device for extracorporeal blood treatment

专利摘要:
BLOOD EXTRACORPOREAL TREATMENT APPLIANCE. The invention describes an apparatus for extracorporeal treatment of blood with a dialyzer that is separated by a semipermeable membrane in a first and second chamber (29,30), in which the first chamber (29) is arranged in a dialysate pathway and the second chamber (30) is connectable to a patient's blood circulation via a blood supply conduit (32) and a blood return conduit (31), an inlet (20) for fresh dialysate, an outlet (30) for dialysate used, a measuring device (37) is designed to generate radiation consisting of several light sources (1) for electromagnetic radiation. The invention is characterized by the fact that the measuring device (37) is designed to generate substantially monochromatic electromagnetic radiation of different wavelengths, and to take only one of these wavelengths (at the same time) through the output (36) to dialysate used, in which at least one detector system (5) is provided for detecting the intensity or absorption of substantially monochromatic electromagnetic radiation passing through the outlet (36) for used dialysate, (figure 3)
公开号:BR112013003122B1
申请号:R112013003122-0
申请日:2011-08-17
公开日:2020-11-10
发明作者:Jörn Meibaum；Stefan Moll；Alex Castellarnau；Jörn Ahrens
申请人:B.Braun Avitum Ag；
IPC主号:

专利说明:

The invention relates to an apparatus for extracorporeal treatment of blood for differentiating uremic toxins in the outflow of the apparatus.
In patients with loss or reduction of renal function, waste products of natural metabolism including uremic toxins are removed by means of renal replacement therapy or dialysis method. In this way, the removal of substances from the blood, which is taken from the patient and taken out of the body, is performed by contacting the blood with a dialysate, in which blood and dialysate come into contact with each other not directly, but through a membrane. The dialysate is mixed with various salts and, thus, brings up diffuse and convective effects that are responsible for the transport of substances from the blood to the dialysate through the extracorporeal membrane. After the performance of removing a portion of the residual substances, the blood treated in this way is fed back to the patient.
For testing a dialysis device, parts of a dialysis device or altered dialysis parameters, the concentrations of uremic toxin will be determined before and after dialysis therapy. The reduction of the respective substances represents the central basis for the assessment of the dialysis dose.
A common marker element is carbamide, which is also known as urea. Consequently, the rate of reduction of urea is considered as a critical parameter in the dialysis technique. The determination of urea reduction can be carried out in different ways.
A classic method represents the chemical determination of the blood urea concentration before and after dialysis therapy. The problem with this method, however, is that the blood sample must be taken from the patient and sent to a laboratory that is equipped to determine the urea concentration. This process can take several days.
In addition, the urea concentration or its change by determining the conductivity in the dialysate can be determined. A product on the market that works according to this principle is the product Biostat® Urea Monitor from Baxter. The problem during conductivity measurement is that the change in conductivity can be affected by other influencing factors, for example, by changes in pH and that the measurement is thus distorted in circumstances.
A third possibility to determine the dialysis dose is the measurement of uric acid reduction which - as is well known - substantially corresponds to the reduction of urea, through dialysis therapy by means of UV absorption measurements in the outflow of the dialysate . Uhlin showed in his dissertation on the topic “Haemodialysis Treatment monitored online by ultra violet absorbance '[Linkoping University Medical Dissertation No 962, 2006] that the alteration in the dialysate in the outflow at 280 nm represents a very good correlation with the change in urea concentration in the patient's blood. Such a measurement device is described in EP 1 083 948 B1. In the state of the art, both the configuration and the position of the sensor for technical dialysis applications are described.
Above all, it is not possible with the devices and methods known in the state of the art to readily provide, during or during the therapy of the patient, a differentiation of residual substances or toxic urea substances preferably simultaneously or at the same time.
DE 29341 £ 0 A1 describes a method for molecular spectroscopy, in particular for the determination of metabolic products, in which the absorption of infrared radiation is measured through a sample containing a substance to be determined. As the most preferred substance to be determined, the action is known. In this way, the glycse determination is performed on the whole sarge or serum or urine with Raman lasers or carbc | β | i (CO2) lasers as a light source. DE 2934190 A1 describes that the concentration ∞ | various substances can be measured, sample lengths. Aclicic | development] The describe i | ím method DE 2934190 A1 shows the person versed in the technique q je it is, in principle, possible to determine, by means of infrared spectroscopy, several substances ^ simultaneously, that is, their presence and presumably also their consequences . This method is, however, unsuitable for measuring blood samples or blood serum samples. In addition, the substances to be determined in the blood flow or dialysate do not indicate clearly differentiable infrared spectra. The substances measured in DE 2934190 A1 are well suited to be determined by means of • 41 j I infrared (IR) means. Due to the properties of significant substance; Jferents that are determined by means of infrared and UV, the measurement arrangement described in DE 2934190 A1 and the measurement methods cannot be applied to the UV range. In the UV range, the absorption of the entire molecule, which is associated with the concentration of a substance, is determined, while certain types of bonds in a molecule are excited by means of IR, and thus IR is mainly used to prove the presence of certain functional groups. The IR measuring device described in DE 2934190 A1 cannot simply be replaced by a UV measuring device or an NMR measuring device, because they are fundamentally different techniques, which are not interchangeable in an equivalent way. DE 69916053 T2 refers to a method for determining residual products in the dialysate during dialysis treatments. The method is for the exact determination of the amount of waste products in the dialysate during dialysis treatment as well as for measuring urea or any other substance contained in the waste products. Thus, the determination can be optionally applied by measuring the substances that are most suitable for the selection of the dialyzer and the control of the dialysis machine in order to adjust the dialysis treatment to the patient. DE 69916053 T2 does not give evidence for the use of light emitting diodes (LEDs) and dispenses with a reference substance. In addition, DE 69916053 T2 does not provide the person skilled in the art with evidence, as several or all of the active substances UV in the blood or in the outflow of dialysate can be determined quantitatively. US 5772606 describes a urinal with a measuring system, with which the amounts of uric components, glucose, hemoglobin, albumin, lithium acetoacetate, ascorbic acid, creatinine, sodium chloride and sodium nitride can be determined. The measurement system described in US 5772606 uses the wavelength range between 400 and 2500 nm. As a light source, lasers are described. JP 02027264 A describes the measurement of proteins in urine at a wavelength of 610 nm. As a light source, light emitting diodes (LED) are used. The proteins absorb, however, also in the UV range below 210 nm and at 280 nm. However, absorption at 280 nanometers requires the presence of the tryptophan and tyrosine amino acids in the amino acid sequence because other amino acids do not absorb in the UV range, where disulfide and phenylalanine bonds influence the minimum UV absorption. Below 210 nm, they absorb peptide bonds in a protein. Due to the simplicity of peptide bonds in a protein, it is a very sensitive area of the protein spectrum. Therefore, a quantitative protein determination in sample liquids is possible, but using the spectrum obtained without knowledge of the respective extinction coefficient, the proteins contained cannot be identified. Also, with the apparatus described in JP 02027264 A and the method, determination of uremic toxins is not possible. The determination of the infrared band has the disadvantage that the sample to be measured is heated by the infrared radiation passing through the sample. This can lead to the redisposition or degradation of uremic toxins to be measured and a change in the extinction coefficient, so that, with the device of the invention for extracorporeal treatment of blood to differentiate uremic toxins in the outflow of the device, the toxins uremic in the outflow of the device may no longer be differentiated. Infrared measurements investigate other substance properties in addition to UV measurements. The measurement methods must therefore be considered specific to the substance, since other optical properties are required. Thus, it is not possible with the experimental configuration described in JP 02027264 When determining several or all UV active substances in the blood or in the outflow of dialysate. As indicated above, IR spectroscopy and UV spectroscopy are directed to clearly different molecular properties and both methods cannot be replaced in an equivalent way.
Known methods for determining protein and uric acid in urine have been proven in practice. It is, however, disadvantageous that until now there is no possibility for differentiation of uremic toxins in the dialysate used, and, therefore, a check-up of the dialysis success of the dialysate of the dialysis machine, or parts of it that contribute to the blood purification was not possible.
The present invention is directed to the provision of an apparatus for extracorporeal treatment of blood for quantitative differentiation and, preferably, for the qualitative and quantitative differentiation of uremic toxins in the outflow of the apparatus.
The inventors have found that, contrary to the assumption in the prior art, qualitative as well as quantitative information on residual substances or additional toxic substances that are generally present in the dialysate used additionally for urea, is possible in real time or during patient therapy, In the case of several wavelengths in the UV range, the absorption of the dialysate used is measured.
Uremic toxins are substances that are excreted under normal conditions in a healthy kidney, but are retained in the event of illness. Uremic toxins can negatively influence biological functions. Soluble water-free substances with low molecular weight (see table 1) are differentiated from substances bound to proteins (see table 2).
Table 1: Soluble substances free of water in blood plasma or blood serum. Modified from Vanholder et al. Review on uremic toxins: classification, concentration and interindividual variability. Kidney International. 2003; 63: 1934-1943. * UV absorption.

In addition to water-free soluble substances, there are substances linked to proteins that are summarized in Table 2.
Table 2: Substances bound to proteins in blood plasma or blood serum. Modified from Vanholder et al. (2003). * UV absorption.


In addition, substances with medium molecular weight are uremic toxins in blood plasma or blood serum, such as adrenomedullin, atrial natriuretic peptide, cystatin, endothelin and parathyroid hormone.
Table 3 finally shows an overview of uremic toxins, of which exact urine concentrations and / or uremic retention must be discussed and, thus, advantageously removed from the blood.
Table 3: Substances in blood plasma or blood serum, whose concentration and / or uremic retention is not guaranteed. Modified from Vanholder et al. (2003). * UV absorption.

