily loss of iron (fe_loss), the method comprising the steps of determining the patient's iron uptake (fe_uptake); determining the quantity of iron stored within the patient's body; and determining the patient's daily loss of iron based on the patient's iron uptake (fe_uptake) and the quantity of non-functional iron stored within the patient's body. The method relates further to apparatuses and an erythropoesis stimulating medicament for use in the treatment of anaemia. Finally the present invention relates to digital storage means, a computer program product, and a computer program.

Claims

1. A method for determining or approximating a daily loss of iron (fe_loss) of a patient with impaired renal function, the method comprising the steps: determining the patient's iron uptake (fe_uptake); determining a quantity of iron stored within the patient's body by adding at least a value representing a quantity of functional iron stored in the patient's body and a value representing a quantity of non-functional iron stored in the patient's body; measuring at least one of: a hemoglobin value (Hb), a blood volume, and a concentration of ferritin in serum; determining the patient's daily loss of iron based on the patient's iron uptake (fe_uptake) and the quantity of non-functional iron stored in the patient's body, using the formula:
fe_loss=fe_non-functional_stored+fe_Hbfe_uptake wherein: fe_uptake =the patient's iron uptake fe_loss =the patient's daily loss of iron fe_Hb =the quantity of iron stored within the haemoglobin (Hb) fe_non-functional stored =the quantity of iron stored within the patient's body outside of Hb; and administering a supplemental dosage of iron to the patient during or between dialysis sessions, wherein the supplemental dosage is determined based on the patient's determined daily loss of iron.

2. The method according to claim 1, wherein at least one of: the functional iron stored in the patient's body is determined using at least one of the haemoglobin value (Hb) and the blood volume; and the quantity of non-functional iron stored within the patient's body is determined using the concentration of ferritin in serum.

3. The method according to claim 1, further comprising at least one of: determining the patient's iron uptake (fe_uptake) based on cumulating the patient's iron uptake over time; and determining a ferritin curve comprising a series of ferritin measurements over time.

4. A medicament comprising iron for use in the treatment or prevention of anaemia or for enhancing haemoglobin concentration in a patient's blood, wherein the dose of iron to be administered as an iron substitution is set equal to the amount of iron determined to have been lost since the last iron substitution based on the daily loss determined by the method according to claim 1.

5. A non-transitory digital storage means with electrically readable control signals which are able to interact with a programmable computer system such that the method according to claim 1 will be executed.

6. A computer program product having a program code stored on a machine readable data medium for executing the method according to claim 1 when executing the program product on a computer.

7. A computer program having a program code for the execution of the method according to claim 1 when executing the program on a computer.

8. An apparatus for determining or approximating a daily loss of iron of a patient with impaired renal function, the apparatus comprising: a device configured to input information on the patient's iron uptake (fe_uptake); a device configured to determine a quantity of iron stored within the patient's body by adding at least a value representing a quantity of functional iron stored within the patient's body and a value representing a quantity of non-functional iron stored within the patient's body; a device configured to measure at least one of: a haemoglobin value (Hb), a blood volume, and a concentration of ferritin in serum; a device configured to determine the patient's daily loss of iron based on the patient's iron uptake (fe_uptake) and the quantity of iron stored within the patient's body, wherein the device is configured to determine patient's daily loss of iron using the formula:
fe_loss=fe_non-functional_stored+fe_Hbfe_uptake wherein: fe _uptake=the patient's iron uptake fe_loss=the patient's loss of iron fe _Hb =the quantity of iron stored within the haemoglobin (Hb) fe_non-functional_stored=the quantity of iron stored within the patient's body outside of Hb; and a device configured to determine a supplemental dosage of iron to be administered to the patient during or between dialysis sessions, wherein the supplemental dosage is determined based on the patient's determined daily loss of iron.

9. The apparatus according to claim 8, further comprising at least one of: a device configured to determine the functional iron comprised by the patient by using at least one of the haemoglobin value (Hb) and the blood volume; or a device configured to determine the quantity of non-functional iron stored within the patient's body by using the concentration of ferritin in serum.

10. The apparatus according to claim 8, further comprising: a device configured to determine the patient's iron uptake (fe_uptake) based on cumulating the patient's iron uptake over time; and a device configured to determine a ferritin curve comprising a series of ferritin measurements over time.

11. A blood treatment apparatus, comprising a device for administering a medicament to a patient, and at least one apparatus according to claim 8, or being in signal communication with the at least one apparatus according to claim 8, wherein the device for administering the medicament is in signal communication with the device configured to determine the daily iron loss.

12. The blood treatment apparatus according to claim 11, configured as a dialysis machine, a hemodiafiltration apparatus, or a hemofiltration apparatus.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1a shows a curve of a cumulated intravenous (short: iv) iron uptake of a patient.

