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    • 专利摘要:
    METHOD AND APPARATUS FOR MONITORING A PATIENT TREATMENT, PREFERREDLY FOR MONITORING HEMODIALYSIS, HEMODIAFILTRATION AND/OR PERITONEAL DIALYSIS. The present invention relates to a method for c) monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, the method comprising the steps of irradiating a sample of a used dialysis fluid in the treatment with light irradiation of at least a first irradiation wavelength, detection of the light emitted by the irradiated sample in at least a first detection wavelength, the detection wavelength being different from the first irradiation wavelength and determining the presence and/or concentration of at least one analyte in the sample on the basis of detected light.
    公开号:BR112013026319B1
    申请号:R112013026319-9
    申请日:2012-04-10
    公开日:2021-05-04
    发明作者:Malte Gross；Pascal Kopperschmidt；Andreas Maierhofer；Alfred Gagel
    申请人:Fresenius Medical Care Deutschland Gmbh；
    IPC主号:
    专利说明:

    Technical Field
    The present invention relates to a method and an apparatus for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis. Previous Technique
    Extracorporeal treatment methods have been used for a long time to treat different conditions. Dialysis is the most commonly known and used extracorporeal treatment method that is intended to replace kidney function when renal failure of the kidneys occurs in a patient.
    When the kidneys fail, it becomes necessary to dialyze a patient to remove waste products such as urea, creatinine, and uremic toxins from the patient's blood. Also, during dialysis, excess water and other substances which are usually eliminated in the urine are removed from the patient's body. The most commonly used method of dialysis is hemodialysis in which the patient's blood flows across a dialysis membrane, where on the other side of this dialysis membrane a dialysis fluid is provided. Consequently, blood and dialysis fluid are separated by the porous membrane.
    Through this membrane, substances that must be removed from the patient's blood diffuse due to a concentration gradient between the blood and the dialysis fluid. Larger molecules, whose diffusion speed is very slow, can also be transported by convection through a liquid flow from the blood side to the dialysis liquid side of the membrane.
    Dialysis fluid is prepared to have a concentration that provides a concentration gradient from the blood side to the dialysis fluid for certain substances, but not necessarily for all substances. In fact, the removal of urea and creatinine as well as other waste products in the human body is desired, but, for example, the removal or change of concentration of electrolytes such as sodium or bicarbonate is not completely desired, but is considered harmful.
    Consequently, dialysis fluid typically contains a concentration of electrolytes that resembles the concentration of electrolytes in the patient's blood plasma, since a concentration gradient is not present for these substances.
    In addition to hemodialysis, peritoneal dialysis is another method for dialysis that also uses a membrane and a dialysis fluid in order to obtain a diffusion of the waste product across the membrane into the dialysis fluid. The membrane, however, is a natural membrane called the peritoneum and dialysis fluid is introduced directly into the abdominal cavity.
    During dialysis, the elimination of excess water and small molecular uremic substances, such as urea and creatinine, typically goes smoothly, larger molecules, however, are more difficult to remove through the porous membrane. In order to address this, specific high flux dialysis membranes are provided in combination with highly convective methods such as hemodiafiltration. This results in improvements in the release of molecules with a molecular mass greater than 1 kDa, which is in the range of so-called medium-sized molecules. In hemodiafiltration, a diffusion method that uses dialysis fluid in the form as described above is combined with hemofiltration, in which a patient's blood is subjected to a pressure gradient across a filter. Consequently, the filtration process along the pressure gradient leads to increased liquid flow and is therefore considered to be a highly convective method that enables the removal of a considerable part of medium-sized molecules. However, due to the pressure gradient, water as well as electrolytes and sugars are also removed from the patient's blood at a high rate so that these blood constituents have to be replaced by infusing a replacement flow.
    The introduction of high flux dialysis membranes in combination with highly convective methods improves the release of medium and large sized molecules.
    Larger molecules are typically proteins, where, for example, beta2-microglobulin has a size of about 11 kDa, where this molecule can induce an amyloidosis if not sufficiently removed. Smaller molecules which are toxic can also be difficult to dialyze if the molecules are bound to proteins. For example, uremic toxins that are bound to proteins are p-cresyl sulfate and indoxyl sulfate.
    Consequently, you want to have pore sizes in dialysis membranes that are large enough to let these medium-sized molecules through. On the other hand, the pore size of the membrane cannot be infinitely extended, since the larger the pore size of the membrane, the greater the risk that vital blood components are similarly lost. Consequently, membrane permeability is typically limited in sizes around 60 kDa. However, this value is only slightly below the molecular mass of human plasma albumin which has a size around 66 kDa. In practice, clinically significant losses of albumin can occur where these losses depend significantly on the respective method parameters, such as the respective pressures and the respective concentrations in the dialysis fluid. In particular, a high flux membrane in combination with the pressure gradient applied during hemofiltration increases the release of human albumin. Another reason for the loss of human albumin may be the multiple use of membranes, as the release of the membrane which is needed between different treatments tends to increase the pore sizes in the membrane. This shifts the permeability of the membrane towards larger molecules. Consequently, even under normal conditions in normal hemodialysis, human serum albumin can penetrate through the membrane.
    It goes without saying that in the case of peritoneal dialysis the membrane pore sizes cannot be influenced, but are given by the condition of the peritoneum of the respective patient. However, a loss of human albumin within the dialysis fluid can nevertheless occur, since the peritoneum has been weakened, for example, by inflammation.
