Information provision method for determining initiation of renal replacement therapy, and end-stage renal disease diagnostic composition for determining same

Abstract

The present invention relates to an information provision method for determining the initiation of renal replacement therapy, the method comprising a step for checking the neutrophil-to-lymphocyte ratio in a sample isolated from an individual. The present invention enables the initiation of renal replacement therapy at an optimal time and the prediction of uremic symptoms, thereby enabling a prognosis of a patient to be greatly improved.

Description

Method for providing information for deciding to initiate new alternative therapy and composition for diagnosing end-stage renal disease for making such decision

[0001] The present invention relates to a method for providing information for deciding on initiation of new alternative therapy and a composition for diagnosing end-stage renal disease for making the decision.

[0002]

[0003] The kidneys are crucial organs that maintain homeostasis in the body. They regulate body fluid volume, blood ion concentration, and pH. They also excrete metabolic waste products, toxins, and drugs. They also regulate blood pressure and perform other metabolic and endocrine functions. Furthermore, they activate vitamin D, which aids calcium absorption in the small intestine, and are involved in the synthesis of various hormones.

[0004] Kidney disease is a condition in which the kidneys fail to perform their excretory, regulatory, metabolic, and endocrine functions normally, resulting in overall functional decline or abnormality. This decline in kidney function due to damage can lead to enlargement of the kidney and related structures, renal atrophy, changes in body fluid volume, electrolyte imbalances, metabolic acidosis, impaired gas exchange, impaired anti-infective function, and the accumulation of uremic toxins.

[0005] Chronic kidney disease (CKD) is a progressive loss of the kidneys' ability to excrete waste, concentrate urine, and conserve electrolytes. The National Kidney Foundation (NWF) defines CKD based on the presence of kidney damage and the level of kidney function, regardless of the type (clinical diagnosis). The primary measure of kidney function is the glomerular filtration rate (GFR), often assessed as serum creatinine clearance and urine creatinine concentration. Chronic kidney disease or failure is defined as a GFR of less than 60 ml / min for three months or longer. The NWF categorizes kidney dysfunction into five stages based on the GFR. Dialysis is generally not required in stages 1 through 4, but once renal degeneration begins, kidney function deteriorates irreversibly toward the end-stage (stage 5). Most patients in stage 5 are unable to survive without renal replacement therapy, such as dialysis or kidney transplantation.

[0006] Therefore, there is a need for a method to provide information to determine when to initiate replacement therapy at an appropriate time.

[0007]

[0008] The present invention aims to provide a method for providing information for deciding to initiate a new alternative therapy.

[0009] The present invention aims to provide a composition for diagnosing end-stage renal disease for determining the initiation of new alternative therapy.

[0010] The present invention aims to provide a kit for diagnosing end-stage renal disease, comprising a composition for diagnosing end-stage renal disease.

[0011]

[0012] 1. A method for providing information for deciding to initiate new replacement therapy, comprising the step of determining the neutrophil to lymphocyte ratio in a sample isolated from an individual.

[0013] 2. A method for providing information for deciding to initiate new replacement therapy, wherein the sample is tissue, whole blood, plasma, serum or blood in the above 1.

[0014] 3. A method for providing information for deciding to initiate renal replacement therapy, further comprising a step of determining to initiate renal replacement therapy when the neutrophil to lymphocyte ratio in the above 1 is 3 to 8.

[0015] 4. A method for providing information for deciding to initiate renal replacement therapy, further comprising a step of determining to initiate renal replacement therapy when the current neutrophil-to-lymphocyte ratio is 1.5 to 5 times higher than the neutrophil-to-lymphocyte ratio 6 months ago in the above 1.

[0016] 5. A method for providing information for deciding to initiate renal replacement therapy, wherein in the above 1, the renal replacement therapy is selected from the group consisting of hemodialysis, peritoneal dialysis, and renal transplantation.

[0017] 6. A composition for diagnosing end-stage renal disease for determining the initiation of renal replacement therapy, comprising a substance for detecting the ratio of neutrophils to lymphocytes among white blood cells in blood.

[0018] 7. A kit for diagnosing end-stage renal disease comprising the composition for diagnosing end-stage renal disease of the above 6.

[0019]

[0020] The method for providing information for deciding to initiate a new alternative therapy of the present invention can have the effect of significantly improving the prognosis of a patient by initiating the new alternative therapy at an optimal time.