(2) FIG. 1b shows a curve of a cumulated daily iron loss of the patient.

(3) FIG. 1c shows a curve of a combined cumulated iv iron uptake and daily loss of the patient.

(4) FIG. 2 reflects the above discussed formulae.

(5) FIG. 3 shows a comparison of different daily iron losses.

(6) FIG. 4 shows the respective correlation of three different iron losses.

(7) FIG. 5 shows the findings of FIG. 4 in another illustration.

(8) FIG. 6 shows the findings of FIG. 4 in another illustration.

(9) FIG. 7 shows a first apparatus according to the present invention comprising a controller for carrying out the method according to the invention.

(10) FIG. 8 shows a second apparatus according to the present invention comprising a controller for carrying out the method according to the invention.

DETAILED DESCRIPTION

(11) According to one exemplary embodiment according to the present invention, it is proposed that ferritin may be used as a marker related to iron stores, in particular to non-functional iron stores. Its concentration over time may be linear (alternatively also non-linear, but defined by a mathematical function) to the iron stores. According to this embodiment, a model is proposed, incorporating iron stored in a first compartment (liver, bone marrow, spleen), a second compartment (iron stored in Hb). Optionally, a third compartment covering iron comprised in muscle is comprised as well. Over a certain period of time, the amount of iron administered to the patient is recorded, together with values for Hb and ferritin. Then a constant value for the average daily iron loss is chosen or estimated, and a value representing the relation between the iron balance (uptake vs. losses and internal shifts between Hb and stores) and ferritin is determined. This procedure is repeated a number of times over a certain range of assumed constant daily iron losses, and the loss which gives the highest correlation marker (e.g., a correlation coefficient or any other measurement for measuring a statistic relationship) is selected as the determined average daily iron loss. The such determined average daily iron loss may then be replaced by intravenously (iv) administered iron in a step subsequent to the method of the present invention. The afore-mentioned exemplary embodiment is further described with respect to the figures.

(12) FIG. 1a shows a curve of a cumulated (iv) iron uptake fe_uptake over time of a patient in a iron concentration (in [mg]) over the time [year] diagram (these dimension have also been chosen for the FIGS. 1b, 1c, 2, 3 and 6 at the top). The inclinations of some of the curve's sections are due to iv iron administrations, administered in or at constant time intervals.

(13) FIG. 1b shows ae. g. estimatedcurve of a cumulatede. g. assumeddaily iron loss fe_loss of the patient. A linear curve is assumed since an individual but yet constant daily iron loss is assumed. Iron is mostly lost by bleeding or due to the dialyser's effect on the erythrocytes.

(14) FIG. 1c shows a curve of a combined cumulated (iv) iron uptake and daily loss of the patient.

(15) In the curves of the preceding figures, inflammation, blood transfusions and changes in dialyzers etc. are neglected. If these were to be considered, the curves would have to be adapted as is also encompassed by the present invention.

(16) FIG. 2 reflects the above discussed formulae. The illustration at the bottom shows in its upper part the development of ferritin as a marker of the non-functional iron store, indicated as fe_non-functional_stored. The ferritin values may be measured. In its lower part the illustration shows the estimated iron stores, depicted as fe_estimated_stored. The latter value may be gained by fe_uptake+fe_lossfe_Hb as indicated by FIG. 2 (see the three diagrams at the top of FIG. 2).

(17) FIG. 2 shows that the ferritin curve has a shape similar to the development of the estimated iron stores over time. Hence, the assumed loss fe_loss illustrated in FIG. 2 (see the middle diagram at the top) which influences the shape of curve fe_estimated_stored quite strongly and which is the only value that has not been measured but estimated in the example of FIG. 2 has been selected quite thoroughly.

(18) FIG. 3 shows a comparison of different daily assumed iron losses. In FIG. 3, the curve fe_non-functional_stored is only indicated by dots representing the ferritin values measured at different points of time.

(19) As can be seen from FIG. 3, assuming the daily loss as 4 mg/day results in a loss curve that follows the (not fully drawn) ferritin curve fe_non-functional_stored more precisely than the curves that correspond to 3 mg/day and 5 mg/day, respectively. Hence, the daily loss may be considered to be closer to 4 mg/day than to 3 mg/day or to 5 mg/day.

(20) FIG. 4 shows the respective correlation of three different iron losses of 3.0 mg/d, 4.0 mg/d and 5.0 mg/d, respectively, in a diagram showing the stored iron fe_stored in [mg] over ferritin in [ng/ml].

(21) As can be seen in the example of FIG. 4, the assumed loss of 4.0 mg/d has the best correlation (expressed by the correlation coefficient R) of all three losses.

(22) FIG. 5 shows the findings of FIG. 4 in another representation. As can be seen from the diagram at the bottom of FIG. 5, in a correlation-coefficient-R over average-daily-iron-loss [mg]-plot the highest correlation coefficient R is found for 4.0 mg/d.