Uremic toxins detectable by UV absorption are marked in tables 1 to 3 by the same symbol “*”. The uremic toxins to be determined are the preferred UV active substances creatinine, uric acid, hypuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and fragments of B2-microglobulin and / or combinations thereof. “Detectable by means of UV absorption” means that the uremic toxin absorbs in the UV range, that is, the uremic toxin is UV active and can therefore also be described as UV active uremic toxin.
It is an object of the invention to provide an apparatus that allows the determination of one or more of an active UV uremic toxin or all active UV uremic toxins during a dialysis session, either within short intervals of time or at the same time in the blood or blood. dialysate outlet flow in order to draw conclusions about the quality of dialysis, as well as of the dialysis apparatus or specific components of the dialysis apparatus, which determine the removal of uremic toxins. The apparatus of the invention and the method of the invention may allow, on the one hand, during or promptly in the therapy of the patient at least qualitative as well as quantitative information of an additional residual substance or other toxic substance which is, for example, additional to urea in the dialysate used. In addition, the apparatus of the invention and the method of the invention are used to make statements about the quality of a dialysis performed, and thus, for example, also of new membranes, filters, coatings, dialysates, dialysers and dialysis machines and their possible properties advantageous compared to known modalities.
The additional residual substance or the additional toxic substances or uremic toxins that are present in addition to the uric acid in the dialysate used, are preferably selected from the group comprising creatinine, malondialdehyde, indoxyl sulfate and p-cresyl sulfate or p-cresol. Combinations of the aforementioned substances are also available. A combination of uric acid, creatinine and malondialdehyde is preferred. A combination of uric acid, creatinine, malondialdehyde, indoxyl sulfate and p-cresyl sulfate is most preferred. Most preferred is a combination of UV active uremic toxins comprising creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and fragments of B2-microglobulin.
This objective is in fact solved by an apparatus with the characteristics of claim 1. Advantageous modalities of the invention are found in the dependent claims, in the figures, in the examples and in the description.
The present invention is directed to an apparatus for extracorporeal treatment of blood, which comprises or consists of the following components: - a dialyzer which is separated by a semipermeable membrane in a first and second chamber (29, 30), in which the first chamber ( 29) is arranged in a dialysate route and the second chamber (30) is connectable to a patient's blood circulation via a blood supply conduit (32) and a blood return conduit (31), - an inlet (20) for fresh dialysate, - an outlet (36) for used dialysate, - a measuring device (37) arranged at the outlet (36), where the measuring device (37) has a radiation source (1) for electromagnetic UV radiation, - where the radiation source (1) consists of at least two monochromatic light sources or at least one monochromatic polychromatic light source for generating monochromatic UV radiation, - a microprocessor unit (14), a unit storage as well as an u output unit (15), characterized by the fact that the measuring device (37) is designed to generate substantially monochromatic electromagnetic UV radiation of different wavelengths and to take it through the output (36) to the dialysate used, in that at least one detector system (5) is provided for detecting the intensity or the absorption of substantially monochromatic UV electromagnetic radiation passing through the outlet (36) for the dialysate used and in the storage unit an equation system is deposited, in which A % is the total absorption of a mixture of substances at a predetermined wavelength Aj is the absorption of each substance within the mixture of substances and è the number of components of interest within the mixture of substances that contribute to the absorption. If at least 2, preferably 5, more preferably 8, even more preferably 10, even more preferably 12, preferably 14 and preferably 16 monochromatic light sources, such as LEDs, are used, they are preferably individually controllable. For the detection of intensity or absorption at a specific wavelength, only one wavelength is irradiated in one position through the dialysate output stream, that is, the dialysate used. Obviously, inventively, several absorption measurements could also be performed simultaneously, in which then, in sufficiently separate and different positions, the monochromatic wavelengths are traversed by the dialysate used.
It is preferable that in a position at the dialysate output at a given time by means of a wavelength, that is, a monochromatic UV radiation or a corresponding polychromatic and filter radiation or monochromators, the absorption of the dialysate used is measured at a known temperature and over a known distance, in order to inventively determine the concentration of UV active uremic toxins in the dialysate used.
In addition, the present invention is directed to a method for determining the concentration of UV active uremic toxins, in which, at the output of dialysate, the absorption of the used dialysate is measured at a known temperature and over a known distance in lengths specific wavelengths and at least as many measurements are performed at different wavelengths, UV active uremic toxins are contained in the dialysate used and by means of an equation system, in which it is the total absorption of a mixture of substances from UV active uremic toxins at a predetermined wavelength 2 ,, Aj is the absorption of a single UV active uremic toxin into the mixture of substances and n is the number of components of interest within a mixture of substances that contribute to absorption, and by this equation, after detecting the absorption at n characteristic measurement points, the concentration of the n UV active uremic toxins in the substance mixture is determined.
With the device of the invention, it is possible to perform a differentiation of preferably uric acid from other toxic substances or residual products in the dialysate of a patient requiring dialysis, in which the device makes use of an optical UV spectroscopy and through which alternate measurements or simultaneous absorption of the dialysate used at substantially different monochrome wavelengths is possible. The apparatus of the invention in particular allows the determination of the concentration of all UV active uremic toxins present in the blood or in the used dialysate, that is, in the outflow of dialysate. In the state of the art, no dialysis machine has been described yet, which allows quantitative determination of all UV active uremic toxins, namely creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and B2-microglobulin fragments during the dialysis session, or within 30 minutes, preferably within 20 minutes, more preferably within 15 minutes, even more preferably within 10 minutes, even more preferably within 8 minutes, even more preferably within 7 minutes, even more preferably 6 minutes, and most preferably within 5 minutes. The UV measurement can be performed simultaneously or at the same time, that is, they are measured at least in 10 characteristic wavelengths (see definition of "characteristic" below) or measurement points simultaneously or successively or immediately successively.
The measurement of the 10 previously known UV active uremic toxins, however, does not require that any other UV active substance should be present. On the contrary, the method of the invention will still work properly, if additional UV active substances are to be present in the blood or dialysate outflow, such as a drug that is UV active or a certain active UV component of the food that is ingested by the patient through the consumption of a large amount of certain food and thus become detectable in the blood or outflow of dialysate. As long as per UV active uremic toxin at least one UV measurement is performed at an appropriate measurement point, all 10 currently known UV active uremic toxins can be determined quantitatively or qualitatively and quantitatively. The way in which the selection of the appropriate measuring point is performed will be described in detail below. UV measurement can be performed on the blood or dialysate outlet flow, while it can be measured on the dialysate outlet flow more accurately than on the blood, that is, the concentration determination in the dialysate outlet flow can be performed with more precision. Thus, it is considered that the concentration of the substance measured in the outflow of dialysate should not necessarily be identical to the concentration of that substance in the blood, unless it is ensured, for example, through a temporarily closed circuit, where the dialysate outlet flow is reintroduced into the dialyzer, the concentrations of the substances in the dialysate outlet flow can adjust blood concentrations.
The term "dialysate outlet flow" as used here, refers to the dialysate used, which comes out after going through the dialyzer as a waste product from the dialyzer. As used herein, the term "toxin" or "uremic toxins" refers to the UV active uremic toxins described here, namely, creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol , retinol binding protein and B2-microglobulin fragments.
Human beta-2-microglobulin is a whey protein that, as a full-length protein, consists of a single polypeptide chain of 119 amino acids (GenBank accession number CAG33347 version CAG33347.1, Gl: 48146249 dated April 17, 2005 ). The molecular weight of full-length human beta-2-microglobulin is 11.6 kD. Fragments of human beta-2-microglobulin can be produced by enzymatic degradation of human beta-2-microglobulin, in which at least two fragments of human beta-2-microglobulin are produced. Each of the beta-2-microglobulin fragments produced by enzymatic degradation consists of a polypeptide chain comprising less than 119 full-length human beta-2-microglobulin amino acids.
In order to carry out possibly accurate measurements, UV measurement is performed at substantially monochromatic wavelengths or more simply at monochromatic wavelengths. Substantially monochromatic wavelengths are characterized by a peak emission wavelength, a dominant wavelength and a centroid wavelength, where the full width at half the maximum (FWHM) is in the range between 10 and 25 nm . A reduction in the full width in half of the maximum thus leads to a narrower wavelength range for the peak emission wavelength. Generally, the full width at half the maximum (FWHM), a function with a maximum means the difference between the two argument values for which they are reduced to half the maximum. As light emitting diodes (LEDs), for example, Hamamatsu LEDs or Laser Components or LEDs from other manufacturers with equivalent specifications can be used.
Absorption measurements on the dialysate used at a wavelength of À = 280 nm have already been described in EP 1 083 948 B1. The sensor described in EP 1 083 948 B1 could be used for the present invention. The novelty of the invention is that, by using several substantially monochromatic individual wavelengths, absorption measurements can be performed. The applied wavelengths are characterized by the fact that no dialysate used, that is, no dialysate outflow, preferably only the residual substances to be determined contribute to the absorption in these wavelengths, in which these adsorption can overlap in length. measured waveform, and could also overlap even with other UV active substances to be determined. For the determination of UV active uremic toxins, it is imperative that wavelengths are used, which represents characteristic points of the dialysate used. As a characteristic measurement point of the dialysate used, it must be understood that, at this point in the spectrum, that is, at this wavelength, the substantially absorption of the substance to be determined or several substances to be determined is determined. A characteristic point of the dialysate spectrum used can be independent of, for example, local maximums, local minimums and / or decisive points, in which at characteristic wavelengths or measurement points, even only one uremic toxin must determine absorption, or in the superposition of several UV active uremic toxins, each toxin must contribute significantly to the total absorption in that wavelength, so that the proportion of each toxin to the total absorption can be determined in that wavelength as precisely as possible, where according to the system of equations described here, the concentration can be calculated back. Additionally, it will be advantageously measured at characteristic points, that is, wavelengths, in which at most two or three or four substances overlap, that is, they absorb there, in which the number of characteristic points, that is, wavelengths, they correspond to at least the number of toxins to be determined, or, otherwise, the equation system cannot be solved. As characteristic wavelengths or measurement points, margin points are also suitable, which are between a maximum or a decisive point, if the overlap of toxins there contributes significantly to absorption. As unsuitable, it can refer to measurement points or wavelengths for measurement, where, for example, 8 toxins overlap and only 2 toxins, each with 40%, determine the total absorption and the remaining 20% are determined for largely the same proportions as the remaining 6 toxins. Each of the six remaining toxins can be neglected in relation to total absorption, in which to neglect all six remaining toxins would lead to an excessive error in relation to two dominant toxins, and simultaneously the 6 remaining toxins individually contribute to the total absorption in an amount very small that the determination of its concentration is also affected by a very big error at that point. Such points are referred to as inappropriate or not characteristic, and should be avoided.
In addition, it should also be mentioned here that the method and apparatus of the invention are not limited to a maximum of 10 currently known uremic toxins, but basically to any number, for example, 5 or more 10 or more 15 or more 20 active substances UV, together with the 10 known uremic toxins, can be determined quantitatively, if the UV spectra of the individual compounds of the additional UV active substances and their extinction coefficients are known.
Such an apparatus of the invention can be realized using several light sources with monochromatic radiation or a polychromatic light source with a selective element of controllable wavelength, in which the determination of the absorption of uremic toxins is carried out at different wavelengths , and with the aid of the wavelength-dependent extinction coefficient the concentrations of uremic toxins are calculated. In principle, the absorption of the dialysate used is always measured, which consists of the sum of the absorption of each uremic toxin. Thus, it is not enough, however, to know the absorption of each uremic toxin. In order to determine the concentration, the specific extinction coefficient of the substance and the optical measurement distance must be known (Equation 1). Each active UV substance or UV active uremic toxin to be determined is unknown to an equation so that for each active UV substance, at least one UV measurement must be performed. For each active UV substance or UV active uremic toxin to be determined, an equation with an unknown is derived, so the measurement must be performed at least at a wavelength in the UV range. In the case of two UV active substances to be determined, an equation with two unknowns is derived, so the measurement must be performed at least at two wavelengths in the UV range. In the case of three UV active substances to be determined, an equation with three unknowns is produced and a measurement of at least three wavelengths must be performed, etc. Generally in the case of n active UV substances to be determined, an equation with n unknowns is produced, so the measurement must be performed at least at n wavelengths in the UV range.
Monochromatic electromagnetic radiation can be understood as radiation with a defined wavelength. Monochromatic electromagnetic radiation can be generated from a light-emitting diode (LED). Light emitting diodes (LEDs) are electronic semiconductor elements, which emit electromagnetic radiation in a spectral range limited by current flow in the forward direction. The electromagnetic radiation emitted is almost monochromatic. The wavelength can, depending on the configuration of the light emitting diode, be in the visible range of the spectrum, in the infrared range or respectively in the ultraviolet range. The radiation source for the apparatus of the invention consisting of several light sources for the emission of monochromatic electromagnetic radiation must be designed for the emission of electromagnetic radiation in the range of 1 nm to 750 nm. In particular, the radiation source consisting of several light sources must be designed to emit electromagnetic radiation in the ultraviolet radiation range from 180 nm to 380 nm. For the measurement of uremic toxins, LEDs are preferred, which emit in the range of ultraviolet radiation from 180 nm to 380 nm, more preferably in the range of ultraviolet radiation from 180 nm to 320 nm. To detect all UV active substances, detectors must be sensitive enough, since some substances are only slightly different in relation to their UV spectrum. In addition, the resolution of the measuring device must be sufficiently high.
In the use of light emitting diodes (LEDs), it is also advantageous that the light emitting diodes are not thermal radiators and that the heat produced for the generation of radiation can be removed, for example, through cooling fins on the rear of the light emitting diodes.
Alternatively, the radiation source consisting of several light sources can be designed to generate polychromatic electromagnetic radiation. To generate substantially monochromatic electromagnetic radiation in the range of 1 nm to 750 nm, preferably in the range of 170 nm to 380 nm, and more preferably 180 nm to 320 nm, corresponding monochromators are provided. In particular, optical filters crossing only a specific wavelength or a bandpass filter with several pass bands are provided. The radiation source consisting of several light sources for the generation of polychromatic electromagnetic radiation in the ultraviolet range of the spectrum is, for example, mercury vapor lamps mercury vapor lamps or deuterium lamps. For the present invention, mercury vapor lamps and / or conventional deuterium lamps, optical filters and bandpass filters with various passages can be used. The adaptation of mercury vapor lamps and / or conventional deuterium lamps, optical filter and bandpass filter with several passage bands for the generation of monochromatic electromagnetic radiation in the range from 1 nm to 750 nm, preferably in the range of 180 nm to 380 nm, and more preferably 190 nm to 320 nm for the absorption behavior of uremic toxins to be determined is within the abilities of a person skilled in the art.
In the following, the theoretical foundations are described in detail.
Absorption is given by the Lambert-Beer law as follows:
where AM is the absorption at a specific wavelength À ,, EM is the wavelength-dependent extinction coefficient, / is the optical path length and c is the respective concentration of a substance. Often, the absorption cross section is also mentioned. That is, ^ A, by equation (1), the normalized absorption for length l. If a mixture of substances consists of several absorbent substances, then the absorption of the mixture of substances consists additively in the absorptions of the individual components for a constant wavelength A:

In equation (2), AM is the total absorption of a mixture of substances, Aj is the absorption of a single substance within the mixture of substances and n is the number of components within the mixture of substances that contribute to the absorption.
j represents the running index of the mathematical sum operation. Formulas (1) and (2) are only valid if the Z wavelength is constant. With this system, the dialysate absorption spectrum used can be disassembled into an equation system of n equations at n different wavelengths in order to identify the concentration of n uremic toxins. This is possible only if the spectra of uremic toxins are known and the spectra of uremic toxins are different enough from each other or the above mentioned characteristic measurement points exist, as is the case with UV active uremic toxins. Selection criteria for a characteristic measuring point or characteristic wavelength:
As a characteristic point of the dialysate used, it is primarily understood that, at this point in the spectrum, that is, in this wavelength, absorption is substantially dominated by the substance to be determined. That is, preferably, the absorption is dominated by at least 90%, preferably by at least 94% and especially preferably by at least 96% by that toxin. A characteristic measurement point can also be found where, in the UV spectrum of the pure toxin, it has a maximum, a decisive point or a margin point located between a maximum and a decisive point. In addition, characteristic measurement points or characteristic wavelengths can be found at a local maximum, a local minimum, margin points and / or decisive points of the total spectrum of the measured sample. A characteristic measurement point, that is, a wavelength can be selected, for example, using local maximums, local minimums and / or decisive points of the uremic toxin spectra, if these are different among the uremic toxins to be determined. For the case where the local maximums, local minimums and / or decisive points of the uremic toxin spectra must be overlaid on a specific wavelength, a characteristic measurement point can be selected in other ranges of the uremic toxin spectra, for example , in bands of the spectra of uremic toxins with positive or negative slope. For the case in which the substance to be determined absorbs at a characteristic point in the spectrum of the solution to be measured, that is, at a specific wavelength, the absorption contributes to the equation system. In the case that at a characteristic point in the spectrum of the solution to be measured, that is, at a specific wavelength, none of the substances to be determined contributes to the absorption, then the absorption at that characteristic point, that is, at that length of wave, does not contribute to the solution of the equation system. It is preferable that at the characteristic points of the spectrum of the measurement solution, such as blood or the dialysate outlet flow, at least one substance to be determined absorbs. It is also possible to measure at characteristic points, that is, wavelengths, in which up to two or three or four substances overlap, that is, they absorb there, in which the number of characteristic points, that is, wavelengths, is at minus the number of substances to be determined, otherwise the equation system cannot be solved. Characteristic measurement points or wavelengths characteristic for UV measurement are thus such measurement points and wavelengths, where only one toxin causes or dominates absorption or where two or more toxins overlap and the overlapping toxins individually contribute significantly to the total absorption at that wavelength, so that the individual contribution of each toxin to the measured wavelength can be determined relatively accurately and its concentration can be calculated. However, measurement points and wavelengths at which several UV active substances overlap with each other are unfavorable, but none of these substances dominate absorption and all UV active substances individually contribute only a little to total absorption. Thus, a wavelength for UV measurement is quite adequate, even if 10 UV active substances overlap if, for example, one substance contributes 50% to total absorption, a second substance contributes 40% to absorption. total and the remaining 8 substances contribute only 10% to the total absorption, because then these 8 substances can be neglected and the two dominant substances can still be measured relatively precisely.
Additionally, it is essential for the selection of the characteristic measurement points and the characteristic wavelengths that in the information of n concentrations to be determined and of n non-redundant measurement points can be obtained, that is, the UV measurement in one of the n wavelengths may not lead to a result or information that has already been obtained from another of the n measurements. This is, for example, the case, if at two wavelengths, absorption is significantly dominated by the same toxin. That is, in the two wavelengths, the concentration of the same toxin is determined and redundant information is obtained, as two measurement points for the determination of the same toxin were required. Such redundant information is advantageous in order to increase the accuracy of the method, however, they require that, for n toxins, more than n measurements have been performed, since redundant information should only be obtained from one measurement (n + 1). If you have n toxins and n measurements with two redundant information, this will make sure that only concentrations of n-2 toxins can be determined. To determine the concentrations of all n toxins in this case, at least 2 more measurements are required.
Assuming that the absorption spectrum of dialysis patients is substantially dominated at a specific wavelength by uric acid, the equation system is simplified and other UV active uremic toxins can be calculated by measuring absorption at other wavelengths ( see tables 1 to 3). This is illustrated by the illustrations in figures 1 and 2. Figure 1 shows the typical dialysis spectrum of a patient requiring dialysis, while figure 2 shows the profile of the uric acid spectrum at a concentration of 1 mg / l. It is evident that the dialysis spectrum in the range of 320 nm to 290 nm substantially follows the uric acid spectrum. In the wavelength range below 290 nm, the spectra differ significantly from each other, so it can be assumed that there are substances other than uric acid from the mixture of dialysis substances involved in absorption, while from about 290 nm, only uric acid contributes to absorption.
Through equations (1) and (2), the system of equations can be established by different wavelengths, which describe the absorption of a mixture for different wavelengths. In connection with the calculation of the uric acid concentration, which substantially constitutes À = 290 nm absorption in the total dialysate, the measurement of absorption at, for example, À = 266 nm, allows the determination of another toxic substance, such as malondialdehyde , if the absorption depends substantially on uric acid and a second substance on the second wavelength. Similar to the example of malondialdehyde, other substances, such as creatinine, which substantially determines the absorbance of the dialysate, can be determined by this method. Since creatinine has its maximum absorption in ca. À = 235 nm, it makes sense to determine the absorption of dialysate at À = 235 nm. The additional substances, which are mentioned in Tables 1 to 3 and which substantially determine the absorption of the dialysate, can also be determined by this method.
From the uric acid spectrum according to figure 2, the proportion of uric acid absorption can be determined at two predetermined wavelengths. This proportion of uric acid absorption also applies to uric acid absorption in the dialysate used. Consequently, a linear equation system having at least two components can be established, and it is possible to determine the concentration or reduction of other uremic toxins other than or in addition to uric acid, such as malondialdehyde. As it is assumed that uric acid will almost always be present in the outflow of dialysate, a measurement at À = 290 nm is almost always advisable.
Following the equations describe the necessary exemplary calculations for the active uremic toxins UV uric acid and malondialdehyde: AK, p lc Í31 A = 290nm acidic, áeidouric '' where AÀ = 2Wnm (dialysate) = A ^ 290nm (acidic). With equation 1, A ^ 290nm (uric acid) = • A ^ 2f> bnm (uric acid) (3a) is additionally valid, where konsté is the proportion of uric acid absorption in the wavelength 290 nm and 266 nm. If absorption is now measured at a wavelength of 266 nm, where absorption is substantially composed only of the two substances, uric acid and malondialdehyde, the absorbance of the dialysate at 266 nm is: A2 = 266nm (dialysate °) = AA = 266nm (. Uric acid) + A Á = 2 (íf) nm (malondiald eido) or is generalized to: A2 = 2 ^ nm {dÍalÍSat °} = A ^ nÁácÍd0ÚrÍC °) + A ^ nm (Substance _x) W with Lambert-Beer, the following equation is obtained: A2 = 2bbnm (diolysis) ~ uric acid uric acid ^ "substance _x, 226 (lnm ^ substance _x (4) After the combination of equation 3a and equation 4, follows up:

If substance_x is known, which, for example, contributes more than uric in a major part to absorption at À = 266 nm, the absorption of substance_x can be determined with the aid of equation 4a at 266 nm and subsequently by equation 4b, the concentration of substance_x can be determined. A precondition is that the corresponding extinction coefficient ^ substance is known, that it is a constant substance and therefore can be measured in the laboratory.
This example can also be used for various concentrations of unknown substance, if the absorption measurement is carried out with various wavelengths. Generally, reference is made here to a linear equation system of arbitrary order. In the following, as one of the substances to be determined, the reference substance is indicated as a preferred wavelength Xi = 290 nm:
where Ài is the wavelength, where the reference substance is substantially the only substance in the dialysate used that contributes to an absorption, thus preferable at 290 nm and
as well as j θ the substance of interest, 4 * (reference substance) ε * Cj is the concentration of the corresponding substance j in the dialysate and Aj is the absorption of substance j at the wavelength Àj.
In the following example, uric acid is preferably given as one of the substances to be determined:
where Ài is the wavelength, where uric acid is substantially the only substance in the dialysate used that contributes to absorption, thus preferably 290 nm
as well as j is the AM (uric acid) εu substance of interest, q is the concentration of the corresponding substance j in the dialysate and Aj is the absorption of substance j at the wavelength Àj.
The reference substance is selected from the group comprising the active uremic toxins UV creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and fragments of B2- microglobulin and / or combinations thereof. As a reference substance, uric acid is preferred. With the use of uric acid as a reference substance, the system of equation (4b) can be simplified. The aforementioned system of equation (4b) can be simplified like the system of equation (4c) below, so that none of the n equations involve more n unknowns. In addition, the number of strangers is reduced to n = 1 for one equation, to n = 2 strangers for two equations, to n = 3 strangers for three equations, etc. By selecting a reference substance, the equation system can be simplified and is easier to solve, if the extinction coefficient of the reference substance is known. The concentration of the reference substance may be known or unknown. With the equation system, it is possible to determine n unknown concentrations at a characteristic measurement point, that is, a specific wavelength, if the proportions of the concentrations of n uremic toxins at the characteristic measurement point, that is, at the wavelength specific, are known. For the selection of one or more characteristic measuring points, the criteria mentioned in the selection criteria section for a characteristic measuring point must be applied.
By a repetitive approach, this system of equations can be solved, for example, by measuring first at the wavelength where only uric acid absorbs in the used dialysate and then changing to wavelengths where in the used dialysate (that is, in the flow dialysate outlet) in addition to uric acid only one additional substance absorbs substantially, then two additional substances and then up to n additional substances absorb. Thus, without direct measurement, the absorption of a substance in the used dialysate and with the knowledge of the extinction coefficient, even the concentration of that substance in the used dialysate can be determined.
The repetitive approach is, however, only one possibility, albeit a preferential one, to solve the above equation system, which begins with the measurement of a reference substance, that is, a reference toxin at a characteristic wavelength, wherein this toxin contributes to UV absorbance only in isolation, or at least in 90%, preferably in 94% and most preferably in 96%. Another possibility to solve the equation system from n equations for n concentrations to be determined for n uremic toxins is the selection of characteristic measurement points, where several toxins together determine the absorption spectrum significantly. If, for example, two measuring points are selected, in which the same two uremic toxins dominate absorption significantly, that is, both contribute together to total absorption by at least 90%, preferably 94% and most preferably 96 %, two variations are considerable. If toxin x has absorption m at wavelength a and, at that wavelength, toxin y has absorption n (including the possibility that m = n), and at the second measurement point at wavelength b, a toxin x has absorption m / 2 and toxin y has absorption n / 2, so the proportions of absorptions of toxins x and y at both measurement points, that is, at both wavelengths are the same, so that no additional information is obtained from the measurement at wavelength b, that is, the 2-equation system with 2 unknowns cannot be solved.
However, if toxin x has absorption m at wavelength a and at that wavelength, toxin y has absorption n (including the possibility that m = n), and at the second measurement point at wavelength wave b, toxin x has absorption m / 2 and toxin y has absorption n / 3, so the proportions of absorption of toxins x and y are different at both measurement points and the equation system from two equations with two unknowns can be resolved and the concentrations of x and y toxins can be determined. In the latter case, the measurement points are characteristic, that is, the spectra of two toxins sufficiently different, so that at the additional measurement points, no redundant information is generated.
Thus, for the determination of n toxin concentrations, it is important that at n wavelengths, absorption is measured without obtaining redundant information. Thus, to always solve the solution of an equation system from n unknowns, that is, n concentrations of n toxins, measurement at n + z wavelengths is recommended, where z = 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10.
To determine the respective absorption as described above, Lambert-Beer is also applied:
where AM is the absorption at a specific wavelength A, IA, O, ÀÍ is the intensity at the absorption detector with a reference solution, and IA.IM is the intensity at the absorption detector during dialysis therapy over time t at a specific wavelength A- As in equation (1), it is the wavelength-dependent extinction coefficient, / is the optical path length, and c (t) is the respective concentration of a substance at time t. By determining the intensity IA, o, AÍ with a reference solution - ideally fresh dialysate, since a possible absorption is not caused by toxins - at the beginning of dialysis therapy and with the continuous determination of the AMI intensity during therapy, the absorption for a specific wavelength A at any time can be determined. Absorption of UV active uremic toxins
As already mentioned above, uric acid is expected in almost all patients on dialysis in the outflow of dialysate, so a measurement at À = 290 nm should be advantageously performed in order to determine the concentration of uric acid.
In order to determine the concentration of malondialdehyde, a measurement at À = 266 nm is recommended.
In order to determine the creatinine concentration, a measurement at À = 235 nm is recommended.
Thus, absorption measurements are performed at the following wavelengths: À = 320 nm, À = 310 nm, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, A = 270 nm, À = 266 nm, À = 260 nm, À = 250 nm, À = 245 nm, À = 240, À = 235 nm, À = 230 nm and À = 220 nm. The toxins to be determined creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malonaldehyde, p-cresol, phenol, retinol binding protein and fragments of B2-microglobulin and / or combinations thereof are preferred.
Preferred measurement points are at the wavelengths À = 310 nm, À = 290 nm, À = 266 nm, À = 235 nm and À = 220 nm. Most preferred wavelengths are À = 310 nm, À = 290 nm, À = 280 nm, À = 2506 nm, À = 250 nm, À = 245 nm, À = 235 nm and À = 220 nm. The most preferred wavelengths are À = 320 nm, À = 310 nm, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, À = 270 nm, À = 266 nm, À = 260 nm, À = 250 nm, À = 245 nm, À = 240 nm, À = 235 nm, À = 230 nm, À = 220 nm and À = 205 nm.
Per uremic toxin to be determined, an absorption measurement is preferable at a characteristic measurement point, that is, at a specific wavelength, where that uremic toxin has a maximum absorption or at least a high absorption or good absorption with little overlap. For the determination of the concentration of, for example, 10 toxins, an equation system with 10 variables is obtained, so that 10 measurements are required, in which the 10 measurements do not lead to redundant information and must be performed at characteristic points in order to get accurate measurements. For the selection of one or more characteristic measuring points, the criteria mentioned in the selection criteria section for a characteristic measuring point must be applied. In addition, if possible, in the measured range, only this uremic toxin should absorb. If there is no such wavelength or such wavelength range for a specific uremic toxin, then that uremic toxin is measured in an absorption maximum or a high absorption, in which an overlap with the absorption of one or more others uremic toxins is present, whether one or at least one of several other uremic toxins, which also absorb in that range, has another measuring range or another wavelength with a maximum absorption, or a high absorption, which is not or it is only slightly overlapped by the absorption of other uremic toxins. Since n general equations with n unknowns must be solved, the person skilled in the art selects the measurement points so that this equation system can be solved in order to determine the concentrations of the UV active uremic n toxins. If an active UV toxin is to be determined, an equation with an unknown results so that the measurement must be performed at least on a wavelength in the UV range. From two active UV toxins to be determined, an equation with two unknowns results so that the measurement must be performed at least on two wavelengths in the UV range, in which no redundant information must be obtained. From the three active UV toxins to be determined, an equation with three unknowns results and a measurement at least three wavelengths, etc. Generally, from n UV active substances to be determined, an equation with n unknowns results so that measurement at least n wavelengths in the UV range must be performed and no redundant information must be obtained. For the selection of wavelengths, it is important that the spectra of uremic toxins are known and the spectra of uremic toxins differ sufficiently from each other. The selection of measurement points can be made, for example, using local maximums, local minimums, margin points and / or decisive points of the uremic toxin spectra, in case they must differentiate between the uremic toxins to be determined. In the case of local maximums, local minimums, margin points and / or decisive points of the uremic toxin spectra should be superimposed on a specific wavelength, a characteristic measurement point can be selected in other ranges of the uremic toxin spectra, for example. example, in bands of uremic toxin spectra with positive or negative slope, especially between a maximum and a decisive point. It is preferable that, at the characteristic measurement points of the spectra of the dialysate used, at least one toxin to be determined absorbs. It is also possible to measure at characteristic measurement points, that is, wavelengths in which up to two or three or four substances overlap, that is, absorb there, in which the number of characteristic measurement points, that is, wavelengths , is at least the number of substances to be determined, since, otherwise, the equation system cannot be solved.
If it is measured at characteristic measurement points, that is, wavelengths, in which up to two or three or four substances overlap, that is, they absorb there, the equation system can be simplified and more easily solved. In addition, there is also the advantage that fewer characteristic measurement points, that is, up to two or three or four, means less deviations in absorptions due to measurement error. In the event that two of the uremic toxins are to be determined, which absorb at two characteristic measurement points, the absorption of the two uremic toxins must differ sufficiently at two characteristic measurement points. The absorption of the two uremic toxins at two characteristic measurement points is then sufficiently different, if the proportion of absorptions of the two uremic toxins in the first of the two characteristic measurement points is not equal to the proportion of absorptions of the two uremic toxins in the second of the two points measurement characteristics. If the proportion of the absorption of the two toxins in the first of the two characteristic measurement points is equal to the proportion of the absorption of the two uremic toxins in the second of the two characteristic measurement points, the equation system cannot be solved, as redundant information is obtained . For the solution of the equation system, another characteristic measurement point, that is, another wavelength is required, in which the proportion of absorptions of the two uremic toxins at the other characteristic measurement point must not be equal to the proportion of absorptions of the two uremic toxins at the second characteristic measuring point. For n uremic toxins to be determined, at least n characteristic measurement points, that is, n wavelengths must be selected, in which the proportion of absorptions of n uremic toxins to be determined at least at a characteristic measurement point, or that is, one of the n wavelengths, must not be equal to the proportion of absorption of uremic toxins at other characteristic measurement points, that is, other wavelengths. This means that, at two of the n measurement points, the proportion of the toxin absorptions absorbed at that measurement point should not be identical or almost identical and, if possible, should have a clear difference.
The extinction coefficient is characteristic for a specific substance at a specific wavelength and depends, on the one hand, on the temperature and the pH value, on the other hand, it also depends on the solvent, which may incur interactions with the absorbent molecules. The extinction coefficient of UV active substances to be determined are known in the prior art and can be found in textbooks, for example, Lange's Handbook of Chemistry (14.Ausgabe, Hrsg. JA Dean, 1992. McGraw-Hill, Inc ., New York), Second Handbook of Chemistry and Physics (56. Ausgabe, Hrsg. RC Weast, 1975. CRC Press, Cleveland) or Third Practical Handbook of Biochemistry and Molecular Biology, Hrsg. D. G. Fasman, 1992. CRC Press, Boston. The determination of the extinction coefficient by the person versed in the technique is also possible, since the determination of the extinction coefficient is within the abilities of the person versed in the technique. Measuring device (37) and radiation source (1)
