Method and apparatus for measuring urine osmolality

Abstract

A method for measuring urine osmolality includes receiving a urine sample, mixing a sorbent with the urine sample to form a urine-sorbent mixture, determining the electrical impedance of the urine sample, measuring the refractive index of the urine-sorbent mixture, and determining the osmolality of the urine sample using both the electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture.

Description

[Technical Field]

[0001] The present disclosure relates generally to measuring urine osmolality. More particularly, the present disclosure relates to methods and devices for measuring urine osmolality. [Background technology]

[0002] Urine osmolality is essential for assessing health status, reflecting kidney function and hydration, and is usually expressed as mOsm / kg. High levels can indicate medical conditions such as dehydration or kidney disease, while low levels can be associated with diseases such as diabetes insipidus. Monitoring osmolality after 12-14 hours of water deprivation can help diagnose diabetes insipidus.

[0003] Urine osmolality aids in the diagnosis of nocturia, a condition in which the need to urinate at night impacts well-being. A variety of conditions, including nocturia, can lead to nocturia. Management can be difficult because the underlying cause is unclear and treatment may be ineffective. Summary of the Invention [Problem to be solved by the invention]

[0004] Accurate diagnosis is crucial, and osmolality complements clinical assessment and voiding diaries to help guide treatment decisions. However, current osmolality tests are often expensive and inconvenient, requiring specialized clinics and bulky testing equipment. For example, the freezing point method, which measures osmolality through freezing point depression in specialized clinics, requires patients to visit the clinic for monitoring of urine osmolality.

[0005] Recently, portable osmometers have been developed that rapidly estimate urine osmolality based on urine specific gravity. However, research has shown that urine specific gravity correlates poorly with urine osmolality, especially in pathological urine. [Means for solving the problem]

[0006] According to an aspect of the present disclosure, there is provided a method for measuring urine osmolality. The method includes receiving a urine sample, mixing a sorbent with the urine sample to obtain a urine-sorbent mixture, determining the electrical impedance of the urine sample, measuring the refractive index of the urine-sorbent mixture, and determining the osmolality of the urine sample using the electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture. The sorbent may include activated carbon powder.

[0007] The sorbent allows the refractive index of the urine-sorbent mixture to accurately reflect the urea concentration in the urine sample, and therefore the method can accurately determine the osmotic pressure of the urine sample through a combination of electrical impedance and refractive index.

[0008] The electrical impedance of the urine sample can be determined by measuring the impedance of the urine sample before mixing the sorbent with the urine sample, or by measuring the electrical impedance of the urine-sorbent mixture.

[0009] A procedure for determining the osmolality of a urine sample can include determining the molality of the conductive solute in the urine sample based on the electrical impedance of the urine-sorbent mixture using an electrical impedance model that models the relationship between the molality of the conductive solute and electrical impedance; determining the molality of urea in the urine sample based on the refractive index of the urine-sorbent mixture and the molality of the conductive solute in the urine sample using a refractive index model that models the relationship between the refractive index and the molality of both the conductive solute and urea; and determining the osmolality of the urine sample using the molality of the conductive solute and the molality of urea.

[0010] Determining the osmolality of the urine sample can further include combining the molality of the conductive solute and the molality of urea, thereby obtaining an initial result, and adjusting the initial result with an empirical factor, thereby obtaining the osmolality of the urine sample.

[0011] The method may further include selecting an electrical impedance model from a plurality of pre-calibrated electrical impedance models and selecting a refractive index model from a plurality of pre-calibrated refractive index models.

[0012] The method can include measuring a current ambient temperature and selecting an electrical impedance model and a refractive index model based on the current ambient temperature, wherein each electrical impedance model of the plurality of pre-calibrated electrical impedance models models the relationship between the molality of the conductive solute and the electrical impedance at a respective ambient temperature, and each refractive index model of the plurality of pre-calibrated refractive index models models the relationship between the refractive index and the molality of both the conductive solute and urea at a respective ambient temperature.

[0013] According to another aspect of the present disclosure, there is provided an apparatus for measuring urine osmolality. The apparatus includes a container containing a urine-sorbent mixture including a urine sample and a sorbent, a measuring unit configured to determine the electrical impedance of the urine sample and measure the refractive index of the urine-sorbent mixture, and a processing unit configured to determine the osmolality of the urine sample using the electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture. The sorbent can include activated carbon powder.

[0014] The device is simple to use as the only action required by the device from the end user may be to collect urine in a container.

[0015] The processing unit may include a memory storing an electrical impedance model that models the relationship between the molality of the conductive solute and electrical impedance, and a refractive index model that models the relationship between the refractive index and the molality of both the conductive solute and urea, and a processor. The processor is configured to use the electrical impedance model to determine the molality of the conductive solute in the urine sample based on the electrical impedance of the urine-sorbent mixture, use the refractive index model to determine the molality of urea in the urine sample based on the refractive index of the urine-sorbent mixture and the molality of the conductive solute, and determine the osmolality of the urine sample using the molality of the conductive solute and the molality of urea.

[0016] The processor may be configured to determine the osmolality of the urine sample by combining the molality of the conductive solute and the molality of urea, thereby obtaining an initial result, and adjusting the initial result with an empirical factor, thereby obtaining the osmolality of the urine sample.

[0017] The memory may store a plurality of pre-calibrated electrical impedance models and a plurality of pre-calibrated refractive index models, and the processor may be configured to select the electrical impedance model from the plurality of pre-calibrated electrical impedance models and select the refractive index model from the plurality of pre-calibrated refractive index models.