    In order to determine the release of an analyte during dialysis, a Raman spectroscopy method is described in US document No. 2008/0158544 A1, in which Raman spectral measurements are performed on the blood after it has been through the dialyzer in order to utilize the unique Raman spectroscopic signature of one or more analytes, e.g., urea, to identify and quantify such analyte against an entire blood background.
    Document WO 2010/091 826 A1 refers to an apparatus for the extracorporeal treatment of blood, in which the absorption of electromagnetic radiation in the dialysis fluid is measured in order to determine the value of Kt/V, called the release of K is the flow volume of clean substances, where t is the treatment time and V is the patient's distribution volume. In renal replacement therapy, urea is typically used as an indicator substance for the treatment of uric acid efficiency measurement, as K is the uric acid release and V is the patient's urea distribution volume, which corresponds, in principle, to the water of the patient's body. However, by measuring total absorption, the overall release for a specific molecule cannot be determined. WO 2008/136548 A1 refers to a device for measuring and monitoring a hemoglobin value through a blood tube. Description Summary
    Accordingly, it is an object of the present invention to provide a method and apparatus for monitoring a patient's treatment.
    Protection is claimed for the method and apparatus as claimed.
    In accordance with the present invention, a method for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, is suggested. The method comprises the steps of irradiating a sample of a dialysis liquid used in the treatment with irradiation of light from at least a first wavelength of irradiation, detection light emitted by the irradiated sample in at least one first detection wavelength , the detection wavelength being different from the first irradiation wavelength and determining the presence and/or concentration of at least one analyte in the sample based on the detected emission light.
    By irradiating the dialysis liquid sample with light of at least a first irradiation wavelength and detecting light of at least a first detection wavelength, wherein the detection wavelength is different from the first wavelength of irradiation, it becomes possible to determine the emission response of an analyte in the dialysis fluid. The presence and/or concentration of specific analytes, such as human albumin, can be monitored in the dialysis fluid in order to monitor the patient's treatment. In case, for example, that the concentration of human albumin in the dialysis fluid exceeds a predetermined concentration, an alarm may be released and replacement of the dialysis membrane may be required. On the other hand, the concentration of uremic toxins such as beta2-microglobulin can be used to monitor and optimize treatment efficiency by adjusting treatment modalities.
    Detected light includes fluorescent light and the presence and/or concentration of at least one analyte in the sample is determined based on the detected fluorescent light.
    To illustrate this, in fluorescence spectroscopy, a sample is irradiated with light irradiation of a predetermined wavelength. The beam of light from light irradiation, usually ultraviolet light, excites the electrons of certain analytes to a higher energy level. Through the absorption of a photon, the molecule is excited from its fundamental electronic state to one of several vibrational states in the excited electronic state. When, after a short period of time, the molecule relaxes back to the ground electronic state, a photon is emitted. Since part of the energy is dissipated by means of non-irradiation transitions, for example, collisions with other molecules that cause the excited molecule to lose vibrational energy, the photon emitted in the process has a lower energy and therefore a length of wave larger than that of the excited photon. Consequently, the irradiation wavelength of the light that excites the molecule is different from the detection wavelength of the emitted photon so that the light irradiation and the emitted light can be easily distinguished spectroscopically.
    Since the excitation wavelength as well as the emission wavelength can be chosen relatively free compared to absorption spectroscopy, more detailed information about the analyte dissolved in the dialysis liquid can be obtained through the method. Furthermore, since the detected light intensity is typically proportional to the concentration of the analyte or specifically the fluorophore in the dialysis fluid, the detected light intensity can serve as a measure for the actual concentration of the respective analyte in the dialysis fluid.
    The wavelength detection is different from each of the irradiation wavelengths. This has an advantage that the setup for detecting light can be simplified as detection is always carried out at wavelengths different from the irradiation so that the light irradiation can be prevented from entering the detector by means of devices known in the art.
    For example, the fluorescence intensity is proportional to the product of the absorption coefficient ε on the excitation wavelength and the quantum yield ΦF. The latter refers to the ratio of absorbed photons to the number of photons emitted through fluorescence.
    By determining the presence and/or concentration of at least one analyte in the sample based on the detected light, based on the fluorescence of the respective analyte, the presence and/or concentration of specific molecules can be determined. With respect to conventional absorption measurement, it is advantageous that only a small number of molecules that are present in the dialysis fluid are active with respect to light emission, eg fluorescence. In particular, substances such as uric acid, which are present in dialysis fluid in very high concentrations, do not show any bloom and therefore do not hinder the measurement of specific molecules. The aforementioned proteins and uremic toxins, however, can be particularly well determined by means of a fluorescence measurement.
    Compared to absorption spectroscopy, fluorescence spectroscopy is much more sensitive. In fact, when comparing the present method to absorption spectroscopy where very low concentrations of certain components only lead to lower absorption and therefore very small attenuations of light sent through the sample, the present method has the advantage that the intensity of fluorescent light is directly proportional to the concentration of the respective analyte in the sample so that the sensitivity of a sensor/detector can be utilized in an optimal way.
    Exemplary groups of proteins that are active in fluorescence are the aromatic side chains of the amino acids phenylalanine, tyrosine, and tryptophan.
    When considering the fluorescence activity of these amino acids, tyrosine and tryptophan dominate the fluorescence of proteins. With a sufficiently long excitation wavelength, that is, an excitation wavelength of Xθx^295nm, tryptophan is the only amino acid that is active in fluorescence. Although tryptophan is an amino acid that is relatively rare, the albumin molecule includes a tryptophan unit. Due to the high fluorescence efficiency of tryptophan, albumin can therefore be detected with sufficient efficiency.