The sensor described for carrying out the measurements, which is also referred to here as a measuring device or UV sensor (37), is similar to the measuring device described in EP 1 083 948 B1. The difference is that the light source (1) now consists of at least two monochromatic light sources or a polychromatic light source, which can be controlled individually by means of a selective wavelength element (2).
The reference detector (6) and the absorption detector (5) are especially characterized by the fact that they can detect the entire spectrum in the UV range between 160 nm and 400 nm wavelength. An illustration of such a sensor is shown in figure 5.
In order to perform the described calculations with such a sensor during dialysis therapy, a method is necessary, which controls the measurement of the optical properties of the dialysate used. In addition, different technical content must be implemented, which are described below. Absorption measurements
At the beginning of dialysis therapy, a calibration of the absorption and reference detectors - at least, however, with two - wavelengths is required. Therefore, the sensor (37) must be filled with a reference fluid and the signal on the absorption detector (5) must be determined. In order to obtain a signal as strong as possible on the absorption detector, it is preferable to configure the preferred circuit, which converts the signal on the optical detector into an electrical signal, so that the intensity on the absorption detector is during calibration with fresh dialysate close to the maximum of the electrical amplification, so that the electrical signal is also at maximum.
Alternatively, the intensity of the LED can also be varied for each wavelength. Preferably, the LED control should be selected so that the current through the LED is less than 50% of the maximum allowed current in order to keep the LED load low and, thus, avoid aging effects. This must be done in coordination with the adaptation of the preferred electrical circuit for the absorption detector during calibration.
The methods described above in connection with dialysis therapy must be performed at the time of preparing a dialysis therapy. Preparation in dialysis therapy is characterized by the fact that the extracorporeal blood circuit is not connected to the patient, so that it is ensured after the preparation of dialysate, which is usually done very early in the preparation, the fresh dialysate is in outflow from the dialysis machine, so that a calibration can be performed.
In addition, the dialysate temperature must also be taken into account when calibrating the electrical signals that are generated by the UV sensor in the dialysis output flow. Since the dialysate temperature represents a critical function within dialysis, temperature detection can be used to ensure the accuracy of the calibration. Therefore, it is necessary that the calibration be performed when the dialysate temperature is in an adequate range, usually around 35 to 37 ° C. The corresponding dialysate temperature is ensured during the preparation of a dialysis therapy by the dialysis machine.
This must be performed for each wavelength (but at least two) of the system separately. Since the intensity of the light source and the sensitivity of the absorption and reference detectors depend on the radiated wavelength, the signals from both detectors must be determined in the calibration for the reference fluid and stored in a storage, where, in real measurements, they can be accessed in the additional process of dialysis therapy at any time. During actual measurement within dialysis therapy at time t, the measured intensity θ determined for a specific wavelength and, through equation (5), is associated with the reference value already determined during calibration. This is done individually for each wavelength - but for at least two wavelengths - of the light source. It should be noted that the method of the invention is not for a therapeutic method or a diagnostic method in the human body, since from the obtained values, neither a therapy nor a diagnosis is derived. The detected data is used only for the dialysis process protocol, as the proper function of a pump on the dialysis machine can be fitted and replaced according to a malfunction or failure, which has no connection with a treatment or diagnosis in the human body. In addition, the data obtained draw conclusions about the quality of the dialysis session, as well as components recently used in the dialysis machine and its suitability in general, as well as for a particular patient.
The measurement of absorption in the dialysate for different wavelengths is done successively, in which the measured intensity IA, I, AÍ and the reference intensity IA, o, AÍ are connected through equation (5). The reference intensities IA, o, AÍ were previously determined in the calibration phase, so that the calculation of the respective absorption AAÍ for each wavelength is carried out individually. In addition, the results of individual absorption measurements can be used in order to be connected using the linear equation system described in equations (2) to (5).
Preferably, the measurement time for a wavelength per LED is in the range between 1 and 30 seconds. The change between wavelengths for the light emitting diode is performed in the range of milliseconds / seconds and is dependent on the manufacturer's specifications for the respective light emitting diode.
For substantially monochromatic radiation sources consisting of several light sources, one light-emitting diode is required per wavelength. Preferably, the number of LEDs per housing is in the range of 1 to 5, preferably in the range of 1 to 8, more preferably in the range of 1 to 10 and most preferably in the range of 1 to 16, where the greatest number of diodes light emission can also be used, as the housing sizes or the LED sizes allow this. Also, two or more housings with one or more light emitting diodes are applicable.
Each UV active uremic toxin to be determined is measured at a wavelength. If a combination of different substances is to be determined, for example, a combination of uric acid, creatinine and malondialdehyde, three wavelengths are required, as is evident from the system of equation (2). Thus, each substance to be determined is an unknown in equation (2). To determine n unknowns, consequently n equations are required. This, in turn, leads to a new equation (2) for each wavelength in which the absorption of a substance must be determined.
The absorption measurement for the range between 180 and 320 nm is performed at discrete wavelengths. Since the spectra of the substances to be determined are sufficiently different, only the number of measurement points is required as the substances to be determined are present. Thus, absorption measurements are performed at the following wavelengths: À = 320 nm, À = 305 nm, À = 290 nm, À = 280 nm, À = 266 nm, À = 245 nm, À = 235 nm and À = 220 nm, when up to eight substances must be determined, and at À = 320 nm, À = 310, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, À = 270 nm, À = 266 nm, À = 260 nm, À = 250 nm, À = 245 nm, À = 240 nm, À = 230 nm, À = 230 nm, À = 220 nm and À = 205 nm, when up to 16 substances and preferably 10 uremic toxins mentioned must be determined. The characteristic measurement points are selected according to the criteria mentioned in the selection criteria section for a characteristic measurement point. Similarly, measurements can be performed over a selection range of the aforementioned wavelengths. Measurements in other than the aforementioned wavelengths are also possible. For the selection of wavelengths, it is important that the spectra of uremic toxins are known and the specimens of uremic toxins differ sufficiently, exemplarily, by local maximums, local minimums or different decisive points or the specimens of uremic toxins differ at local maximums, local minimums or decisive points. In addition, the extinction coefficients of uremic toxins must be known at that wavelength. Determining the extinction coefficient of uremic toxins is within the skills of a person skilled in the art or can be found in textbooks.
Each light emitting diode in the measuring device is individually controlled, that is, wavelength light emitting diodes in which currently no measurements are made, are switched off. Consequently, the time of a measurement cycle is between 1 to 30 seconds for a wavelength, in which it is measured. If measurements for two wavelengths are performed, the measurement time is in the range of 2 to 60 seconds. The measurement cycle time is therefore dependent on the number of measurement points or wavelengths.
With polychromatic radiation sources consisting of several light sources, all required wavelengths are emitted simultaneously, where at least one detector is present. If only a single detector is present, an adjustable filter must be installed upstream of the detector, where the adjustable filter must be controlled in such a way that the adjustable filter allows all the required wavelengths to run sequentially. In this case, the measurement cycle time is in the range between 10 seconds and 5 minutes. The measurement cycle time is therefore dependent on the length the filter needs to switch back and forth between wavelengths. If two or more detectors such as each different wavelength selective element are present, the time for a measurement cycle is in the range of one to thirty seconds. It is preferred that a measuring device with three detectors, where each detector has a filter and the filter of the first detector allows only light of the wavelength to pass through, the filter of the second detector allows only light of the wavelength 12 and the filter the third detector allows only light of the À3 wavelength to pass through.
As an adjustable filter, diffraction grids or crystals can be used, in which the wavelength selection is determined by the angle of incidence. The aforementioned filters are micromechanically adjustable by a stepper motor that rotates the crystal or the mesh. Alternatively, electronically adjustable filters can be used, in which the material properties can be manipulated throughout the application of tension, so that only light with a specific optical wavelength passes through the crystal, or the network. In the case where a source of polychromatic radiation consisting of several light sources with two or more detectors is applied, where each detector has a separate filter, the standard filter, such as the conventional bandpass filter for the UV range can be applied. used. Additional filter modalities are within the skill of the person skilled in the art.
A measuring device comprises or consists of a radiation source and at least one detector. The radiation source can be one or more sources of polychromatic light. In the case where only one source of polychromatic light is used, the source of radiation and the source of light are identical. The radiation source can also consist of two or more sources of polychromatic light. In suitable polychromatic light sources, filters should be used in order to limit the spectrum for the wavelength to be measured. It is preferable if the radiation source consists of several monochromatic light sources. Monochrome light sources do not require filters. Monochrome light sources must emit the desired wavelengths, that is, the characteristic wavelength, such as A = 320 nm, A = 310 nm, A = 305 nm, A = 300 nm, À = 290 nm, A = 280 nm, A = 270 nm, A = 266 nm, A = 260 nm, A = 250 nm, A = 245 nm, A = 240 nm, A = 235 nm, A = 230 nm, A = 220 nm and A = 205 nm (A represents the wavelength).
If a single radiation source is used, it must be designed as a source of polychromatic radiation. In the case of a single polychromatic radiation source with a single light source and a detector, the filters must be designed as adjustable filters. Measurements are performed sequentially at different wavelengths, in particular at A = 320 nm, A = 310 nm, A = 305 nm, A = 300 nm, A = 290 nm, A = 280 nm, A = 270 nm, À = 266 nm, A = 260 nm, A = 250 nm, À = 245 nm, À = 240 nm, A = 235 nm, A = 230 nm, A = 220 nm and A = 205 nm. Preferred is a modality of the measuring device with a source of polychromatic radiation with a single light source and several detectors, in which each detector is provided with a specific filter. In this case, the measurement is performed simultaneously for all wavelengths. It is more preferable to use a substantially monochromatic radiation source consisting of several light sources with a detector, in which two or more of such configured measuring devices are arranged sequentially at outlet 36 of the dialysate used. Measurements at different wavelengths are performed substantially simultaneously. Most preferred is a modality of the measuring device with at least two substantially monochromatic light sources consisting of several light sources and a detector, in which measurements for different wavelengths are carried out sequentially. Alternatively, measurements for different wavelengths can be performed simultaneously, if at least two measuring devices are available, which are arranged sequentially at output 36 leading to the dialysate used and each measuring device is configured with at least one radiation source substantially monochromatic consisting of a light source and a detector.
A radiation source consisting of 10 monochromatic light sources is preferred for absorption measurements at wavelengths A = 320 nm, À = 305 nm, À = 290 nm, À = 280 nm, À = 266 nm, À = 245 nm, À = 240 nm, À = 235 nm, À = 230 nm and À = 220 nm.
Most preferably a radiation source consisting of 12 monochromatic light sources for measurements of absorption at wavelengths 320 nm, 305 nm, 300 nm, 290 nm, 280 nm, 266 nm, 260 nm, 250 nm, 245 nm, 240 nm, 235 nm e220 nm or 320 nm, 305 nm, 300 nm, 290 nm, 280 nm, 266 nm, 250 nm, 245 nm, 240 nm, 235 nm, 230 nm and 220 nm.
Even more preferably, a radiation source consisting of 16 monochromatic light sources for absorption measurements at wavelengths À = 320 nm, À = 310 nm, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, À = 270 nm, À = 266 nm, À = 260 nm, À = 250 nm, À = 245 nm, À = 235 nm, À = 235 nm, À = 230 nm, À = 220 nm and À = 205 nm.
The aforementioned radiation sources are particularly suitable for measuring the absorption of the following uremic toxins and for determining their concentration: creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, protein-binding retinol and fragments of B2-microglobulin.
If a polychromatic light source is used, then such filters are used so that measurements are allowed at the aforementioned 10,12 or 16 wavelengths.