[0018] The measuring unit may further include a thermometer configured to measure a current ambient temperature, and the processor is configured to select an electrical impedance model and a refractive index model based on the current ambient temperature measured by the measuring unit, wherein each electrical impedance model of the plurality of pre-calibrated electrical impedance models the relationship between the molality of the conductive solute and the electrical impedance at a respective ambient temperature, and each refractive index model of the plurality of pre-calibrated refractive index models models the relationship between the refractive index and the molality of both the conductive solute and urea at a respective ambient temperature.

[0019] The container and measuring unit may be configured to be connectable such that when the container and measuring unit are connected, the measuring unit seals the container and mixes the sorbent with the urine sample.

[0020] The measuring unit may be configured to determine the electrical impedance of the urine sample by measuring the electrical impedance of the urine sample.

[0021] The measuring unit may be configured to determine the electrical impedance of the urine sample by measuring the electrical impedance of the urine-sorbent mixture.

[0022] The sorbent may be disposed in a container, and the container may be further configured to receive a urine sample.

[0023] The container may enclose a sealed space containing the adsorbent, and the container and measuring unit may be configured such that the sealed space opens when the measuring unit is inserted, thereby allowing the adsorbent to come into contact with the urine sample and be mixed with the urine sample by the measuring unit.

[0024] The device may further include a display for displaying the osmolality value of the urine sample.

[0025] In embodiments, the device has a smaller size than a test device, and therefore has lower manufacturing costs, and can provide patients with an acceptable format for measuring urine osmolality. In some embodiments, the device is portable, allowing patients to conveniently use it at home without visiting a clinic.

[0026] Thus, disclosed herein are methods and apparatus for measuring urine osmolality in accordance with the present disclosure. The various features, aspects, and advantages of the present disclosure will become more apparent from the following detailed description of embodiments thereof, by way of non-limiting example only, taken in conjunction with the accompanying drawings.

[0027] In the following, embodiments of the invention will be described by way of non-limiting example with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0028] [Figure 1] 1 is a flow chart showing a flow chart of a method for measuring urine osmolality. [Figure 2] 1 is a flow chart showing the steps of a method for measuring urine osmolality. [Figure 3] 1 is a flow chart illustrating a prototype of an apparatus for measuring urine osmolality. [Figure 4] 1 is a flowchart illustrating a calibration process for an electrical impedance model. [Figure 5] 1 is a graph illustrating an electrical impedance model. [Figure 6] 1 is a flowchart illustrating a calibration process for a refractive index model. [Figure 7] 1 is a graph showing a refractive index model. [Figure 8] 1 is a graph showing the relationship between urine osmolality estimated by the present method and urine osmolality determined by clinical testing. [Figure 9A] 1 is a graph showing results from a validation study of a method for measuring urine osmolality. [Figure 9B] 1 is a graph showing results from a validation study of a method for measuring urine osmolality. [Figure 10] FIG. 1 shows a first apparatus and corresponding procedure for measuring urine osmolality. [Figure 11] FIG. 1 shows a second device for measuring urine osmolality. [Figure 12] FIG. 1 shows a third device for measuring urine osmolality. [Figure 13] 10 is a flow chart showing a procedure corresponding to a third device for measuring urine osmolality. [Figure 14A] 1 is a chart showing results from another validation study of a method for measuring urine osmolality. [Figure 14B] 1 is a graph showing results from another validation study of a method for measuring urine osmolality. DETAILED DESCRIPTION OF THE INVENTION

[0029] For brevity and clarity, the description of the embodiments of the present disclosure will be directed to methods and devices for measuring urine osmolality according to the drawings. While aspects of the present disclosure will be described in conjunction with the embodiments illustrated herein, it will be understood that it is not intended to limit the disclosure to these embodiments. On the contrary, the present disclosure is intended to encompass alternatives, modifications, and equivalents to the embodiments described herein, which are included within the scope of the present disclosure as defined by the appended claims. Furthermore, in the following detailed description, specific details are set forth to provide a thorough understanding of the present disclosure. However, those skilled in the art will recognize that the present disclosure may be practiced without certain details and / or with multiple details resulting from the combination of aspects of certain embodiments. In some instances, well-known systems, methods, procedures, and components have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0030] In embodiments of the present disclosure, the depiction of a given element or discussion in a particular figure or use of a particular element number or reference thereto in corresponding descriptive material can encompass the same, equivalent, or similar element or element number identified in another figure or descriptive material associated therewith.

[0031] References to an "embodiment / example," "another embodiment / example," "some embodiments / examples," "some other embodiments / examples," etc., indicate that the embodiment / example so described may include a particular feature, structure, characteristic, property, element, or limitation, but that not all embodiments / examples necessarily include that particular feature, structure, characteristic, property, element, or limitation. Furthermore, repeated use of the phrase "in an embodiment / example" or "in another embodiment / example" does not necessarily refer to the same embodiment / example.

[0032] The terms "comprising," "including," "having," etc. do not exclude the presence of features / elements / steps other than those listed in an embodiment. The description of certain features / elements / steps in mutually different embodiments does not indicate that combinations of these features / elements / steps cannot be used in an embodiment.