    In order to increase the accuracy of the method, the sensing light is detected at at least a first sensing wavelength and a second sensing wavelength, the first and second sensing wavelengths being different from each other. Preferably, the detection light is detected by detecting a part or all of the spectrum of light from the emitted sample. By detecting more than one wavelength of the emitted light, the correlation of the detection light and a corresponding emission fingerprint, in particular a fluorescent identification, of a specific analyte becomes even more accurate. The emission spectrum for a specific irradiation wavelength can be compared with specific emission tags of the analyte that are relevant, in particular with the emission identification of specific molecules of interest that are intended to be monitored in the extracorporeal treatment method. In fact, it is interesting to monitor, in the dialysis fluid, the presence and/or concentration of free fluorescent amino acids, albumin, indoxyl sulfate and any fluorescent uremic toxins in order to determine the release for the respective molecules.
    As an adjunct to fluorescent light analysis, Raman scattered light can be used to determine the presence and/or concentration of a certain analyte in the sample. For this purpose, the Raman emission of the sample is measured both over the entire Raman spectrum, over a part of it and over certain detection wavelengths and the respective intensities or spectra are compared to the Raman Identifications of the respective analytes of interest .
    In order to further increase the accuracy of determining the presence and/or concentration of the analyte, the sample is irradiated by light irradiation in the UV range, with light irradiation having a wavelength between 180nm and 400nm, more preferably 250nm at 300nm, more preferred 280nm and/or 295nm. Preferably, the sample is irradiated with light irradiation of at least two separate and distinct irradiation wavelengths, preferably 280nm and 295nm. The two different emission spectra induced by the two irradiation wavelengths can be compared and the efficiency and accuracy of analyte determination further increased.
    In order to compensate for the absorption of light irradiation in the sample, the intensity of the light irradiation in the sample is preferably determined and the determination of the presence and/or concentration of the analyte in the sample is compensated for the intensity of the light irradiation. Preferably the absorption of light irradiation in the sample is measured and the intensity of light irradiation is determined based on the measured absorption, preferably the absorption in the sample is measured by means of a photo detector which detects transmitted light irradiation through the sample.
    Alternatively, the intensity of the scattered Raman light from the sample is measured and is used to determine the intensity of light irradiation. This Raman stray light measurement can be performed at the peak intensity of the Raman stray light in water.
    The step of compensating for the absorption of light in the sample cares about the fact that the dialysis liquid may have a different absorption depending on the efficiency of the dialysis process as well as based on the different conditions of the respective patient. In fact, at the start of a dialysis session, dialysis fluid may contain a significantly higher portion of uric acid, creatinine, and other waste products that exhibit greater absorption for excitation light than at the last stage of the process. dialysis. In order to be in a position to reliably determine the presence and/or concentration of the respective analyte in the sample, it is important to determine the respective sample absorption so that it is evident that it is the effective excitation intensity that results in the respective fluorescent spectrum and the respective fluorescence intensity.
    Additional information about the presence and/or concentration of an analyte in the sample can be obtained when, preferably, fluorescent light is detected in a time-resolved form, preferably where the light irradiation is pulsed.
    Other forms of analyte analysis may be present by irradiating the sample with polarized light, preferably with left circularly polarized light and/or right circularly polarized light.
    In order to further improve the method, the fluorescent light of the sample is preferably detected at least twice, whereby between the first and second detections the sample is physically and/or chemically treated and the presence and/or concentration of the analyte is determined by taking the difference between the first and second detections is taken into account, where the sample is preferably treated by heating, by adding and/or removing reagents and/or by adding and/or removing an acid, a chemical base and/ or a salt.
    To be in a position to perform more complex measurements, the sample can be separated from the dialysis fluid flow to carry out the determination of the presence and/or concentration of the analyte.
    In an alternative, determination of the presence and/or concentration of the analyte can be carried out continuously over the dialysis fluid flow.
    In yet another preferred version, before irradiating the sample with light irradiation, the sample is separated into two different fractions, preferably by means of ultrafiltration, electrophoresis, chromatography, the addition of absorber and/or the addition of a fluorescent indicator and at least one of the sample fractions is irradiated with light irradiation.
    By monitoring the analyte in the dialysis fluid, in particular by monitoring the presence and/or absence of albumin, it can be seen that human albumin emits a fluorescent light that has a maximum of 340nm when it is excited at about 280nm.
    Indoxyl sulfate (indican), which is a waste product of tryptophan, is known to be present in uremic patients in a significant concentration in the blood serum. Indoxyl sulfate is known to be a uremic toxin. The fluorescent spectra of tryptophan and indoxyl sulfate are remarkably similar so that despite dialysis proteins the release of indoxyl sulfate is interesting in diagnostic aspects. As an alternative, fluorescent indicators that bind to certain molecules can be used to determine the presence and/or concentration of the respective molecules.
    In order to determine even more precisely the composition of the dialysis fluid used, the presence and/or concentration of at least two different analytes can be determined based on the detected light.