To ensure that measurements of intensities over a long period can be performed, it must be ensured that the light source constantly emits the intensity set in the calibration also during dialysis therapy, which usually takes about four hours. In addition to the current required running along the LED, the intensity of the /R.OMÍ reference detector is also deposited in a storage after the calibration of a wavelength is completed. When measuring the absorption of a specific wavelength it is ensured that the intensity of the IRW reference detector at a given time t is identical or almost identical to the calibration value! R, O, M. If this is not the case, then the intensity of the light source must be adjusted accordingly. To do this, an intensity check is performed on the reference detector.
The variable controlled here is the intensity of the radiated current of a wavelength of the light source, which is detected in the reference detector, IR, I, M- This also simultaneously represents the actual value of the control. The value is the respective reference intensity at the same wavelength from the calibration: IR ^ AÍ. By comparing the actual value and the established value, a control algorithm can be implemented, which minimizes the control deviation ~ IrMí ~ Iri ^. This can be done, for example, with a PI control element. The control actuator is thus the current through the light source, which influences the intensity of the light source directly (usually linear). System disturbance variables that bring about the control deviation are, for example, temperature changes or aging processes of the light source. Only after adjusting the current value to the established value, the measurement of the intensity IA.Í, AÍ in the absorption detector can be continued.
By using at least two wavelengths, it is also possible to perform a plausibility test. This plausibility test serves several purposes. First, when measuring absorption at, for example, Ài = 290 nm and À2 = 230 nm, the A ^ / AM ratio can be formed. From Figure 1, it is shown that AA2 absorption is typically much higher than AAI in patients requiring dialysis. By forming this proportion, the functional capacity of the sensor can be checked. For example, if the ratio is AA ^ AAI <2, for example, an error message can be sent to the dialysis machine, which signals the sensor's inadequate function.
On the other hand, the absorption of different AAÍ wavelengths can be used in order to divide patients dependent on parameters such as nutritional status, etc., into different groups. Vasilevsiky and Konoplyov pointed out in 2005 in their article "Peculiar character of dialyzate ultraviolet extinction spectra as in indicator of nucleic acid metabolism in humans" (Journal of Biomedical Optics 10 (4), 44026, July / August 2005) that patients differ in part widely each other based on the absorption curve of the dialysate depending on the wavelength. From the method described, using two wavelengths (for example Ài = 290 nm and À2 = 260 nm), the respective group of patients can be determined. Thus, it is possible to distinguish patients whose AM / AA2θ ratio approximately equal to 1 (cf. figure 1), is> 1 (for example, more than 1.2) or their ratio is <1 (for example, less than 0, 9). Information about the patient's condition can possibly be an indicator of parameters such as nutritional status or morbidity / mortality.
For a more detailed description of the invention, the illustrations are attached with corresponding references. Additional objectives, advantages, characteristics and application possibilities of the present invention will be provided with the following description of the modality examples with the illustrations and examples. All the features described and / or illustrated form in themselves or in any significant combination of the subject matter of the present invention, also independent of their summary in the claims and their references. Description of the figures
Figure 1: Dependence on the normalized absorption of the irradiated wavelength for a typical dialysate spectrum of a patient requiring dialysis.
Figure 2: Dependence of normalized absorption of the irradiated wavelength for uric acid of small molecule substance.
Figure 3: the normalized absorption of the irradiated wavelength for small molecule substance malondialdehyde.
Figure 4: Dependency of absorption of the irradiated wavelength for small molecule substance creatinine.
Figure 5: Absorption behavior of uric acid, creatinine and malondialdehyde in dialysate used in comparison with individual substances.
Figure 6: Apparatus of the invention.
Figure 7: Exemplarily, the configuration of a sensor for the differentiation of the different uremics in the dialysate with a broadband light source, a monochromator and a broadband detector.
Figure 8: Exemplarily, the configuration of a sensor for the differentiation of different uremic toxins in the dialysate with a broadband light source, several broadband detectors and several narrowband filters that are designed differently, in which they are dispensed with the monochromators if detectors 1 an are of sufficiently narrow band.
Figure 9: Exemplarily, configuration of a sensor for the differentiation of different uremic toxins in the dialysate with a monochromatic light source and a detector. For the implementation of this invention, n sensors of this modality with different sources of monochrome light serve for n wavelengths.
In figures 7 to 9.1 it always represents the light source, which is projected poly- or monochromatic according to the respective modality, 2 always represents the monochromator, 3 always represents the divider of the light beam, 4 always represents the distance of measurement, 5 always represents the optical detector which is designed as narrow band or broadband according to the respective modality, and 6 always represents the reference detector. Examples Example 1
The dialysate sample from a patient requiring dialysis was taken 10 minutes after the start of treatment and its absorption in the wavelength range from 200 nm to 400 nm was determined spectrophotometrically. For wavelengths longer than À = 340 nm, in this case the absorption is negligible. In the range from À = 340 nm to À = 290 nm, the absorption initially increases markedly, then, behaves steadily up to ca. À = 260 nm, in order to increase sharply again. At À = 230 nm, a local maximum is observed. At wavelengths below À = 220 nm, an additional increase in absorption was observed. Dialysate spectra of different patients generally differ in intensity and the course of absorption in the range from À = 290 nm to À = 255 nm. During the course, a local minimum (for example with A ^ eonm = 0.5) or a strictly increasing function (for example with AA = 26O nm = 1.5) remains almost constant in the image shown in this range. . Figure 1 shows the spectrum of the dialysate sample from the dialysate outlet flow of the patient requiring dialysis. Example 2
The absorption behavior of uric acid at a concentration of c = 1 mg / l was determined spectrophotometrically in water for the wavelength range from 200 nm to 400 nm. Figure 2 describes the behavior of uric acid absorption in the range of À = 400 nm to À = 200 nm qualitatively. Clearly, three local maximums at À = 290 nm, À = 235 nm and À = 205 nm are observed, where the maximum absorption is at the wavelengths of À = 205 nm and À = 290 nm (AA = 2osnm = 1.5 or A »= 28nm = 0.7). Example 3
The absorption behavior of malondialdehyde at a concentration of c = 1 mg / l was determined spectrophotometrically in water for the wavelength range from 200 nm to 400 nm. Figure 3 describes the absorption behavior of malondialdehyde in the range of À = 400 nm to À = 200 nm qualitatively. Clearly, a local maximum at À = 266 nm (A = 26β nm = 1,005) is observed. Example 4
The behavior of creatinine absorption at a concentration of c = 1 mg / l was determined spectrophotometrically in water for the wavelength range from 200 nm to 400 nm. Figure 4 describes the behavior of creatinine absorption in the range of À = 400 nm to À = 200 nm qualitatively. Clearly, two local maximums at À = 205 nm and À = 235 nm (A = 0.19 or A = 0.076) are observed. Example 5
In a dialysate, 20 mg / l uric acid, 30 mg / l creatinine and 10 mg / l malondialdehyde were added. The dialysate replaced with uric acid, creatinine and malondialdehyde was then measured spectral (continuously, in 1 nm steps from 200 nm to 400 nm). According to the apparatus of the invention, an equation system with three strangers is prepared at three wavelengths and the concentrations of uric acid, creatinine and malondialdehyde are calculated, where the accuracy was +/- 10%. Figure 5 shows the absorption behavior of uric acid, creatinine and malondialdehyde in used dialysate and confirms the good applicability of the method by reproducing the used dialysate from the linear combination of the mentioned substances.
The spectra shown are: - dialysate used, ••• compound spectrum, OOO creatinine, xxx uric acid and +++ malondialdehyde. Example 6
The calculation of uric acid, malondialdehyde and creatinine concentrations was performed for the samples from Example 5. The characteristic measurement points were selected according to the criteria mentioned in the selection criteria section of a characteristic measurement point. was measured at 235 nm, 266 nm and 290 nm wavelengths; so that the following equations are produced:
The extinction coefficient ε is dependent on the substance and the wavelength, but is known for the substances to be determined. Length I is just one size of the measurement configuration. Thus, as the unknowns and sizes to be determined are left, the concentrations of single creatine and malondialdehyde by which the system of equation (4b) has been resolved. Extinction coefficients ε were known or results from equation (1) of the substance spectra (see figures 1 to 3) and are shown in table 4: Table 4: Extinction coefficients
This system of equation is solved, thus, the concentrations are obtained as follows: Uric acid = 21.8 mg / l, Ccreatinina = 27.9 mg / l β Cmalondialdehyde = 10.3 mg / l. The maximum deviation here was ca. 9%. The equation system could be simplified, as already mentioned (see table 5). Table 5: Simplified representation of the extinction coefficients.
The concentrations are results in: Uric acid = 21.8 mg / l, Ccreatinina = 27.9 mg / l 6 Cmalondialdaido = 10.3 mg / l. This simplification substantially reduced the computing effort while increasing the maximum error of ca. 16%. The initial concentrations and calculated concentrations are shown in table 6. Table 6: Initial concentrations and calculated concentrations
The wavelengths used in this calculation and the substances are exemplary. It is understood by a person skilled in the art that any combination of the uremic toxins listed here can be measured with the apparatus of the invention. Example 7
Only a few of the more than 50 different uremic toxins in the dialysate used actually show optical activity in the UV range. Uremic toxins with optical activity in the UV range comprise creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malonaldehyde, p-cresol, phenol, retinol binding protein and fragments of B2-microglobulin and / or combinations thereof . These uremic toxins differ in their optical properties, especially in their wavelength, which is mainly strong. In principle, it is therefore possible to determine the respective concentration from a mixture of various uremic toxins, as long as the spectra are sufficiently different and at least in the same amount of wavelengths the absorption is determined, as UV active substances to be determined are present in the dialysate used. In order to bring additional security to the system and increase the accuracy of the method, it can be measured at even more wavelengths, since there are substances, which dominate the absorption measurement. Such a system is called overdetermined. In principle, it is useful to measure at points in the spectrum where the absorption signal has specific characteristics. Thus, for example, the characteristic wavelengths in the dialysate used are 320 nm, 305 nm, 290 nm, 280 nm, 266 nm, 245 nm, 235 nm and 220 nm. However, other wavelengths are, in principle, possible. With the aforementioned wavelength combination, the concentration of up to eight optically active uremic toxins from the dialysate used can be determined. If, at the wavelengths À = 320 nm, À = 310, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, À = 270 nm, À = 266 nm, À = 260, À = 250 nm, À = 245 nm, À = 240 nm, À = 235 nm, À = 230 nm, À = 220 nm and À = 205 nm must be measured, up to 16 substances can be determined. The characteristic measurement points must meet the criteria mentioned in the selection criteria section for a characteristic measurement point.
This amount of uremic toxins that partially differs in the spectrum strongly from one another and influences the absorption spectrum significantly is realistic in dialysis. There are, of course, a plurality of other uremic toxins which, however, have no effect on irradiation with UV light, that is, they are not UV active and therefore do not interfere with UV measurements. In dialysis, the blood that is enriched with uremic toxins has been purified in the dialyser of the extracorporeal tube system. The toxins passed through a washing solution in which they were first diluted by the different blood flow rates and dialysate flow rates and were finally rinsed. During deposition, they crossed a segment of tube, which was irradiated with ultraviolet light. According to each modality, the absorption of the aqueous liquid was measured at various wavelengths, for example, 320 nm, 305 nm, 300 nm, 290 nm, 280 nm, 266 nm, 250 nm, 245 nm, 240 nm, 235 nm and 220 nm. The characteristic measurement points must meet the criteria mentioned in the selection criteria section for a characteristic measurement point. Together with the substance constants deposited in the storage of the evaluation unit, which are specific for wavelength (cf. Table 1 and Example 1) an equation system of n unknown and even n equations can be established and solved, where n is the minimum number of measurement points and the concentrations to be determined (cf. Example 1). In the present case, for the determination of 9 uremic toxins at 11 wavelengths, they are measured in order to solve the equation system even with the appearance of two redundant information.
A validation of the system was done by simultaneous HPLC analyzes. Generally, the concentration of uremic toxins in the dialysate used is lower by a factor of 10 than in the blood. This relates to, first, the dilution caused by the blood flow and dialysate flow and is, on the other hand, also influenced by the purification performance of the dialyzer, which is, each according to the size of the substance typically <90 %, each according to the blood flow and dialyzer. Physiological parameters, such as recirculation in the diversion of dialysis patients, further reduce the concentration of uremic toxins in the dialysate. Due to the high dilution, therefore, only uremic toxins were detected by the measuring device, which already had a measurable optical activity in the undiluted state. The concentrations of UV active uremic toxins in blood plasma or blood serum known in the prior art are shown in table 7.
Table 7: Concentrations of UV active uremic toxins. Modified from Vanholder et al. (2003).