[0033] As used herein, the terms "a" and "an" are defined as one or more than one. The use of " / " in the figures or related documents is understood to mean "and / or" unless otherwise indicated. The term "set" is defined as a non-empty finite organization of elements that mathematically exhibits a cardinality of at least one, in accordance with known mathematical definitions (e.g., a set as defined herein may correspond to a unit set, a singlet set, or a single-element set, or a multiple-element set). Recitation of a particular numerical value or numerical range herein is understood to include or be a recitation of the approximate numerical value or numerical range.

[0034] FIG. 1 is a flowchart illustrating a method for measuring urine osmolality according to an embodiment of the present invention. As shown in FIG. 1, method 100 includes step 110 of receiving a urine sample and step 120 of mixing a sorbent with the urine sample to form a urine-sorbent mixture. Method 100 also includes step 130 of determining the electrical impedance of the urine sample and step 140 of measuring the refractive index of the urine-sorbent mixture. Step 130 can be accomplished by measuring the electrical impedance of the urine sample or the urine-sorbent mixture. Finally, method 100 includes step 150 of determining the osmolality of the urine sample using both the electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture.

[0035] Adsorbents include materials capable of absorbing large molecular weight components, such as activated carbon, activated charcoal, and / or charcoal.

[0036] In a normal urine sample, the urine composition can be divided into conductive ions and non-conductive solutes. The conductive ions (approximately 44%) consist of sodium ions (approximately 18%), potassium ions (approximately 7%), chloride ions (approximately 19%), and trace amounts of other dissolved ions. The non-conductive solutes (approximately 56%) consist primarily of urea (approximately 55%) and the remaining solutes (approximately 1%), such as creatinine, inorganic sulfur, and other inorganic and organic compounds. Urine osmolality can be determined by summation. Urine osmolality can be determined with an accuracy of up to approximately 99% by quantifying the conductive ions (approximately 44%) and non-conductive urea (approximately 55%) present in a urine sample.

[0037] Electrical impedance measurements allow for effective characterization of the molar concentration of conductive solutes in a urine sample, but they do not provide the ability to determine the concentration of urea, the largest non-conductive component in urine.

[0038] Liquid refractive index measurements are widely used to measure the concentration of solutes in a solution. However, it is not feasible to determine the concentration of urea in a urine sample solely based on the overall refractive index. This limitation arises because urine samples also contain large molecular weight components and conductive solutes. Large molecular weight components such as creatinine, uric acid, glucose, and protein have a greater impact on the refractive index of a urine sample than the dominant components (conductive solutes and urea). In addition, the presence of conductive solutes also affects the overall refractive index reading. For example, a solution with 1 mol / kg sodium chloride (the dominant conductive solute in urine) and a solution with 1 mol / kg urea have nearly identical refractive index readings, yet the osmolality of the former is twice that of the latter.

[0039] To address this limitation, the method 100 shown in Figure 1 integrates refractive index measurements with electrical impedance measurements and employs activated charcoal absorption to determine the osmolality of a urine sample. Activated charcoal absorbs large molecular weight urinary components, such as creatinine, uric acid, glucose, and protein, thereby reducing their influence on the refractive index reading. Electrical impedance measurements are first employed to assess the contribution of conductive solutes to osmolality, followed by refractive index measurements to determine the contribution of urea.

[0040] 2 illustrates a procedure 200 for measuring urine osmolality. Procedure 200 includes receiving a urine sample 210 and mixing it with activated carbon 220 to obtain a urine-activated carbon mixture 230. This is followed by steps 130, 140, of measuring the electrical impedance of urine-activated carbon mixture 230 and measuring the refractive index of urine-activated carbon mixture 230.

[0041] The electrical impedance readings 242 measured by step 130 are input into an electrical impedance model 240 to determine the NaCl molality 244 in the urine sample 210. Simultaneously, the refractive index readings 252 measured by step 140 are input into a refractive index model 250 to determine the urea molality 254 of the urine sample 210. In step 150, the NaCl molality 244 and the urea molality 254 are combined with empirical coefficients 270 to determine the osmolality 260 of the urine sample 210.

[0042] Electrical impedance model 240 models the relationship between the molality of the conductive solute and the electrical impedance, and refractive index model 250 models the relationship between the refractive index and the molality of both the conductive solute and urea.

[0043] 3 shows an apparatus 300 for measuring urine osmolality. Apparatus 300 includes a container 310 containing a urine sample 210 and activated charcoal 220 before step 120. After step 120, container 310 contains a urine-activated charcoal mixture 230.

[0044] A first droplet (300 μL) of urine-activated charcoal mixture 230 is measured by impedance analyzer 320. Alternatively, although not shown, this droplet may be a droplet of urine sample 210 measured by impedance analyzer 320. Impedance analyzer 320 consists of a printed circuit board (PCB) 322 having electrodes 324 and an impedance analyzer module 326. Electrodes 324 are connected to impedance analyzer module 326. The first droplet of urine-activated charcoal mixture 230 is placed on PCB 322 so as to cover the area of ​​electrodes 324, thereby enabling impedance analyzer module 326 to determine an electrical impedance reading 242 of urine-activated charcoal mixture 230. A second droplet (300 μL) of urine-activated charcoal mixture 230 is measured by refractometer 330. Refractometer 330 consists of a light source 332, a measurement chamber 334, and a photodiode 336. A second droplet of urine-activated charcoal mixture 230 is placed onto measurement chamber 334, thereby enabling refractometer 330 to determine a refractive index reading 252 of urine-activated charcoal mixture 230 using light source 332 and photodiode 336. Impedance analyzer 320 and refractometer 330 collectively comprise measuring unit 340.

