Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
  • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
  • A61B5/0531—Measuring skin impedance
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
  • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
  • A61B5/0537—Measuring body composition by impedance, e.g. tissue hydration or fat content
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/34—Genitourinary disorders
  • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

• the present disclosure relates to a method for determining a patient's filtration rate, in particular a patient's glomerular filtration rate or an equivalent creatinine clearance. It relates further to a corresponding apparatus and to a diuretic. Finally, the present disclosure relates to a computer program product and a computer program. Background
• GFR glomerular filtration rate
• Creatinine is freely excreted by the kidney - if creatinine concentrations are known in blood and urine and urine output can be measured over 24 hours, the GFR can be determined. To that end direct measurement of GFR is possible using techniques such as creatinine clearance, [Rodrigo E, et. al.: Measurement of renal function in pre-ESRD patients. Kidney International Supplements 2002: May; (80): 1 1 -17.] Methods of determining GFR requiring urine samples require reliable urine data, which is often problematic for a variety of reasons and as a result much effort has been expended on methods that require only a blood (or plasma) sample of creatinine.
• a method for determining or approximating a patient's glomerular filtration rate or a patient's creatinine clearance comprises the following steps: determining a serum creatinine concentration of the patient, determining a lean tissue mass of the patient, and determining the glomerular filtration rate of the patient or the creatinine clearance of the patient based on the serum creatinine concentration of the patient and the lean tissue mass of the patient.
• the step of determining the lean tissue mass includes measuring the lean tissue mass.
• the step of measuring the lean tissue mass includes applying a bioimpedance measurement. This provides for a particular convenient method.
• the step of determining the serum creatinine concentration includes measuring the serum creatinine concentration from a blood sample. This provides for a particular reliable method.
• a typical value for the dimensionless proportionality constant ⁇ ⁇ 5 is 1 .15.
• the method includes a step of determining a criterion for applying a renal replacement therapy to the patient based on the determined glomerular filtration rate or creatinine clearance of the patient, the renal replacement therapy including a dialysis treatment, in particular a hemodialysis treatment or a peritoneal dialysis treatment.
• the criterion may be a criterion whether to commence dialysis treatment for the patient or not.
• the criterion may be a criterion whether to change the treatment modality applied for the patient from a first treatment modality to a second treatment modality, e.g. from peritoneal dialysis to haemodialysis or vice versa.
• the criterion may be a criterion for applying a certain dosage when applying a renal replacement therapy, e.g. an amount of fluid to be withdrawn from a patient or a target clearance associated with a haemodialysis session.
• the patient is a patient undergoing a renal replacement therapy, the renal replacement therapy including a peritoneal dialysis or a haemodialysis.
• the step of determining the serum creatinine concentration includes determining a first serum creatinine concentration at a first time between treatment sessions of the renal replacement therapy and determining a second serum creatinine concentration at a second time between treatment sessions of the renal replacement therapy.
• the first time may be immediately after concluding the renal replacement therapy, in case of haemodialysis: post HD
• the second time may be when preparing for the renal replacement therapy, in case of haemodialysis: pre HD.
• the step the step of determining the patient's GFR or creatinine clearance is based on the first and on the second creatinine concentration.
• the method includes a step of determining, in particular measuring the weight gain of the patient between the first time and the second time and wherein the step of determining the patient's GFR or creatinine clearance is based on the weight gain of the patient.
• the method includes a step of determining the total body water of the patient, in particular measuring total body water by applying a bioimpedance measurement of a patient and wherein the step of determining the patient's GFR or creatinine clearance is based on the total body water of the patient.
• the patient's GFR or creatinine clearance is determined at a plurality of times and wherein a timely average is determined of the patient's GFR or creatinine clearance and wherein one or more extreme values or outliers are disregarded from the determination of the timely average.
• a median filter may be applied for filtering the time series.
• the method includes a step of determining a criterion for the subscription of a medication promoting the production of urine for use in the treatment of a patient suffering from a reduced glomerular filtration rate or creatinine clearance, i.e.
• the criterion may be a criterion whether to commence a diuretics therapy for a patient or not.
• the criterion may be a criterion for determining a dosage of a diuretic for a patient.
• a medication preferably a diuretic to be administered to a patient is provided, wherein the dosage and/or the administration scheme of the medication is determined based on said determined criterion.
• an apparatus for determining or approximating a patient's GFR or a patient's creatinine clearance comprises a first determination unit configured to determine a serum creatinine concentration of the patient, a second determination unit configured to determine a lean tissue mass of the patient, and a processing unit configured to determine the GFR of the patient or the creatinine clearance of the patient based on the serum creatinine concentration of the patient and the lean tissue mass of the patient.
• the apparatus is susceptible to the same advantageous modifications or improvements as the above disclosed method.