[0021] The composition for diagnosing end-stage renal disease and the diagnostic kit thereof for determining the initiation of new alternative therapy of the present invention can serve as a marker for predicting the optimal time to initiate hemodialysis.

[0022] The composition for diagnosing end-stage renal disease and the diagnostic kit thereof for determining the initiation of new alternative therapy of the present invention can serve as a marker for predicting uremic symptoms in patients with stage 5 chronic kidney disease.

[0023]

[0024] Figure 1 illustrates the overall workflow for patient registration for the study.

[0025] Figure 2 shows the results of changes in NLR 6 months before and at the start of hemodialysis.

[0026] Figures 3 to 8 show scatter plots of positive and negative correlations of NLR.

[0027] Figures 9 and 10 show the receiver operating characteristic curve (ROC) between NLR and neurological symptoms at the start of hemodialysis (A), and the receiver operating characteristic curve (ROC) between NLR and gastrointestinal symptoms (B).

[0028]

[0029] The present invention provides a method for providing information for determining the initiation of replacement therapy, comprising the step of determining the neutrophil to lymphocyte ratio in a sample isolated from an individual.

[0030] The above-mentioned individual may be an animal for which replacement therapy has been initiated or has a history of replacement therapy initiation, an animal suspected of needing a decision on replacement therapy initiation, or an animal for which information for a decision on replacement therapy initiation is desired. The above-mentioned animal may be a mammal, including a human.

[0031] The above sample is separated from an individual and may be tissue, whole blood, plasma, serum, blood, bone, bone marrow or cerebrospinal fluid (CSF), and is preferably tissue, whole blood, plasma, serum or blood, but is not limited thereto.

[0032] The information providing method of the present invention may further include a step of determining that new replacement therapy is to be initiated when the neutrophil to lymphocyte ratio is 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3.5 to 8, 4 to 8, 4.5 to 8, 3.5 to 7.5, 4 to 7, or 4.5 to 6.5.

[0033] The information providing method of the present invention may further include a step of determining that new replacement therapy is to be initiated when the current neutrophil-to-lymphocyte ratio is 1.5 to 5 times, 1.5 to 4.5 times, 1.5 to 4 times, 1.5 to 3.5 times, 1.5 to 3 times, 1.5 to 2.5 times, 1.5 to 2 times, 2 to 5 times, 2 to 4.5 times, 2 to 4 times, 2 to 3.5 times, or 2 to 3 times the neutrophil-to-lymphocyte ratio 6 months ago.

[0034] The above-mentioned renal replacement therapy is a treatment performed when life cannot be maintained with conservative treatment such as medication or dietary control due to kidney disease, and may be hemodialysis, peritoneal dialysis, or kidney transplantation, and is preferably hemodialysis, but is not limited thereto.

[0035] The above kidney disease means a disease that causes damage to the kidney, and includes, but is not limited to, at least one disease selected from the group consisting of acute kidney injury, chronic kidney disease (CKD), end-stage renal disease (ESRD), systemic lupus erythematosus, diabetic nephropathy (DN; or diabetes mellitus nephropathy (DMN), IgA nephritis (IgAN), HIV-associated nephropathy, non-diabetic chronic kidney disease, focal segmental glomerulosclerosis (FSGS), minimal change nephrotic syndrome (MCD), and xanthine oxidase deficiency.

[0036] The present invention provides a composition for diagnosing end-stage renal disease for determining the initiation of renal replacement therapy, comprising a substance for detecting the ratio of neutrophils to lymphocytes among white blood cells in blood.

[0037] All of the above-described matters regarding the neutrophil-to-lymphocyte ratio and renal replacement therapy are applied as is to the composition for diagnosing end-stage renal disease for determining the initiation of renal replacement therapy at this hospital.

[0038] The substance for detecting the ratio of neutrophils to lymphocytes among white blood cells in the blood is not limited in type as long as it can detect neutrophils and lymphocytes in the blood by interacting with them, such as by binding to or reacting with them. For example, it can be an antibody, aptamer, protein, peptide, nucleic acid, polymer, compound, or reagent.

[0039] The ratio of neutrophils to lymphocytes among the above white blood cells may be detected in a sample isolated from the individual.