    Preferably, after excitation at a specific wavelength by irradiating the sample with light irradiating, the detected light can be analyzed due to the presence of at least N different analytes. This is done by analyzing the detected spectrum f(À), that is, the intensities at the respective emission wavelength À, which is assumed to be given in the form of a linear superposition of the emission spectra of the N analytes:
    Ci being the unknown concentration of the yenth analyte and si(X) being the known emission sensitivity of the yenth analyte as a function of the respective emission wavelength X. This equation is preferably solved for the unknown concentrations ci by the determination of the spectrum in M discrete and different emission wavelengths Xj, considering the above equation in the form of the following system of M equations with unknown N:

    This system is solved numerically, preferably by considering as the best solution to the above system of equations the one that provides, when it is inserted in the matrix above, the superposition spectrum that presents the smallest squared deviation from the actually measured spectrum. By means of this analysis, it becomes possible to determine the composition of the dialysis fluid by analyzing the detected emission light and in particular by analyzing the respective spectrum of the detected emission light. In particular, the unknown concentrations ci, are determined and therefore the composition of the dialysis fluid with respect to the concentrations ci, of the respective analytes can be determined.
    This method can be extended to more than one, ie P, radiation wavelengths Xirr, P being greater than one, when for each radiation wavelength Àirr a separate emission spectrum f(Àirr, À) is detected at the respective emission wavelength À. Consequently, the detected spectrum f(Àirr, À) for an irradiation wavelength Àirr is again assumed to be given in the form of a linear superposition of the emission spectra of the N analytes:
    Ci being the unknown concentration of the yenth analyte and Si (ÀirrÀ) being the known emission sensitivity of the yenth analyte as a function of the emission wavelength À at the respective irradiation wavelength Àirr.
    By adding the respective equations to the linear equation system provided above, it reads:
    By solving the above equation system, preferably in the same manner as indicated above, a solution for the ci concentrations can be determined and therefore the concentrations of the respective analytes in the dialysis liquid used can be determined.
    The objective provided above is also solved by means of a device for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, with the characteristics of claim 1.
    Consequently, the apparatus for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, the apparatus comprises a light source for irradiating a sample of a dialysis liquid used in the treatment with light irradiation of hair. minus a first irradiation wavelength, a detector for detecting light emitted by the irradiated sample at at least a first detection wavelength, the detection wavelength being different from each irradiation wavelength, and a control unit and analysis for determining the presence and/or concentration of at least one analyte in the sample based on the detected light.
    Additional preferred embodiments of the apparatus are provided in the dependent apparatus claims of independent claim 12. Brief Description of Drawings
    The present description will be more readily appreciated by reference to the following detailed description when considered in connection with the accompanying drawings in which: Figure 1 is a schematic view of an apparatus for monitoring an analyte in an extracorporeal treatment; Figure 2 is a detailed schematic view of a part of the apparatus according to Figure 1; Figure 3 is a schematic diagram showing the fluorescent spectrum of human albumin at different concentrations after excitation at an irradiation wavelength of 280nm; Figure 4 is a schematic diagram showing the fluorescence intensity of albumin at a detected light wavelength of 340nm at two different irradiation wavelengths, i.e., 280nm and 295nm; and Figure 5 is a schematic diagram showing the absorption spectrum of uric acid. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
    In the following, the description will be explained in more detail with reference to the accompanying figures. In the figures, similar elements are denoted by identical reference numerals and their repeated description may be omitted in order to avoid redundancies.
    Figure 1 is a schematic view of a system for treating a patient, in particular a dialysis device. The system includes a device for monitoring a patient's treatment.
    In particular, figure 1 shows a dialyzer comprising a semipermeable and porous membrane 3. On the right side of figure 1 the patient's blood circulation is connected to membrane 3 and on the left side the dialysis liquid circulation is connected to membrane 3 The principle of hemodialysis is well known and involves the diffusion of solutes in the blood through the semipermeable membrane 3. Diffusion is induced by a concentration gradient of certain substances across the membrane 3.
    The patient's blood is transported through a tube 1 to the membrane 3 and passes along the membrane on one side of it towards the tube 2, from which blood is transported back to the patient.
    The dialysis fluid is transported through a tube 4 to the membrane 3 and is discarded through the tube 5. From figure 1, it becomes immediately apparent that, in this particular modality, the blood circulation and the circulation of the dialysis fluid involve opposing fluid currents on membrane 3. The method uses opposing current flows so that fresh dialysis fluid comes in contact with the patient's blood which will be transported back to the patient again and the patient's fresh blood comes in contact with the dialysis fluid that is to be discarded. This is standard practice to increase the efficiency of the dialysis process, as the opposite current flow keeps the concentration gradient across the membrane at a maximum and increases the dialysis efficiency. However, in alternative solutions a parallel blood flow and dialysis flow can also be used, depending on the patient's therapeutic needs.
    Membrane 3 is a semi-permeable and porous membrane, as it is usual when in dialysis apparatus. Due to the concentration gradient between the patient side and the dialysis liquid side of the membrane 3, the molecules diffuse from the blood side through the semipermeable membrane 3 to the dialysis liquid side and are thereby removed from the blood.
    Depending on the patient's current conditions and depending on the effect which one wishes to achieve, the dialysis fluid includes concentrations of different substances that are intended to match the concentrations in the blood, so that a concentration gradient is not present. This may be the case, for example, for electrolytes which consequently do not diffuse across the membrane 3. However, other substances may not be fully present in the fresh dialysis liquid so that a strong concentration gradient is induced. This strong concentration gradient is desired, in particular, for substances that are normally eliminated through the urine such as uric acid, creatinine and uremic toxins. It is also intended to remove excess water from the blood. Depending on the pore sizes of membrane 3, however, diffusion of larger molecules such as, for example, human albumin may also occur. This is, however, unwanted.