[0045] The osmolality 260 of the urine sample 210 is determined by the processing unit 350 using both the electrical impedance readings 242 and the refractive index readings 252 .

[0046] 4 illustrates an exemplary calibration process 400 for the electrical impedance model 240. The calibration process 400 begins at step 410, where six sodium chloride (NaCl) solutions are prepared having molalities ranging from 0.05 mol / kg to 0.5 mol / kg. At step 420, each of the six NaCl solutions is dispensed onto a printed circuit board (PCB) 322 so as to cover an area of ​​an electrode 324. At step 430, the impedance analyzer module 326 is activated to determine the electrical impedance of the NaCl solutions. The calibration process 400 ends at step 440, where the electrical impedance model 240 is generated.

[0047] A graph 500 representing the electrical impedance model 240 generated by step 440 is shown in Figure 5. Graph 500 shows the R as a function of NaCl molality. NaCl The relationship between molality of conductive solutes and electrical impedance is shown by plotting the inverse of R (the electrical impedance of the NaCl solution determined by step 430). The black circles represent the R at NaCl molality of 0.05 M, 0.10 M, 0.20 M, 0.30 M, 0.40 M, and 0.50 M, respectively. NaCl The solid line is the best fit curve obtained by constraining the curve to pass through the origin.

[0048] Constrained fitting, which ensures that the fitted curve passes through the origin, is available in R. 2 =0.9936, which indicates a high degree of fit. NaCl is the NaCl molality M in mol / kg NaCl Alternatively, the electrical impedance model 240 can be expressed by the following equation: 1 / R NaCl =C0M NaCl (1) In the formula, the coefficient C0 = 0.0266 kg / (mol·Ω).

[0049] 6 illustrates an exemplary calibration process 600 for refractive index model 250. Calibration process 600 includes step 610 for preparing sample mixtures containing NaCl at concentrations of 0.05 mol / kg, 0.10 mol / kg, 0.20 mol / kg, 0.30 mol / kg, 0.40 mol / kg, and 0.50 mol / kg and urea at concentrations of 0 mol / kg, 0.10 mol / kg, 0.20 mol / kg, 0.30 mol / kg, 0.40 mol / kg, and 0.50 mol / kg. Following step 620, 36 calibration samples are obtained. Referring to apparatus 300, calibration process 600 further includes step 630 of introducing 300 μL of each calibration sample into refractometer 330 and step 640 of obtaining the refractive index of the calibration sample at room temperature (25° C.). The calibration process 600 concludes at step 650 where the refractive index model 250 is generated.

[0050] 7 shows a graph 700 representing the refractive index model 250 generated by step 650. Graph 700 includes graph 710, which plots the refractive index as a function of urea molality for the NaCl-urea mixtures obtained in step 620, and graph 720, which plots the refractive index as a function of NaCl molality for the NaCl-urea mixtures obtained in step 620.

[0051] In graph 710, the circular symbols (○) are the refractive index experimentally measured at 0.05 mol / kg NaCl, the rectangular symbols (□) are the refractive index experimentally measured at 0.1 mol / kg NaCl, the cross symbols (x) are the refractive index experimentally measured at 0.2 mol / kg NaCl, the diamond symbols (◇) are the refractive index experimentally measured at 0.3 mol / kg NaCl, the asterisk symbols (*) are the refractive index experimentally measured at 0.4 mol / kg NaCl, and the triangle symbols (▽) are the refractive index experimentally measured at 0.5 mol / kg NaCl. In graph 720, the circular symbols (○) are the refractive indices experimentally measured without urea, the rectangular symbols (□) are the refractive indices experimentally measured with 0.1 mol / kg urea, the cross symbols (x) are the refractive indices experimentally measured with 0.2 mol / kg urea, the diamond symbols (◇) are the refractive indices experimentally measured with 0.3 mol / kg urea, the asterisk symbols (*) are the refractive indices experimentally measured with 0.4 mol / kg urea, and the triangle symbols (▽) are the refractive indices experimentally measured with 0.5 mol / kg urea. The solid lines in both graphs 710 and 720 are best fit curves. The goodness of fit, R, of all fitted lines in graph 700 is 2 Since is at least 0.995, there is a strong linear relationship between the refractive index and the molality of both urea and NaCl. The linear model is s The refractive index of the calibration sample is denoted by M NaCl and M urea and can be related to the molality in mol / kg of both urea and NaCl, denoted by n s =C NaCl M NaCl +C urea M urea +C0(2), where C in kg / mol NaCl and C urea are coefficients defining the contribution to the refractive index per unit molar contribution of NaCl and urea, respectively, and C = 1.333 is a constant due to pure deionized (DI) water. Based on the data presented in graph 700, CNaCl = 0.01041 kg / mol and C urea = 0.00966 kg / mol is R 2 It can be seen that =0.997 gives the best fitting result.

[0052] Impedance readings may vary from device to device, and refractive index readings are affected by ambient temperature. Therefore, when setting up a device for measuring urine osmolality at different ambient temperatures, three coefficients, C0, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54 NaCl , and C urea may require recalibration after process 400 and process 600.

[0053] For simplicity, the end user of a device for measuring urine osmolality will need to calculate the three coefficients (C0, C NaCl , and C urea ) only requires measuring two samples with known chemical concentrations. For example, an end user could measure the electrical impedance and refractive index of 300 μL of a 0.5 mol / kg NaCl solution. Therefore, C and C NaCl The two coefficients can be determined based on equations (1) and (2). The end user can then measure the refractive index of 300 μL of a mixture with 0.5 mol / kg NaCl and 0.5 mol / kg urea, and determine the final coefficient, C urea can be determined by equation (2): Experimental estimations indicate that this calibration process takes approximately 6 minutes.