[0040] All of the above-described matters regarding the above objects and samples are applied as is to the composition for diagnosing end-stage renal disease for the purpose of deciding to initiate new alternative therapy at this hospital.

[0041] The above diagnosis refers to the confirmation of the presence or characteristics of a pathological condition. For the purposes of this document, diagnosis may refer to the confirmation of the presence of end-stage renal disease for the purpose of determining the initiation of renal replacement therapy, or further, the confirmation of the progression or worsening of end-stage renal disease for the purpose of determining the initiation of renal replacement therapy.

[0042] The diagnosis may include determining a subject's susceptibility to a particular disease or condition, determining whether a subject currently has a particular disease or condition, determining a prognosis for a subject with a particular disease or condition, or therametrics (e.g., monitoring a subject's condition to provide information about the efficacy of a treatment).

[0043] The composition can be used to detect the ratio of neutrophils to lymphocytes among white blood cells in the blood, and can be used to diagnose whether end-stage renal disease requiring a decision to initiate renal replacement therapy has occurred or to diagnose the severity thereof, but is not limited thereto.

[0044] The present invention provides a kit for diagnosing end-stage renal disease comprising the composition for diagnosing end-stage renal disease.

[0045] The kit of the present invention may include an antibody that specifically binds to a marker component, a secondary antibody conjugate conjugated with a label that develops color by reaction with a substrate, a chromogenic substrate solution that reacts with the label, a washing solution, an enzyme reaction stop solution, etc., and may be manufactured with a plurality of separate packagings or compartments containing the reagent components used, but is not limited thereto.

[0046] The kit of this hospital may include not only a preparation capable of detecting the neutrophil-to-lymphocyte ratio among white blood cells in a patient sample, but also one or more compositions, solutions, or devices suitable for detection. For example, the kit may include, but is not limited to, reagent components used in an automated analyzer for detecting neutrophils and lymphocytes.

[0047]

[0048] The present invention is described in more detail below with reference to the following examples. These examples are intended to illustrate the present invention and are not intended to limit its scope.

[0049]

[0050] Experimental example

[0051] 1. Method

[0052] 1.1. Method of selecting objects

[0053] The Institutional Review Board (IRB) of Gyeongsang National University Hospital (GNUH) approved this study (IRB number: 2021-04-011) and waived the need for informed consent due to its retrospective study design. We retrospectively reviewed the medical records of patients who began chronic maintenance hemodialysis between January 2011 and December 2016. Patients aged 18 to 75 years were initially enrolled. Data on demographic and clinical characteristics, laboratory findings, and comorbidities were obtained from medical records. Patients with acute infections, those receiving steroids or immunosuppressants, and those undergoing hemodialysis for acute kidney injury were excluded. Patients with insufficient laboratory data for the 6 months prior to initiation of dialysis were also excluded. A total of 323 chronic hemodialysis patients were initially enrolled, and 44 were excluded (Figure 1). Laboratory data obtained 6 months prior to initiation of dialysis were compared with data at the time of initiation.

[0054]

[0055] 1.2. Six categories of symptoms in patients who have started hemodialysis

[0056] Symptoms of patients initiating maintenance hemodialysis were classified into six categories. Neurological symptoms included mental changes, fatigue, headache, insomnia, and general weakness. Pulmonary symptoms included dyspnea due to uremic pleurisy and pulmonary edema due to heart failure. Gastrointestinal (GI) symptoms included anorexia, nausea, and vomiting. Dermatological symptoms included dry skin and pruritus. The last two categories included weight loss >10% and refractory peripheral edema. Patients with chronic kidney disease (CKD) were considered for maintenance hemodialysis after assessing six or more uremic symptoms and signs, regardless of mean estimated glomerular filtration rate.

[0057]

[0058] 1.3. NLR calculation method

[0059] Automated complete blood counts (CBC) and differential counts, total white blood cells (WBC), neutrophils, and lymphocytes were obtained, and the neutrophil-to-lymphocyte ratio (NLR) was calculated as the ratio of neutrophils to lymphocytes. The Modification of Diet in Renal Disease formula, eGFR = [1.86 × (plasma creatinine)] -1.154 ×(age) -0.203 ]×(0.74 for women)×(1.210 for blacks) was used.