    A sample of the used dialysis fluid, which is discharged through tube 5, is analyzed in a cell 6 for the presence and/or concentration of at least one analyte. For this purpose, a light source 7 is present which radiates the dialysis liquid sample present in the cell 6 with an excitation light. The light source 7 preferably emits at least a first wavelength, preferably a wavelength of light in the ultraviolet range, i.e. in a range between 180nm and 400nm. In the specific embodiment shown in Figure 1, the light source 7 is a semiconductor based light source for the ultraviolet range, in particular an AllnGaN diode that emits light at a wavelength of 280nm. However, any other light source can be used.
    The dialysis fluid sample present in cell 6 is illuminated by light impinging on it and emitted from the light source 7. The photons of light excite certain molecules present in the dialysis fluid so that the fluorescent light emission can be induced in the sample. The presence, wavelength and intensity of fluorescent light are detected by means of a detector in the form of a spectrometer 9 in a direction perpendicular to the illumination direction of the light emitted from the light source 7. Any other direction whatsoever. other than being coaxial with the illumination direction of the light source 7 could be used to detect fluorescent light induced on selected molecules in the dialysis fluid in cell 6. A coaxial array of the spectrometer would typically result in a strong distortion by light irradiation , but this could also be made possible by the use of filters, reflection grids or a wavelength dependent beam splitter to split the detected light emitted from the sample from the illuminating light. Since the wavelengths of the illuminating light and the detected light are different from each other, many devices for splitting light beams different from each other are known in the art.
    The intensity of the emitted fluorescent light and, in a preferred modality, a part or all of the fluorescent spectrum is detected by means of the spectrometer 9. In an alternative, when only selected emission wavelengths are of interest, filters or other selective devices wavelengths could also be present in place of the spectrometer 9 in order to select specific wavelengths to be analyzed for their intensity.
    Since, in a preferred embodiment, the detection wavelength is different from each of the irradiation wavelengths, the light emitted from the sample can be easily detected by the simple fact of preventing light irradiation from entering the detector. by means of devices known in the art.
    These emitted and detected light intensity data are communicated to a control and analysis unit 11. In the control and analysis unit 11, the presence and/or concentration of at least one analyte in the sample present in cell 6 is determined based on the information regarding the irradiation wavelength and intensity of irradiation, as well as the intensity and wavelength of the detected fluorescence light detected by the spectrometer 9. Each fluorescent molecule has a specific identification regarding its fluorescent light spectrum for a length of specific radiation wave.
    This determination can be carried out in different ways, one of which is further described below.
    In the apparatus shown in figure 1, additionally, a photo detector 8 is present which is located coaxially with the beam of light irradiation emitted from the light source 7. The photo detector 8 is situated on an opposite side to the of the light source 7 with the cell 6 between them and consequently receives the light irradiation from the light source 7 which has passed through the cell 6. In other words, the photo detector 8 is intended to detect the light intensity of the light that has been transmitted through cell 6 and thus has been partially absorbed and is thus attenuated by the sample present in cell 6. The light intensity received by the photo detector 8 is also communicated to the control and analysis unit 11 .
    In order to be in a position to carry out a calibration of the relationship of the light source 7 and the photo detector 8, as well as a calibration of the spectrometer 9, the bypass valve 10 is present which can be controlled by means of the spectrometer unit. control and analysis 11. By opening the bypass valve 10, fresh dialysis liquid can be distributed to cell 6 such that only fresh dialysis liquid is present in cell 6. Once the bypass valve 10 is closed again, the dialysis liquid flows through filter 3 and cell 6 receives the used dialysis liquid again.
    The control and analysis unit 11 can determine the presence and/or concentration of a specific analyte, for example, human albumin, in the dialysis fluid based on the fluorescent light received by the spectrometer 9. This can be done, for example, by the comparing the fluorescence spectrum measured by the spectrometer 9 with a fluorescence spectrum of a specific molecule - a so-called fluorescence identification - which can be stored in a storage 12 in figure 1. By comparing the measured fluorescence spectrum with an identification of a specific molecule, the presence of a specific analyte can be determined.
    In order to be in a position to determine analyte concentration, the current intensity of the spectrum is also of relevance.
    Although in the present description of preferred embodiments the focus is on the analysis of fluorescent light as the detected light, the analysis of other forms of light emission from an excited sample is also contemplated, such that Raman scattered light analysis for the determination of presence and/or concentration of at least one analyte in the dialysis fluid used. The principles of this determination are comparable to the principles outlined above with respect to the analysis of fluorescent light.
    In this regard, Figure 3 shows the fluorescence spectra for human albumin of different concentrations when excited with light of a wavelength of 280 nm. Four different concentrations of human albumin are measured in figure 3, namely, concentrations of 7 mg/l, 23 mg/l, 45 mg/l and 98 mg/l. It is immediately apparent from Figure 3 that the maximum fluorescence peak is at approximately 340 nm, but that the intensities vary according to the respective concentrations.
    Figure 4 shows the fluorescence intensity at 340 nm for human albumin at two different excitation wavelengths, namely, at 280 nm and at 295 nm.
    It is contemplated that in the apparatus of Figure 1 to excite the sample present in cell 6 at more than one wavelength, for example at two different wavelengths, in order to be even more precisely in a position to determine the presence of a specific molecule, for example, human albumin and also be in a position to determine the current concentration of this molecule in the dialysis fluid present in the cell 6.
    When considering the mechanism of dialysis, it also becomes apparent that it is not only the albumin that will be present in the dialysis liquid in tube 5 after it has passed along the semi-permeable membrane 3, but many other waste products will be present in the dialysis liquid. One is, for example, uric acid.