• Fig. 1 depicts a flow diagram of a method for determining a filtration rate or clearance of a patient.
• Fig. 2 depicts a further flow diagram for determining a filtration rate or a clearance of a patient.
• Fig. 3 shows a first apparatus according to the present disclosure comprising a controller for carrying out a method in accordance with the present teaching.
• Fig. 4 shows a second apparatus according to the present disclosure comprising a controller for carrying out a method in accordance with the present teaching.
• Fig. 5 - 7 respectively show a scatter diagram of a statistical analysis of comparing methods of determining creatinine clearance.
• Fig. 8 - 13 respectively show simulated measurement results comparing a method in accordance with the present teaching and conventional methods of determining GFR.
• Fig. 1 depicts a method 100 for determining or approximating a patient's glomerular filtration rate (GFR) or a patient's creatinine clearance.
• GFR glomerular filtration rate
• the method 100 includes a step 101 of determining a serum creatinine concentration of the patient, in one embodiment the step 101 is preceded with or includes a step 1 1 1 of measuring the serum creatinine concentration on a blood sample previously taken from the patient. Alternatively, the serum creatinine concentration is inputted manually into a user interface of the system 300.
• the method 100 further includes a step 102 of determining a lean tissue mass of the patient. In one embodiment the step 102 is preceded with or includes a step 1 12 of measuring the lean tissue mass by applying a bioimpedance measurement.
• the method 100 also includes a step 103 to determine the GFR of the patient or the creatinine clearance of the patient based on the serum creatinine concentration of the patient determined in step 101 and based on the lean tissue mass of the patient determined in step 102.
• the creatinine clearance K Cr WB is determined in step 103 by applying the formula:
• M LT m ⁇ s the lean tissue mass of the patient
• [Cr] s is the serum creatinine concentration
• the glomerular filtration rate Q gfr is determined in step 103 as follows:
• the method 100 includes a step 1 14 of determining a criterion for the subscription of or a dosage or a dosing scheme for a medication promoting the production of urine for use in the treatment of a patient suffering from a reduced GFR or creatinine clearance, i.e. a diuretic, based on the determined GFR or creatinine clearance of the patient.
• the criterion may be a criterion whether to commence a diuretics therapy for a patient or not.
• the method 100 includes a step 1 15 of determining a criterion for applying a renal replacement therapy to the patient based on the determined GFR or creatinine clearance of the patient, the renal replacement therapy including a dialysis treatment, in particular a haemodialysis treatment or a peritoneal dialysis treatment.
• the criterion may be a criterion whether to commence dialysis treatment for the patient or not.
• the criterion may be a criterion whether to change the treatment modality applied for the patient from a first treatment modality to a second treatment modality, e.g. from peritoneal dialysis to haemodialysis or vice versa.
• the criterion may be a criterion for applying a certain dosage when applying a renal replacement therapy, e.g. an amount of fluid to be withdrawn from a patient or a target clearance associated with a haemodialysis dialysis session.
• Fig. 2 depicts a method 200 for determining the creatinine clearance and/or the GFR of a patient undergoing a renal replacement therapy, the renal replacement therapy including a peritoneal dialysis or a HD (haemodialysis) treatment.
• the method 200 includes a step 205 of determining a first serum creatinine concentration at a first time between treatment sessions of the renal replacement therapy, the first time preferably being immediately after concluding the renal replacement therapy, in case of haemodialysis: post HD.
• the method 200 further includes a step 204 of determining a second serum creatinine concentration at a second time between treatment sessions of the renal replacement therapy, in case of haemodialysis: pre HD.
• the method 200 further includes a step 203 of determining, in particular measuring the weight gain of the patient between the first time and the second time.
• the weight gain will be referred to as: Q - t, wherein t is the time that has elapsed between the first time and the second time, in a preferred embodiment t is the time that has elapsed between treatment sessions.
• the method 200 further includes a step 201 of determining the total body water of the patient, in particular measuring a total body water by applying a bioimpedance measurement of a patient, preferably at the first time, more preferably immediately after conducting renal replacement therapy, i.e. post HD.
• the method 200 includes a step 202 of determining creatinine generation rate from the lean tissue mass of the patient which has been previously determined by applying a bioimpedance measurement.
• step 208 wherein ⁇ ⁇ 5 is as explained above in relation to Figure 1 .
• the glomerular filtration rate Q g f r or creatinine clearance K Cr WB thus determined may be utilized as a criterion for applying certain dose of a renal replacement therapy as has been described above in relation to Figure 1 .
• Figure 3 depicts a system 309 adapted for carrying out any of the methods described above in relation to Figure 1 or Figure 2.
• the system 309 comprises an apparatus 300.