[0054] After calibrating for the effects of conductive solutes and urea on the electrical impedance and refractive index, in other words, after generating the electrical impedance model 240 and the refractive index model 250, the osmolality of the urine sample can be determined.

[0055] Referring to procedure 200, first, 600 μL of urine sample 210 is mixed with 50 mg of activated carbon 220 to obtain a urine-activated carbon mixture 230. Referring to apparatus 300, the urine-activated carbon mixture 230 is then divided into two equal portions. One portion is measured for electrical impedance (R NaCl) measurement and one portion is dropped onto a refractometer 330 to obtain a refractive index reading (n).

[0056] Referring to step 150, urine osmolality is calculated by combining the NaCl molality and urea molality using equations (1) and (2), so that

[0057]

number

[0058] is determined by In the formula, (M osm ) estimate is the urine osmolality estimated by method 100 in FIG. 1 before combining with empirical coefficient 270. While activated charcoal exhibits good absorbance for some compounds in urine, such as creatinine and uric acid, the absorbance does not reach 100%, and many compounds other than conductive solutes and urea cannot be absorbed by activated charcoal. These chemicals tend to increase the refractive index reading of a urine sample, resulting in an overestimation of the urine osmolality. Therefore, the empirical coefficient e can be used to correct the urine osmolality value. Referring to step 150, the accurate urine osmolality (M osm ) exact can be determined by multiplying the estimated urine osmolality by an empirical factor. (M osm ) exact =e·(M osm ) estimate (4) The factor e can be determined empirically.

[0059] Ten calibration experiments are performed to determine the empirical coefficient 270. First, the urine osmolality is measured by inputting the electrical impedance and refractive index readings into equation (3), and this urine osmolality is compared with the urine osmolality measured by a commercially available freezing point osmometer (6002 Touch Micro OSMETTE™, Precision System, Inc., USA). The urine osmolality ((M osm )estimate ) and urine osmolality ((M) determined by freezing point osmometry osm ) exact ) is shown in graph 800 as shown in FIG. 8. In graph 800, the circular symbols represent experimental data and the line is the best fit curve forced through the origin. A constrained fit that forces the fit line through the origin yields R 2 = 0.994, demonstrating a strong goodness of fit, indicating a strong linear relationship between the two osmolality readings. In this example, the empirical coefficient e can be calculated to be 0.9082.

[0060] A validation clinical trial was conducted to blindly examine how accurately method 100 can measure urine osmolality. Urine samples were obtained from 10 subjects at four time points: 1) before dinner, 2) before bedtime, 3) midnight, and 4) upon first awakening in the morning. Table 1 summarizes the results of the clinical trial for the first 40 urine samples.

[0061] [Table 1]

[0062] As shown in Table 1, method 100 predicts urine osmolality with an accuracy of up to 95.3±3.6% compared to results obtained from validation studies using a clinical freezing point osmometer. The urine osmolality determined by method 100 is plotted against the urine osmolality determined by a freezing point osmometer in graph 900 of FIG. 9A (based on 224 urine samples). In graph 900, R 2 = 0.9959, indicating a high goodness of fit. The linear correlation coefficient between these two osmolalities is 0.9975, with an average accuracy of 94.4 ± 5.0%.

[0063] Alternatively, other curve fitting functions such as power functions and polynomials can be applied instead of the linear empirical coefficients shown in equation (4). For example, (M osm) estimate and (M osm ) exact The power function relationship with (M osm ) exact =A·[(M osm ) estimate ] B (5) can be expressed as where coefficients A and B were determined from experimental data. Using Table 1 and data from 103 additional urine samples, the experimental values ​​were determined to be A = 1.176 and B = 0.9625. Among these 103 additional urine samples were pathological urine samples from diabetic patients with high glucose concentrations exceeding 1000 mg / dL. The presence of these glucose molecules would result in a significant overestimation of the urea concentration from the refractometer. Therefore, an additional protocol was applied. If the concentration of the measured conductive solute [conductive] is less than 0.1 M and the [non-conductive] solute is greater than 0.5 M, the upper limit for the [non-conductive] solute is set to 0.5 M. This would correspond to the calibration range shown in Figure 7.

[0064] The relationship between the urine osmolality obtained using equation (5) and the urine osmolality determined by freezing point osmometry (based on 143 urine samples) is shown in Figure 9B. As plotted in graph 910, the linear correlation coefficient between these two osmolalities is 0.9962, with an average accuracy of 94.5 ± 4.7%.

[0065] An exemplary point-of-care device 1010 derived from device 300 is shown in schematic diagram 1000 in FIG. 10. Device 1010 consists of a measurement unit 1020 and a disposable urine container 1030. Designed for single use, disposable urine container 1030 is pre-filled with a portion of activated charcoal (e.g., 40 mg of activated charcoal powder) and can be sealed with a plastic film 1032. Note that other ratios of activated charcoal amount to urine volume may also be used, and corresponding empirical coefficients will need to be determined. Referring to FIG. 1 , disposable urine container 1030 can receive a urine sample in step 110, which allows the urine sample to mix with the activated charcoal in step 120, resulting in a urine-activated charcoal mixture. Measurement unit 1020 includes a temperature probe 1022, an impedance probe pair 1024, and a refractometer 1026. When the disposable urine container 1030 and the measurement unit 1020 are connected, the temperature probe 1022, the impedance probe pair 1024, and one of the prismatic surfaces of the refractometer 1026 come into contact with the urine-activated carbon mixture.