    Uric acid, however, has a specific absorption spectrum which is shown schematically in figure 5. Figure 5 is taken from "Photoelectric Spectrometry Group, London; Institut fur Spektrochemie und Angewandte Spektroskopie, Dortmund 99.9 68): DMS UV Atlas of Organic Compounds. 5 Volumes. Weinheim, London: Verlag Chemie; Butterworths".
    When considering Figure 5, it becomes apparent that a uric acid absorption peak is at about 280 nm which corresponds to the excitation wavelength used for measuring the fluorescence intensity of the human albumin shown in Figure 3. Consequently , the greater the concentration of uric acid in the dialysis fluid, the greater the absorption of light irradiation. When the excitation wavelength is set to 280 nm, the intensity that is currently applied to a certain volume of dialysis liquid in cell 6 is strongly attenuated by means of the presence of uric acid in the dialysis liquid. Uric acid, however, does not emit any fluorescent light. However, in order to be in a position to reliably determine the intensity of the fluorescent light emitted based on the intensity of the light emitted by light source 7, the actual attenuation must be determined. Figure 2 shows an arrangement for compensating the excitation light absorption in the sample present in cell 6. The intensity of the light source 7 can be easily determined by measuring the light intensity in cell 6. However, since the concentration uric acid in dialysis fluid varies widely during a dialysis session, it needs to be compensated.
    Consequently, the intensity of light in the excitation volume can be calculated based on LambertBeer's law, dealing with the absorption of light in the material through which the light is passing:

    Here, IO is the initial intensity of light interfering with the cell, I(x) is the intensity after the light has traveled a distance x through the cell 6, and the coefficient α is a measure for the absorption resistance.
    Consequently, after light has passed through the entire cell 6 of length L, the intensity is:

    Consequently, assuming that the sample from which the fluorescent light is emitted is distanced by distance I
    of light entering the cell, the intensity in the sample is:
    The photo detector 8 continuously measures the intensity I(L), namely the intensity of the light that has traveled through the entire cell 6. As long as the initial intensity IO of the light source 7 remains constant, the coefficient α can be determined such that the intensity of light I(I) in the sample that emits the fluorescent light can be calculated at any time. Consequently, all fluorescence or fluorescent light spectra can be compensated for by the absorption in the dialysis liquid present in the cell 6. In other words, the concentration of the respective analyte can be determined due to the intensity 1(1) of the light irradiation in the sample. known.
    As an alternative or in addition to measuring the absorption, the excitation intensity of the light emitted by the light source 7 can be determined by analyzing the Raman scattering in water molecules present in the sample in the cell 6. For this purpose, preferably a spectrum of Raman of the sample is obtained. In an alternative, it may suffice if only the peak intensity of Raman scattered light in water for the respective light irradiation is measured. In other words, it is enough to measure the Raman peak of water for the respective light irradiation in order to determine the damping of the light irradiation in the water.
    The intensity of the Raman scattering is substantially proportional to the intensity of the excitation light and the density of the water molecules in the sample.
    The density of the water molecules in the sample is, however, substantially constant in the dialysis fluid. Consequently, by obtaining the Raman spectrum of the sample that also emits fluorescent light, it becomes possible to determine the intensity of the excitation present in the sample. The Raman spectrum can be obtained using spectrometer 9 in the same way.
    The spectrometer 9 used can be a conventional spectrometer that is readily available on the market. Such a spectrometer typically comprises an input lens for focusing incident light, a diffraction grating and a CCD (line) camera for detecting the light.
    Fluorescence spectra in an actual dialysis fluid are, however, typically not emitted by a single fluorescent molecule alone, but generally comprise at least two spectra that are superimposed. At least the albumin and indoxyl sulfate molecules should be considered here.
    For the purpose of reliable monitoring of a patient's treatment, however, it is desirable to know about the presence and/or concentration of more than one analyte in the dialysis fluid used. For example, the doctor is interested in the presence or not of human albumin and/or indoxyl sulfate in the dialysis fluid used and if any of these analytes are present, the doctor likes to know their concentration.
    For the following analysis, it is assumed that the fluorescence spectrum that is emitted from the sample after excitation at a specific irradiation wavelength is currently measured by means of the spectrometer 9. The fluorescence spectrum meant f(A) and is considered to be represented by the linear superposition of the different fluorescence spectra of simple N fluorophores:

    In this equation, ci is the concentration of the yenth fluorophore and si (À) is the respective fluorescence sensitivity of the yenth fluorophore as a function of its emission wavelength À. If the spectrum is recorded at M different wavelengths Àj, the above equation can be given as a system of M equations with unknown N:

    Consequently, the unknown concentrations ci can be calculated from the measured spectral intensities f(Àj) taking into account the known matrix elements si(Àj) . The matrix elements si(Àj) can be considered representative of the "fluorescence identification" of the respective analytes. The above system of equations can be solved, in particular, numerically. For example, the best solution for the above system of equations is considered the only one that provides, when inserted in the matrix above, the superposition (theoretical) spectrum that has the smallest squared deviation from the currently measured spectrum. Through this analysis, it becomes possible to determine the composition of the dialysis fluid by the analysis of fluorescent light detected, and in particular by analyzing the respective spectrum of the detected fluorescence light. In particular, the unknown ci concentrations are determined and thus the composition of the dialysis fluid used with respect to the ci concentrations of the respective analytes can be determined.