If an equation system analogous to Example 6 is applied, where absorption is determined at least 9 wavelengths (for example, À = 320 nm, À = 305 nm, À = 290 nm, À = 280 nm, À = 266 nm, À = 250 nm, À = 240 nm, À = 230 nm and À = 220 nm), thus, the equation system is solved by avoiding redundant information and the concentrations of the 9 uremic toxins are determined. In the present case, the absorption at the 11 wavelengths 320 nm, 305 nm, 300 nm, 290 nm, 280 nm, 266 nm, 250 nm, 245 nm, 240 nm, 235 nm and 220 nm was determined. After applying the equation system according to equation (1) (cf. also equation system in Example 6) the following values were results:


These measurements were performed on the dialysate used and are therefore partly clearly under the concentration of the blood concentration. Example 8
Figure 6 shows a configuration of the dialysis apparatus with which the method of the invention is implemented. On the dialysate side, there is at least one optical measuring device 37 which is also described here as a UV sensor. A patient's blood is taken from the patient to an extracorporeal circulation. Blood flows through conduit 32 into the blood-side chamber 30 of a dialyzer and is returned through conduit 31 to the patient. The flow rate of the blood circulation is controlled by a blood pump 33. The dialysis solution consists of a series of physiologically relevant substances that are dissolved in water, so that they are not removed due to a lack of concentration gradient from of blood during the dialysis procedure. Therefore, the dialysis apparatus described in figure 5 comprises a water inlet 12, two inlets 16 and 18 for concentrates of physiologically relevant substances that are dissolved in water, and two pumps 17 and 19. The water flow determines together with the concentrate flow or concentrate flows, the composition of the dialysis solution. Through the dialysate circuit 20, the dialysis solution of the dialysis chamber 29 of the dialyser, which is separated from the blood chamber 30 by a semipermeable membrane is fed. The dialysis solution is thus fed from a pump 21 to the dialyzer. Another pump 34 sucks the dialysate and the ultrafiltrate is removed from the blood. A secondary connection 35 is arranged between pump 21 and 34. Also several valves 26, 27 and 28 are provided in order to control the flow of dialysate. A conduit (outlet) 36 serves the dialysate used for a UV 37 sensor with a radiation source 1 consisting of four light sources for substantially monochromatic electromagnetic radiation of the wavelengths À = 290 nm, À = 266 nm, À = 235 nm and À = 205 nm, which are individually controlled, which measures the absorption of the dialysate used, where the UV 37 sensor is connected via an interface with a computer 14. The characteristic measurement points must meet the criteria mentioned in the criteria section selection for a characteristic measuring point. Computer 14 processes the measured data. The result of the data processing is displayed on a device 15 and / or printed, where the device 15 is connected to the computer 14 via an interface. The conduit (outlet) 36 takes, after the measurement with the UV sensor 37, the dialysate used to the outlet flow system 13. The dotted lines 22, 24 and 25 represent an adaptation of the apparatus described for treatments by means of hemodiafiltration. The replacement liquid is supplied from a source of replacement fluid 11, flowed through tube 22 and is pumped by a pump 23 into the patient's blood inlet tube. In the case of post-dilution hemodiafiltration, conduit 24 carries the replacement fluid to the venous conduit of the extracorporeal blood system. During pre-dilution hemodiafiltration, both conduit 24 and conduit 25 can be used. The computer 14 controls all the elements shown in figure 5 by means of appropriate interfaces, in which said interfaces are not shown due to lack of clarity. Computer 14 collects information on other parameters of the dialysis device, for example, blood flow, dialysate flow and / or treatment time. These parameters are processed in conjunction with the measured data. The dialysis apparatus described in this example is additionally provided with additional intended means, as they are commonly used for dialysis devices. These additional means are not described, as they are not relevant to the implementation of the described method of the invention. The obtained absorption curves are stored on a patient card, which is connected to computer 14, or in a database, which is implemented on computer 14. The number of absorption curves to be saved and being saved is variable and depends on storage capacity of the medium. In one embodiment, the last 20 treatments will be stored on an appropriate memory card. The stored treatment data will be overwritten by a First In and First Out (FIFO) process. In addition, a treatment to be determined by a user or by a attending physician can be defined as not being overwritten. In this case, the treatment data will be preserved until the treatment data is again defined as being capable of being overwritten. The storage of dialysis performance (Kt / V), or curves for the urea reduction rate (URR) is also possible. Example 9
Figure 7 shows a modality of sensor configuration 37 for measuring absorption at various wavelengths. There, (1) represents a light source, which consists of several (at least two) monochrome wavelengths that are individually controlled, or designed as a broadband light source. In the latter case, a wavelength selective element (2) is required, which can be controlled in order to filter individual wavelengths. (3) represents a splitter of the beam of light (3) that divides the beam of light l0 (Àj) into two parts: lR (Àj) and ls (Àj). the proportion lR (Àj) directly meets the reference detector (6), while the proportion of Is (Àj) finds the sample to be examined (4). Depending on the absorption of the sample liquid, an intensity IA (ÀÍ) finds the absorption detector (5) which is less than or equal to the original intensity ls (Àj). The number of wavelengths n that can be used in the sensor is, in principle, arbitrary, but it must be at least two (at least i = [1,2]). Example 10
A patient requiring dialysis was treated with an apparatus according to Example 7, where the sensor configuration was designed to measure absorption according to Example 8. A sample of dialysate from patients requiring dialysis was taken 10 minutes after the beginning of the treatment and its absorption was determined spectrophotometric in the wavelengths À = 290 nm, À = 266 nm and À = 235 nm. Subsequently, the concentrations of uric acid, creatinine and malondialdehyde were calculated according to Example 6. The calculated concentrations were: Uric acid = 40.0 mg / l, Ccreatinine = 65.3 mg / l β Cmalondialdehyde = 250 pg / l . The characteristic measurement points were selected according to the criteria mentioned in the selection criteria section for a characteristic measurement point.