[0066] Exemplary electronic components within the measurement unit are shown in schematic diagram 1040. A power module 1042 having a DC power source, e.g., two AA batteries, drives a main board 1044, which acquires and processes temperature, electrical impedance, and refractive index readings from the probes (temperature probe 1022, impedance probe 1024, and refractometer 1026), determines a urine osmolality value, and displays the urine osmolality value on a display module 1046 (e.g., an LCD screen). The main board 1044 can select an electrical impedance model and a refractive index model to determine a urine osmolality value based on the temperature readings acquired from temperature probe 1022.

[0067] With reference to the device 300 , the disposable urine container 1030 serves as the container 310 , the measurement unit 1020 serves as the measuring unit 340 , and the main board 1044 serves as the processing unit 350 .

[0068] As illustrated by step 1050 in FIG. 10 , the usage of the device can include six steps. For example, the end user can first peel the plastic film 1032 from the disposable urine container 1030. Then, the end user can fill the disposable urine container 1030 with a urine sample up to the position indicated by the bold marker line 1034. Third, the end user can hold the disposable urine container 1030 and turn the measuring unit 1020 to seal the liquid. This allows the three probes to contact the urine sample and mix it with the pre-filled activated carbon. A screw thread 1036 is designed on the neck of the disposable urine container 1030 to facilitate the temperature probe 1022 and the impedance probe pair 1024 mixing the activated carbon with the urine sample when the disposable urine container 1030 is sealed by the measuring unit 1020. After a three-minute waiting period, the urine osmolality reading can be displayed on the display module 1046. In a final step, the end user can open the point-of-care device 1010 and discard the used disposable urine container 1030 in a trash can.

[0069] Compared to existing devices on the market, the design shown in FIG. 10 ensures that the point-of-care device 1010 has a much smaller footprint than laboratory-based freezing point osmometers. The device is expected to be simple to use and have a much lower manufacturing cost, while having the excellent measurement accuracy demonstrated by the present method as shown in Table 1. The device is suitable as a point-of-care device for elderly people to use at home, providing diagnostic utility with a short turnaround time in large-scale screening events. The consumables for each test are plastic containers pre-filled with activated charcoal, which is expected to be acceptable to the general public while ensuring sustainable revenue growth for the manufacturer.

[0070] An exemplary tethered portable urine osmometer 1100 derived from device 300 is shown in FIG. 11. The tethered portable urine osmometer 1100 consists of a reading unit 1110, a detachable measurement probe 1120, and a urine cup 1130 pre-filled with a portion of activated carbon powder. The reading unit 1110 may include a motherboard, a battery, and a display. The detachable measurement probe 1120 is responsible for measuring electrical impedance, refractive index, and temperature. The reading unit 1110 can select an electrical impedance model and a refractive index model to determine a urine osmolality value based on a temperature reading obtained from the detachable measurement probe 1120.

[0071] With reference to the device 300 , the urine cup 1130 serves as the container 310 , the detachable measurement probe 1120 serves as the measuring unit 340 , and the reading unit 1110 serves as the processing unit 350 .

[0072] An exemplary integrated portable urine osmometer 1200 derived from the device 300 is shown in FIG. 12. The integrated portable urine osmometer 1200 consists of a reading unit 1210 and a urine cup 1220 pre-filled with a portion of activated carbon powder. The reading unit 1210 includes a refractive index module 1212, which may consist of a light-emitting diode (LED) light, a prism, and a linear charge-coupled device (CCD) sensor. The reading unit 1210 further includes electrodes 1214 for measuring electrical impedance and a temperature sensor 1216. The refractive index module 1212 can be mounted on a vertical sidewall of the reading unit 1210 to avoid trapping bubbles. In addition, the reading unit 1210 also includes other necessary components, such as a motherboard, battery, display, probe, and memory. The reading unit 1210 can select an electrical impedance model and a refractive index model to determine a urine osmotic pressure value based on a temperature reading obtained from the temperature sensor 1216.

[0073] The urine cup 1220 serves to receive the urine sample. It may enclose a measurement chamber 1222 pre-loaded with activated carbon powder. The urine cup 1220 is designed with a mechanism that allows the measurement chamber 1222 to open (e.g., spring-loaded) when a probe included in the reading unit 1210 is inserted, allowing the activated carbon powder to mix with the urine sample. In addition, the urine cup 1220 may further include a component such as a vibrator to vibrate and mix the activated carbon powder and urine sample. Alternatively, the activated carbon powder and urine sample may be mixed using other feasible methods, such as magnetic stirring or manual shaking. The measurement chamber 1222 may be a sealed space before being inserted by the probe.

[0074] 12, it is possible for the device to be configured to measure the electrical impedance of the urine sample before mixing it with the activated carbon powder. This can be achieved by configuring the electrode 1214 outside of the measuring chamber 1222, so that the electrode 1214 can measure the electrical impedance of the urine sample before activating the mixing mechanism.

[0075] The integrated portable urine osmometer 1200 may also be configured to automatically detect the presence of a urine sample, start a timer for a specified incubation period (e.g., 3 minutes), and transmit data to a digital device (e.g., a cell phone) for viewing the urine osmolality profile. The probe included in the reading unit 1210 may have additional features such as being replaceable and waterproof to allow for immersion in urine and easy cleaning.