    In an alternative, more than one wavelength of irradiation is used in light irradiation. In particular, P different irradiation wavelengths Àirr are used in this method - for example, by the provision of different light irradiation diodes. For each radiation wavelength Àirr, the intensities f(Àirr,À) are recorded for the respective emission wavelength À. The so-called detected spectrum f(Àirr,À) for an irradiation wavelength is again assumed to be given in the form of a linear superposition of the fluorescence spectra of the N analytes:

    Ci being the unknown concentration of the yenth analyte and si(Àirr,À) being the unknown fluorescence sensitivity of the yenth analyte as a function of the fluorescence wavelength À at the respective irradiation wavelength Àirr. By adding the respective equations to the linear equation system given above, it reads:

    By solving the above system of equation, preferably in the same way as indicated above, a solution for the concentrations c can be determined and thus the concentrations of the respective analytes in the dialysis liquid used can be determined.
    In other preferred embodiments, the fluorescence spectra are measured by means of the spectrometer 9 with fixed time periods. In order to accomplish this, the excitation light emitted from the light source 7 is preferably provided in a non-continuous manner, for example in a pulsed manner. For example, a pulsed laser can be used to test the sample. By providing time-limited fluorescence spectra, additional information regarding the presence and/or concentration of certain analytes can be derived from the sample.
    In order to separate several fluorophores in a dialysis liquid, it is also possible, in addition to numerical analysis of the fluorescence spectrum as outlined above, to use techniques to separate the sample into different fractions. This fractionation can be done, for example, by ultrafiltration of proteins that can be separated due to their high mass number of substances with lower mass content such as indoxyl sulfate. To achieve filtration, the dialysis solution to be analyzed is fed through a filter with a suitable pore size. The filtrate and/or concentrate can then be analyzed by irradiating it with light of at least the first wavelength and detecting the fluorescent light emitted by the respective fraction.
    For the analysis of the dialysis liquid in the sample, it is contemplated to analyze it either in a separate field of the dialysis device or to store it in a separate volume, where it is treated and then fed again through measurement cell 6.
    Figure 6 schematically shows a layout of an apparatus which is arranged for carrying out the analysis on spent dialysis fluid separate from the main stream of spent dialysis fluid. To this end, a bypass tube 13 is shown through which the larger portion of the spent dialysis fluid passes. Consequently, only a fraction of the outflow flow of used dialysis fluid, after it has passed through membrane 3, flows through cell 6.
    Preferably, a valve 14 is present before cell 6 such that samples can be separated from the constant flow of analyte used. The separate streams can be analyzed for a long enough time such that time-limited analysis on the identical sample can also be performed before it is downloaded again. By means of valve 14, it is also possible to switch between a constant flow mode in cell 6 when valve 14 is always open or a separate sample mode when valve 14 is just open to let some used dialysis fluid flow into the cell 6 and then close the valve as the respective sample is analyzed in cell 6.
    A separation of different sample fractions can also be achieved in and before the cell 6 by means of electrophoresis, chromatography, filtering cascades, by the use of specific absorbers or by labeling specific substances or molecules by means of active fluorescent labels. A respective apparatus for carrying out the respective treatments on the sample before it is analyzed in cell 6 is schematically shown at reference numeral 15.
    In a further preferred embodiment, the sample can be measured at least twice where the second measurement is performed after the sample is physically and/or chemically treated. The actual treatment can be carried out by heating, adding and/or removing reagents such as an acid, a chemical base or a salt, or any other suitable treatment. The presence and/or concentration of a specific analyte is then determined by taking into account the difference between the at least two measurements, namely the measurement before treatment and the measurement after treatment. Combining the difference of the two fluorescence spectra and the fluorescence spectrum as such can provide additional information as to the respective analyte - or the composition of different analytes - in the dialysis fluid.
    The respective sample treatment apparatus is shown schematically in figure 6 at reference numeral 16, which may be a dosing apparatus for adding chemicals to the sample and no reference numeral 17, which is a treatment apparatus. such as a heater.
    As for the light source 7, it is also contemplated to use, in a preferred embodiment, polarized light for the excitation of the dialysis liquid, in particular, left circularly polarized light and/or right circularly polarized light.
    权利要求:
    Claims (15)
    [0001]
    1. Method for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, the method comprises the steps of: - irradiating a sample of a liquid used in the treatment with light irradiation of at least a first wavelength of radiation; - detecting the light emitted by the irradiated sample at at least a first detection wavelength wherein the detection wavelength is different from the first irradiation wavelength and; - determination of the presence and/or concentration of at least one analyte in the sample based on the detected light, characterized in that the liquid is a dialysis liquid and the detected light includes fluorescent light and the presence and/or concentration of at least one analyte in the sample is determined on the basis of the detected fluorescence light, where the irradiation light is UV light with a wavelength comprised between 180 nm and 400 nm.
    [0002]
    2. Method according to claim 1, characterized in that the presence and/or concentration of the analyte in the sample is determined based on the detected light of at least a first detection wavelength and a second wavelength of detection, the first and second detection wavelengths being different from each other and/or; wherein the presence and/or concentration of the analyte in the sample is determined based on the spectrum of a detected light from the sample.
    [0003]
    3. Method according to claim 1 or 2, characterized in that the light irradiation is UV light having a wavelength between 250 nm and 300 nm, preferably light having a wavelength of 280 nm and/or 295 nm, and/or wherein the sample is irradiated with light irradiation of at least two separate, distinct wavelengths, preferably at a wavelength of 280 nm and 295 nm.