• the apparatus 300 is connected to an external database 302 comprising the results of the measurements carried out on a patient and all other data needed for one of the described methods.
• the database 302 may also be an internal means to the apparatus 300.
• the apparatus 300 may optionally have means 304 for inputting data and providing the data to the processing unit 306. Such data may be any data required in connection with a method described in relation to Figure 1 or Figure 2.
• the apparatus 300 comprises a first determination unit 307 configured to determine a serum creatinine concentration of the patient, either based on a measurement or on data received from the database 302 or from the means 304.
• the apparatus 300 comprises a second determination unit 308 configured to determine a lean tissue mass of the patient, either based on a measurement or on data received from the database 302 or from the means 304.
• the apparatus 300 comprises the processing unit 306 configured to determine the GFR of the patient or the creatinine clearance of the patient based on the serum creatinine concentration of the patient and the lean tissue mass of the patient.
• the processing unit may be further adapted to carry out any of the methods described above in relation to the description of Figure 1 and Figure 2.
• the results of the determination can be displayed on the monitor 305 or stored by means of the database 302 or any other storage means.
• Figure 4 depicts a system 310 which is a modification of the system 309.
• the apparatus 300 may be connected (by means of a wire or wireless) with a bioimpedance measurement means 317 as one measurement means for providing measurement results for determining the lean tissue mass of the patient to the determining unit 308.
• the bioimpedance measurement means 317 may provide measurement results to determine the total body water of the patient to the processing unit 306.
• Determining the lean tissue mass of the patient from bioimpedance measurements and/or to determining the total body water of the patient from bioimpedance measurements may be performed as described in WO 2006/002685 A1 , the disclosure of which is hereby explicitly incorporated in the present application by reference.
• bioimpedance measurement means 317 may be provided in addition to the database 302 comprising the results of the measurement and the data required for the methods described above in relation to Figure 1 or Figure 2 or in place of the database 302.
• the bioimpedance measurement means 317 can be capable of automatically compensating for influences on the impedance data like contact resistances.
• An example of a bioimpedance measurement means 317 is a device from Xitron Technologies, distributed under the trademark HydraTM that is further described in WO 92/19153, the disclosure of which is hereby explicitly incorporated in the present application by reference.
• the bioimpedance measurement means 317 may comprise various electrodes for being attached to the patient. In Figure 4 only two electrodes 317a and 317b are shown which are attached to the bioimpedance measurement means 317. Additional electrodes are of course also contemplated. Each electrode implied can comprise two or more ("sub"-) electrodes in turn.
• Electrodes can comprise a current injection (“sub"-) electrode and a voltage measurement (“sub"-) electrode. That is, the electrodes 317a and 317b shown in Figure 4 can comprise two injection electrodes and an two voltage measurement electrodes (i.e. four electrodes in total).
• the apparatus may have further means 319 for measuring body parameters of the patient required for a method to be carried out by the apparatus.
• the means 319 for measuring a body parameter may be a scale for measuring the patient's weight or any laboratory equipment required for determining the patient's serum creatinine concentration.
• Figure 5 depicts a statistical analysis comparing results of a creatinine clearance determined using the method described in relation to Figure 1 and a method from the related art which is based on using both blood and urine samples. Both methods were applied to a patient cohort including 124 patients not undergoing renal replacement therapy, so called pre-ESRD (pre-end-stage renal disease) patients. The measurements from the related art serve as a reference and are denoted as 'Lab'.
• Figure 5 is a plot of a statistical analysis plotting differences between the measurement results from the different methods against the mean value from both methods. The difference between measurement values is plotted on the vertical axis, wherein the mean value is plotted on the horizontal axis.
• Figure 6 depicts a similar statistical analysis as the statistical analysis provided in Figure 5, wherein the results of a further method from the related art, the so called Cockroft Gault method are compared with results of the method which is based on blood and urine samples on the same above mentioned patient cohort, wherein results of the Cockroft Gault method are noted as 'CG'.
• the result of the Bland- Altman analysis provides for an agreement of 0.3 ⁇ 14.7 ml/min.
• Figure 7 depicts a similar statistical analysis as the statistical analysis provided in Figures 5 and 6, wherein the results of the method described in relation to Figure 1 are compared to results from the Cockroft Gault method. As can be seen differences between the two methods may be attributed to whether the patient may be diagnosed Obese' or 'lean'.
• Figures 8 - 13 depict simulation results of a patient body model having a varying body composition and a constant glomerular filtration rate.
• Figure 8 depicts two subjects having different body compositions namely an obese (upper diagram) and lean subject (lower diagram), that are used for the simulation, the result of which are depicted in Figures 10 - 13.
• the lower of the diagrams in Figure 8 represents the body composition that has been fed into the simulations, the result of which are shown in Figure 10 and Figure 12.