[0076] Referring to the device 300, the urine cup 1220 serves as the container 310, while the reading unit 1210 serves as both the measuring unit 340 and the processing unit 350. In the reading unit 1210, the refractive index module 1212, the electrodes 1214, and the temperature sensor 1216 serve as the measuring unit 340.

[0077] An exemplary process 1300 for measuring urine osmolality using the integrated and portable urine osmometer 1200 is presented in the flowchart in FIG. 13. Referring to FIG. 12, process 1300 begins at step 1310, where an end user collects a urine sample (e.g., by urinating) in a sample bottle (urine cup 1220). In the next step 1320, the end user attaches the sample bottle (urine cup 1220) to a device (integrated and portable urine osmometer 1200) for measuring urine osmolality. Process 1300 proceeds to step 1330, where the measurement chamber 1222 opens (spring loaded) when a probe is inserted to mix the urine sample with activated carbon powder for measurement. Thereafter, in step 1340, the device (integrated and portable urine osmometer 1200) detects whether the urine sample volume is sufficient, for example, through a change in electrical impedance. In the next step 1350, the device (integrated portable urine osmometer 1200) determines the temperature, electrical impedance, and refractive index.

[0078] In step 1350, multiple substeps are included. In substep 1351, the temperature of the urine sample is measured. With reference to calibration process 400, substep 1352 of measuring the electrical impedance of the urine sample is followed by another substep 1353, in which the NaCl concentration of the urine sample (denoted as [NaCl]) is determined from the calibration curve generated in step 440. With reference to calibration process 600, substep 1354 includes measuring the light intensity profile from the linear CCD sensor, followed by substep 1355, in which the refractive index of the urine sample is calculated from the calibration curve generated from step 650. In addition, there is another substep 1356, in which the equivalent urea concentration (denoted as [Urea]) is determined.

[0079] The NaCl and urea concentrations determined in step 1350 are combined in step 1360 to calculate the osmolality of the urine sample based on the following equation: Urine osmolality = 2 [NaCl] + [urea]

[0080] The process 1300 may conclude with step 1370, which displays the urine osmolality value on the device (integrated and portable urine osmometer 1200) via a display (e.g., a small liquid crystal / organic light emitting diode screen) included in the reading unit 1210.

[0081] A validation clinical trial is conducted to examine in a blinded manner how accurately and specifically method 100 can measure urine osmolality. Urine samples were obtained from a total of 48 subjects, including 41 patients with nocturnal polyuria (NP) and 7 healthy volunteers. Urine samples were obtained from the subjects at four time points: 1) before dinner, 2) before bedtime, 3) midnight, and 4) upon first awakening in the morning.

[0082] In FIG. 14A, graph 1400 shows the sensitivity and specificity of the freezing point osmometer and activated charcoal method (i.e., method 100). In chart 1402, the evaluation results for the freezing point osmometer are recorded. As shown in chart 1402, for individuals experiencing nocturia, 28 individuals tested positive, while 13 individuals tested negative. In the healthy control group, 2 individuals tested positive and 5 individuals tested negative. The sensitivity of the method, which indicates the ability of the method to accurately identify true positives in individuals suffering from nocturia, is 0.683. The specificity, which represents the ability of the method to accurately identify true negatives in healthy individuals, is 0.714.

[0083] Another chart 1404 included in graph 1400 shows the evaluation results for the activated charcoal method, as follows: Of the individuals experiencing nocturia, 29 test positive and 12 test negative. In the healthy group, 2 test positive and 5 test negative. The sensitivity of this method is 0.707. The specificity is 0.714.

[0084] Comparing the results shown in chart 1404 with those in chart 1402, the activated charcoal method appears to exhibit slightly higher sensitivity while maintaining a similar level of specificity. In summary, the activated charcoal method performs well or at least similarly to the freezing point osmometer.

[0085] 14B, graph 1410 shows urine osmolality measurements obtained from freezing point osmometry versus the activated charcoal method for NP patients (unshaded) and healthy volunteers (shaded). It can be seen that urine osmolality obtained from the activated charcoal method shows a similar trend to that of freezing point osmometry. [Explanation of symbols]

[0086] 210 Urine Samples 220 Activated carbon 230 Urine-Activated Carbon Mixture 240 Electrical Impedance Model 242 Electrical Impedance Readings 250 Refractive Index Model 252 Refractive Index Reading 260 Osmotic Pressure 270 Empirical Coefficients 300 equipment 310 Container 320 Impedance Analyzer 322 Printed Circuit Board (PCB) 324 electrode 326 Impedance Analyzer Module 330 Refractometer 332 Light source 334 Measuring Chamber 336 Photodiode 340 Measuring Unit 350 Processing Unit, Impedance and Refractive Index Model 400 Calibration Process 600 Calibration Process 1010 Point-of-care devices 1020 measuring unit 1022 Temperature Probe 1024 Impedance Probe Pair 1026 Refractometer 1030 Disposable urine container 1032 Plastic film 1034 Bold Marker Lines 1036 thread 1042 Power Supply Module 1044 mainboard 1046 Display Module 1100 Tethered Portable Urine Osmometer 1110 Reading unit 1120 Detachable Measurement Probe 1130 Urine Cup 1200 Integrated Portable Urine Osmometer 1210 Reading Unit 1212 Refractive Index Module 1214 Electrode 1216 Temperature Sensor 1220 Urine Cup 1222 Measurement Chamber