    [0004]
    4. Method according to any one of claims 1, 2 or 3, characterized in that the intensity of light irradiation in the sample is determined and the determination of the presence and/or concentration of the analyte in the sample is compensated for the intensity of light irradiation, preferably the absorption of light irradiation in the sample is measured and the intensity of light irradiation is determined on the basis of the measured absorption, preferably the absorption in the sample is measured by means of a photo detector detecting the light irradiation transmitted through the sample and/or wherein the Raman scattered light of the sample is obtained and the intensity of the light irradiation in the sample is determined based on the Raman scattered light obtained and/or; wherein preferably a Raman spectrum of the sample and/or the intensity in a water Raman peak of the Raman scattered light is obtained.
    [0005]
    5. Method according to any one of claims 1, 2, 3 or 4, characterized in that the detected light is detected with a fixed period, preferably in which the light irradiation is pulsed.
    [0006]
    6. Method according to any one of the preceding claims 1, 2, 3, 4 or 5, characterized in that the sample is irradiated with polarized light irradiation, preferably with left circularly polarized light irradiation and/or right circularly polarized light irradiation.
    [0007]
    7. Method according to any one of claims 1, 2, 3, 4, 5 or 6, characterized in that the light emitted by the sample is detected at least twice, in which, between the first and second detections, the sample is treated physically and/or chemically and the presence and/or concentration of the analyte is determined taking into account the difference between the first and second detections, where the sample is preferably treated by heating, adding and/or removing reagents and/or by the addition and/or removal of an acid, a chemical base and/or a salt.
    [0008]
    8. Method according to any one of claims 1, 2, 3, 4, 5, 6 or 7, characterized in that the sample is separated from the dialysis liquid flow to carry out the determination of the presence and/or analyte concentration or wherein determination of the presence and/or concentration of the analyte is carried out continuously in the dialysis fluid flow.
    [0009]
    9. Method according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that before irradiating the sample with light irradiation, the sample is separated into different fractions , preferably by means of ultrafiltration, electrophoresis, chromatography, the addition of absorber and/or the addition of a fluorescent label and at least one of the sample fractions is irradiated with light irradiation.
    [0010]
    10. Method according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, characterized in that the presence and/or concentration of at least two different analytes is determined based on in detected light, wherein preferably after excitation at a specific irradiation wavelength, a detected light is analyzed for the presence of at least N different analytes by analyzing a detected light f(À) to be given in the form of a linear superposition of the N analytes spectra:
    [0011]
    11. Apparatus for monitoring a patient's treatment, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis, the apparatus comprising: - a light source (7) for irradiating a sample of a used liquid in the treatment with light irradiation of at least a first irradiation wavelength; - a detector (9) for detecting the light emitted by the irradiated sample at at least a first detection wavelength wherein the detection wavelength is different from the first irradiation wavelength and; - a control and analysis unit (11) for determining the presence and/or concentration of at least one analyte in the sample based on the detected light, characterized in that the liquid is a dialysis liquid and the detector (9) is arranged for detecting light including fluorescent light and the control and analysis unit (11) is arranged to determine the presence and/or concentration of at least one analyte in the sample based on the detected fluorescence light, wherein the source emits light from irradiation in the UV range having a wavelength between 180 nm and 400 nm.
    [0012]
    12. Apparatus according to claim 11, characterized in that the light source emits light irradiation in the UV range between 250 nm and 300 nm, preferably at 280 nm and/or 295 nm, and/or in which the light source preferably is an AllnGaN diode and/or; wherein the light source is adjusted to provide illuminating light at at least two separate, distinct wavelengths, preferably at 280nm and 295nm.
    [0013]
    13. Apparatus according to claim 11 or 12, characterized in that the means for determining the intensity of light irradiation in the sample are provided, wherein the means preferably comprise a photo detector (8) for the determination the absorption of light irradiation in the dialysis liquid sample and/or comprise means for obtaining a Raman spectrum and/or the intensity of the Raman scattered light in at least one specific wavelength.
    [0014]
    14. Apparatus according to any one of claims 11 to 13, characterized in that the means (16, 17) for the treatment of the sample physically and/or chemically are present, preferably for the treatment of the sample by heating, by addition and/or removing reagents and/or by adding and/or removing an acid, a chemical base and/or a salt and/or; wherein means (15) for separating the sample into different fractions are given, preferably ultrafiltration, electrophoresis and/or chromatography equipment and/or means for adding an absorber and/or a fluorescent label.
    [0015]
    15. Apparatus according to any one of claims 11 to 14, characterized in that the control and analysis unit (11) is arranged to determine the presence and/or concentration of at least two different analytes based on the detected light , wherein preferably the control and analysis unit (11) is arranged to analyze the detected light, after excitation at a specific irradiation wavelength, for the presence of at least N different analytes by analyzing the detected light f(À ) which is assumed to be given in the form of a linear superposition of the spectra of the N analytes: Ci being the unknown concentration of the yenth analyte and si (À) being the unknown sensitivity of the yenth analyte as a function of the respective emission wavelength À, where the control and analysis unit (11) is preferably arranged to solve this equation for the unknown concentrations ci by determining the spectrum at M different wavelengths Àj, considering the above equation in the form of the following system of M equations with unknown N: and solving them numerically, preferably considering as the best solution to the above system of equations the one which provides, when entered into the matrix above, the superposition spectrum which has the smallest square deviation from the currently measured spectrum.
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    法律状态:
    2018-12-18| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-10-01| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61M 1/36 , A61B 5/00 Ipc: A61B 5/00 (1968.09), A61B 5/145 (2000.01), A61B 5/ |
    2019-10-22| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-01-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-05-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
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    EP11161916.9|2011-04-11|
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