(23) FIG. 6 shows a sliding window 1 (see the dotted lines) used for calculating the correlation and/or for detecting changes in daily iron loss. The rectangular measurements 2 reflect the measured ferritin values gained at the day of testing. The line fe_non_functional_stored represents the curve of or at an estimated iron loss of 3 mg/day.

(24) As is indicated by the short arrow attached to the sliding window 1, the window 1 moves along the time axis over or with time.

(25) As is indicated by the long arrow C interconnecting the diagram at the top of FIG. 6 with that at the bottom thereof, the correlation is calculated for each position of the sliding window 1 over the time axis. The result is checked or even plotted against a pre-determined correlation threshold 3 (see the lower diagram in FIG. 6 illustrating the correlation over time). The pre-determined correlation threshold 3 may be or represent the best fitting correlation gained by the method described with respect to FIGS. 3 to 5. However, the predetermined correlation threshold 3 may also be determined another way or simply set.

(26) The vertical line 4 marks the day when the up to that point true loss of 3 mg/day turns into a loss of 4 mg/day. As can be seen in FIG. 6, the change in daily loss that takes place at the vertical line 4 is only detected when the correlation threshold 3 is crossed by the correlation curve 5 at a crossing point 6. Because of the nature of sliding windows, there is a time delay between the day when the true iron loss changes due to whatever reason and the day when the change is detected. In the example of FIG. 6, this time delay corresponds to the difference between the vertical line 4 and the crossing point 6. It is marked by the reference numeral 7.

(27) FIG. 7 shows an apparatus 9 comprising a controller 11 for carrying out the method according to the invention. The apparatus 9 is connected to an external database 13 comprising the results of measurements and all other data needed for the method according to the invention. The database 13 can also be an internal means. The apparatus 9 may optionally have means 14 for inputting data into the controller 11 or into the apparatus 9. Such data may be information about the functional iron store such as the mass, the volume, the concentration of Hb and/or information about the non-functional iron store such as ferritin as is set forth above. Such data input into the apparatus 9 mayadditionally or instead ofalso comprise information about the blood volume of the patient or an approximation thereof. The results of the determination performed by the controller 11 and/or the apparatus 9 can be displayed on the monitor 15 or plotted by means of anot displayed but optionally also encompassedplotter or stored by means of the database 13 or any other storage means. The database 13 can also comprise a computer program initiating the method according to the invention when executed.

(28) In particular, the controller 11 can be configured for carrying out any method according to the invention.

(29) As can be seen from FIG. 8, for corresponding measurements the apparatus 9 can be connected (by means of wires or wireless) with a bioimpedance measurement means 17 as one example of a means for measuring or calculating the blood volume. Generally, the means for measuring or calculating the blood volume can be provided in addition to the external database 13 comprising the results of measurements and the data needed for the method according to the invention, or in place of the external database 13 (that is, as an substitute).

(30) The bioimpedance measurement means 17 can be capable of automatically compensating for influences on the impedance data like contact resistances.

(31) An example for such a bioimpedance measurement means 17 is a device from Xitron Technologies, distributed under the trademark Hydra that is further described in WO 92/19153, the disclosure of which is hereby explicitly incorporated in the present application by reference.

(32) The bioimpedance measurement means 17 may comprise various electrodes. In FIG. 8, only two electrodes 17a and 17b shown which are attached to the bioimpedance measurement means 17. Additional electrodes are, of course, also contemplated.

(33) Each electrode implied can comprise two or more (sub-)electrodes in turn. Electrodes can comprise a current injection (sub-)electrode and a voltage measurement (sub-)electrode. That is, the electrodes 17a and 17b shown in FIG. 8 can comprise two injection electrodes and two voltage measurement electrodes (i.e., four electrodes in total).

(34) Similarly, the apparatus 9 may have means 19 for measuring or calculating means for obtaining a value reflecting the mass, the volume or the concentration of ferritin and/or Hb that can again be provided in addition to the external database 13 already comprising the results of measurements and the data needed for the method according to the invention, or in place of the external database 13 (that is, as a substitute).

(35) The means 19 can be provided as a keyboard, touch screen etc. for inputting the required data, sensors, interconnections or communication links with a lab, a ferritin or Hb concentration probe, any other input means, etc.

(36) The apparatuses of FIGS. 7 and 8 may be comprised by a blood treatment apparatus (not shown) according to the present invention or connected therewith.

(37) Again, it is noted that the figures relate examples showing how one embodiment according to the invention may be carried out. They are not to be understood as to limit the invention.

(38) Also, the embodiments according to the invention may comprise one or more features as set forth below which may be combined with any feature disclosed somewhere else in the present specification wherever such combination is technically possible from the perspective of the skilled person.