• the upper diagram of Figure 8 represents the body composition used in the simulations depicted in Figure 1 1 and in Figure 13.
• the total body weight is composed of MAT (mass of adipose tissue or adipose tissue mass) and MLT (mass of lean tissue or lean tissue mass).
• Cross like dots represent the evolution of the adipose tissue mass which is substantially constant, rectangular dots represent the varying lean tissue mass.
• Figure 9 depicts the result of a simulation, simulating the timely evolution of the creatinine concentration in the model body depicted in the lower diagram of Figure 8.
• the simulation of the timely evolution of the creatinine concentration is based on the following assumptions:
• the rate of change of creatinine mass with time — ⁇ - depends on the generation rate of creatinine G Cr , creatinine concentration [Cr] creatinine clearance K Cr and also the rate of change of total body water dVTBW .
• This equation may be integrated to simulate a timely evolution of the creatinine concentration depending on the creatinine clearance K Cr and the body composition parameters fed into the simulation.
• the distribution space of creatinine in the body is considered equivalent to the total body water (V T BW) and hence this may be determined from the methods described in described in WO 2006/002685, i.e.
• VTBW H tWLT M LT + H tWAT M AT + Mpo
• MAT is the adipose tissue mass
• MLT is the lean tissue mass
• Ht W _LT and Htw_AT are the hydration coefficients of lean and adipose tissue
• MFO is the mass of fluid overload (OH (overhydration) where present. Over time (weeks to months) changes in body composition will modify the total body, changing the creatinine distribution space. Therefore, differentiating equation for V T BV leads to: dV TB w _ together dM LT
• the time dependent creatinine concentration is subsequently fed into the method for determining the GFR described in relation to the method of Figure 1 .
• the glomerular filtration rate GFR is determined from the time dependent creatinine concentration and other parameters according to further methods for determining an estimate of the GFR from the prior art, that will be termed conventional methods in the following.
• Figure 10 depicts the simulated measurement results for a body model simulating a lean patient having a glomerular filtration rate Q g f r — 20 ml/min and a relative fat mass of 20%. If the lean tissue mass is varied in accordance with Figure 8, then the results of Figure 10 shows than in lean subjects at low glomerular filtration rates the conventional methods for determining the glomerular filtration rate underestimate the reference GFR that has been fed into the simulation. Remarkably the conventional methods show an apparent variation in the simulated measurment of the GFR due to the change in creatinine concentration. The reason for this is that the conventional methods for determining the GFR do not compensate for the variations of the lean tissue.
• Figure 1 1 depicts the simulated measurement results for a body model simulating a patient having a glomerular filtration rate Q g f r — 20 ml/min and a fraction of 40% adipose tissue, i.e. a model of a patient that that may be characterized an obese subject.
• Figure 12 depicts the simulated measurement results for a body model simulating a patient having a glomerular filtration rate Q g f r — 100 ml/min and a fraction of
• adipose tissue i.e. fat, i,e
• simulating a patient that may be characterized an lean subject at a physiological GFR.
• the agreement between the GFR that has been inputted into the simulation which depicted with BCM and most of the results from the conventional methods is good (typically ca. ⁇ 5ml/min).
• the method termed "Quadratic Mayo Clinic" significantly overestimates the inputted GFR.
• Figure 13 depicts the simulated measurement results for a body model simulating a patient having a glomerular filtration rate Q g f r — 100 ml/min and a fraction of
• adipose tissue i.e. fat, i,e, simulating a patient that that may be characterized an obese subject at a physiological glomerular filtration rate.
• a physiological GFR in an obese subject represents some of the largest sources of error in conventional methods of determining the GFR. Most of the conventional methods generate GFR levels above the upper physiological range of GFR.
• Figures 10 - 13 depict the magnitude of errors incurred using conventional methods for estimating GFR that are used in routine practice in comparison with simulation results from applying the method described in relation to Figure 1 .
• the simultations show that assuming there is no change in kidney function the and thus GFR as an input into the simulation, the simulated measurement result from applying the method of Figure 1 also remains unchanged independent of variations in muscle mass (MLT).
• MLT muscle mass
• the concentration of creatinine and its rate of generation will vary in response to MLT changes, but this should not affect the GFR.
• the GFR should be independent of variations in body composition. This is in contrast to the conventional methods for estimating GFR, showing a variation of the GFR estimate, depending on the variation of the body composition inputted into the simulation.
• a method and an apparatus for determining or approximating a patient's glomerular filtration rate or a patient's creatinine clearance are disclosed.
• the method comprises the following steps: determining a serum creatinine concentration of the patient, determining a lean tissue mass of the patient, and determining the glomerular filtration rate of the patient or the creatinine clearance of the patient based on the serum creatinine concentration of the patient and the lean tissue mass of the patient.

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