Claims

1. receiving a urine sample; mixing a sorbent with the urine sample to obtain a urine-sorbent mixture; determining the electrical impedance of the urine sample; measuring the refractive index of the urine-sorbent mixture; determining the osmolality of the urine sample using the electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture; 1. A method for measuring urine osmolality, comprising:

2. determining the osmolality of the urine sample, determining the molality of the conductive solute in the urine sample based on the electrical impedance of the urine sample using an electrical impedance model that models the relationship between the molality of the conductive solute and the electrical impedance; determining the molality of urea in the urine sample based on the refractive index of the urine-sorbent mixture and the molality of the conductive solute in the urine sample using a refractive index model that models the relationship between the refractive index and the molality of both the conductive solute and urea; determining the osmolality of the urine sample using the molality of the conductive solute and the molality of the urea; 2. The method of claim 1, comprising:

3. determining the osmolality of the urine sample, combining the molality of the conductive solute with the molality of the urea, thereby obtaining an initial result; and adjusting the initial result by an empirical factor to thereby obtain the osmolality of the urine sample.

4. 4. The method of claim 2 or 3, further comprising selecting the electrical impedance model from a plurality of pre-calibrated electrical impedance models and selecting the refractive index model from a plurality of pre-calibrated refractive index models.

5. measuring a current ambient temperature; and selecting the electrical impedance model and the refractive index model based on the current ambient temperature; each electrical impedance model of the plurality of pre-calibrated electrical impedance models models the relationship between the molality of the conductive solute and the electrical impedance at a respective ambient temperature, and each refractive index model of the plurality of pre-calibrated refractive index models models the relationship between the refractive index and the molality of both the conductive solute and urea at a respective ambient temperature; The method of claim 4.

6. 2. The method of claim 1, wherein determining the electrical impedance of the urine sample comprises measuring the electrical impedance of the urine sample.

7. 2. The method of claim 1, wherein determining the electrical impedance of the urine sample comprises measuring the electrical impedance of the urine-sorbent mixture.

8. 8. The method of claim 1, wherein the adsorbent comprises activated carbon powder.

9. a container configured to contain a urine-sorbent mixture comprising a urine sample and a sorbent; Determining the electrical impedance of the urine sample and measuring the refractive index of the urine-sorbent mixture a measuring unit configured as follows: The electrical impedance of the urine sample and the refractive index of the urine-sorbent mixture are used to determine the osmolality of the urine sample. a processing unit configured to 1. An apparatus for measuring urine osmolality, comprising:

10. The processing unit a memory storing an electrical impedance model that models the relationship between the molality of a conductive solute and the electrical impedance, and a refractive index model that models the relationship between the refractive index and the molality of both the conductive solute and urea; determining the molality of a conductive solute in the urine sample based on the electrical impedance of the urine-sorbent mixture using the electrical impedance model; determining the molality of urea in the urine sample based on the refractive index of the urine-sorbent mixture and the molality of the conductive solute using the refractive index model; determining the osmolality of the urine sample using the molality of the conductive solute and the molality of the urea; a processor configured to:

10. The apparatus of claim 9, comprising:

11. the processor: combining the molality of the conductive solute with the molality of the urea, thereby obtaining a first result; Adjusting the initial result by an empirical factor to obtain the osmolality of the urine sample.

11. The apparatus of claim 10, configured to determine the osmolality of the urine sample by:

12. 12. The apparatus of claim 10 or 11, wherein the memory stores a plurality of pre-calibrated electrical impedance models and a plurality of pre-calibrated refractive index models, and the processor is configured to select the electrical impedance model from the plurality of pre-calibrated electrical impedance models and select the refractive index model from the plurality of pre-calibrated refractive index models.

13. the measuring unit further includes a thermometer configured to measure a current ambient temperature, and the processor is configured to select the electrical impedance model and the refractive index model based on the current ambient temperature measured by the measuring unit; 13. The apparatus of claim 12, wherein each electrical impedance model of the plurality of pre-calibrated electrical impedance models models the relationship between the molality of the conductive solute and the electrical impedance at a respective ambient temperature, and each refractive index model of the plurality of pre-calibrated refractive index models models the relationship between the refractive index and the molality of both the conductive solute and urea at a respective ambient temperature.

14. 14. The device of claim 9, wherein the container and the measuring unit are configured to be connectable such that when the container and the measuring unit are connected, the measuring unit seals the container and mixes the adsorbent with the urine sample.

15. 15. The device of claim 9, further comprising the sorbent disposed in the container, the container being configured to receive the urine sample.

16. 16. The device of claim 15, wherein the container encloses a sealed space containing the adsorbent, and the container and the measuring unit are configured such that the sealed space opens when the measuring unit is inserted, thereby allowing the adsorbent to come into contact with the urine sample and be mixed with the urine sample by the measuring unit.

17. 10. The apparatus of claim 9, wherein the measuring unit is configured to determine the electrical impedance of the urine sample by measuring the electrical impedance of the urine sample.

18. 10. The device of claim 9, wherein the measuring unit is configured to determine the electrical impedance of the urine sample by measuring the electrical impedance of the urine-sorbent mixture.

19. 19. The apparatus of any one of claims 9 to 18, wherein the adsorbent comprises activated carbon powder.

20. 20. The device of claim 9, further comprising a display for displaying the osmolality value of the urine sample.

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