权利要求:
Claims (14)
[0001]
1. Apparatus for extracorporeal treatment of blood with - a dialyzer that is separated by a semipermeable membrane in a first and second chamber (29, 30), in which the first chamber (29) is arranged in a dialysate pathway and the second chamber (30) is connectable to a patient's blood circulation via a blood supply conduit (32) and a blood return conduit (31), - an inlet (20) for fresh dialysate, - an outlet (36) for dialysate used, - a measuring device (37) disposed at the outlet (36), where the measuring device (37) has a radiation source (1) for electromagnetic UV radiation, - where the radiation source (1 ) consists of at least two monochromatic light sources or at least one monochromatic light source with monochromators for the generation of monochromatic UV radiation, - a beam splitter to direct part of the light to a reference detector, - one microprocessor unit (14), a storage unit as well as an output unit (15), characterized by the fact that the measuring device (37) is designed to generate substantially monochromatic electromagnetic UV radiation of different wavelengths and to take it through the output (36) to the dialysate used, in which at least one detector system (5) is provided for detecting the intensity or absorption of substantially monochromatic electromagnetic UV radiation crossing the outlet (36) for the dialysate used and in the = ΣAJ storage unit an equation system j = 1 is deposited, where AAI is the total absorption of a mixture of substances at a predetermined wavelength, A / ,, Aj is the absorption of each substance within the mixture of substances and n is the number of components of interest within of the mixture of substances that contribute to absorption.
[0002]
2. Apparatus according to claim 1, characterized by the fact that the radiation source (1) consisting of several light sources is designed for the emission of electromagnetic radiation in the range of 180 nm to 380 nm.
[0003]
3. Apparatus according to claim 1, characterized by the fact that the radiation source (1) has a plurality of light emitting diodes that are designed, each, for the generation of a substantially monochromatic electromagnetic UV radiation.
[0004]
4. Apparatus, according to claim 1, characterized by the fact that the radiation source (1) is designed for the generation of polychromatic electromagnetic radiation and for the generation of substantially monochromatic electromagnetic radiation corresponding to monochromators, in which, in particular, filters Optical devices that allow only a specific wavelength to pass through or a bandpass filter with several bands are provided.
[0005]
Apparatus according to any one of claims 1 to 4, characterized in that the microprocessor unit (14) is designed to solve the system of equation • '=' using equations * l * c ja 'j ( 1) at measurement points and the absorption Ai of a reference substance at a reference wavelength 2r, where Aj is the absorption of substance j at a specific wavelength, 2 /, is the extinction coefficient dependent on the wavelength, / is the length of the optical path and cyé the respective concentration of the substance.
[0006]
6. Apparatus according to any one of claims 1 to 4, characterized by the fact that, by means of the microprocessor (14), with the aid of a reference absorption curve for a reference substance and following the equation system stored in a storage unit, the determination of absorption and / or concentrations of uremic toxins at the outlet (36) is simplified
[0007]
7. Apparatus according to claim 5, characterized by the fact that the reference substance is selected from the group comprising the active uremic toxins UV creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and fragments of 32-microglobulin and / or combinations thereof.
[0008]
8. Apparatus according to claim 6, characterized by the fact that the reference substance is selected from the group comprising the active uremic toxins UV creatinine, uric acid, hippuric acid, indoxyl sulfate, 4-hydroxynonenal, malondialdehyde, p-cresol, phenol, retinol binding protein and fragments of 32-microglobulin and / or combinations thereof
[0009]
9. Apparatus according to claim 7, characterized by the fact that uric acid is used as a reference substance.
[0010]
10. Apparatus according to claim 8, characterized by the fact that uric acid is used as a reference substance.
[0011]
11. Apparatus according to claim 5, characterized by the fact that the reference wavelength is in the range between 280 nm and 300 nm.
[0012]
12. Apparatus according to claim 6, characterized by the fact that the reference wavelength is in the range between 280 nm and 300 nm
[0013]
13. Apparatus according to any of claim 1, characterized by the fact that 10 monochromatic light sources are used as a radiation source (1).
[0014]
Apparatus according to any one of claims 1 to 4, characterized by the fact that the detection of intensity or absorption is performed at wavelengths À = 320 nm, À = 310 nm, À = 305 nm, À = 300 nm, À = 290 nm, À = 280 nm, À = 266 nm, À = 260 nm, À = 250 nm, À = 245 nm, À = 240 nm, À = 235 nm, À = 230 nm, À = 220 nm and À = 205 nm.

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法律状态:
2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-07-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-10| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/08/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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DE102010034626.8|2010-08-17|

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DE1020100346268|2010-08-17|

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DE102010034626A|DE102010034626A1|2010-08-17|2010-08-17|Device for extracorporeal blood treatment|

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PCT/DE2011/001606|WO2012022304A1|2010-08-17|2011-08-17|Apparatus for extracorporeal blood treatment|

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