[0060]

[0061] 1.4. Methods for measuring biochemical parameter values ​​from individuals

[0062] As shown in Figure 1, venous blood was collected from all subjects, and the levels of albumin, alkaline phosphatase (ALP), uric acid, total cholesterol, C-reactive protein (CRP), blood urea nitrogen (BUN), creatinine, calcium, phosphorus, electrolytes, and total CO2 were measured using an automatic analyzer.

[0063]

[0064] 1.5. Method for analyzing the correlation between NLR and the severity of renal disease

[0065] All data are presented as mean ± standard deviation or frequency. Paired t-tests were used to compare continuous variables recorded 6 months before and at the start of chronic maintenance hemodialysis (HD). Dichotomous variables were compared using the chi-square test. The relationship between the presence or absence of the six aforementioned symptom categories and disease severity as indicated by the NLR was examined using the t-test. Linear associations between the NLR and other continuous variables were assessed using the Pearson correlation test. NLR cutoffs for the six categories of uremic symptoms were derived by plotting receiver operating characteristic (ROC) curves. Multiple logistic regression analysis was performed to identify independent risk factors for all six categories of uremic symptoms at the start of HD. All statistical analyses were performed using SPSS for Windows (version 21.0; SPSS Inc., Chicago, IL, USA). Statistical significance was defined as p <0.05.

[0066]

[0067] 2. Results

[0068] 2.1. Biochemical parameter measurements 6 months before and after initiation of hemodialysis

[0069] The clinical and biochemical characteristics of 279 patients with end-stage renal disease (ESRD) at and 6 months before initiation of dialysis are summarized in Table 1. 68.5% of patients were male. The etiologies of ESRD were diabetic nephropathy (58.8%), chronic glomerulonephritis (26.5%), hypertensive nephropathy (11.1%), polycystic kidney disease (2.2%), and unknown etiology (1.4%). The mean eGFR at initiation of dialysis was 5.7 mL / min / 1.73 m 2 But 6 months ago it was 7.7 mL / min / 1.73 m 2 was (p < 0.001). CRP (acute-phase reactant) levels remained unchanged over 6 months, but total WBC counts increased significantly (p < 0.001). Hemoglobin, albumin, and total CO2 levels decreased significantly (all p < 0.001) (Table 1). NLR increased from 2.5±1.0 to 4.9±2.8 (p < 0.001) (Fig. 2). NLR increased by 50% or more in 70.1% of patients.

[0070]

[0071]

[0072] 2.2. Correlation analysis between NLR and biochemical parameter measurements

[0073] Figures 3 to 8 show the results of bivariate correlation analysis. NLR was positively correlated with CRP (r=0.202, p=0.009) (Figure 3), platelet (r=0.170, p=0.004) (Figure 4), and phosphorus (r=0.202, p=0. 009) (Figure 5) levels, and negatively correlated with albumin (r=-0.192, p=0.001) (Figure 6), calcium (r=-0.125, p=0.034) (Figure 7), and total CO2 (r=-0.134, p=0.023) (Figure 8) levels. There was no relationship between NLR and eGFR (r=-0.058, p=0.328), total cholesterol level (r=0.058, p=0.356), or hemoglobin level (r=-0.076, p=0.199).

[0074]

[0075] 2.3. Relationship between symptoms and NLR in patients starting hemodialysis

[0076] The mean number of uremic symptom categories observed was 3.0±0.9. The proportion of patients exhibiting symptoms in only one of the six categories was 2.8%. No patient complained of symptoms in all six categories. The proportions of patients complaining of symptoms in categories 2, 3, 4, and 5 were 30.7%, 35.9%, 23.3%, and 7.3%, respectively. Neurological symptoms were reported in 93.4% of patients, gastrointestinal symptoms in 78.8%, pulmonary symptoms in 44.6%, and skin symptoms in 34.1% of patients. Weight loss and peripheral edema were evident in 5.2% and 39.7% of patients, respectively. The NLR was significantly correlated with the mean number of observed symptom categories (p<0.001).

[0077]

[0078] 2.4. NLR cutoffs for two categories of symptoms in patients initiating hemodialysis

[0079] The NLR cutoff for neurological symptoms (determined using ROC curve analysis) was 2.4 [area under the curve (AUC) 0.975; 95% confidence interval (CI) 0.960–0.993; sensitivity 92.2%; specificity 94.7%] (Fig. 9).

[0080] Additionally, the NLR cutoff for gastrointestinal symptoms (determined using receiver operating characteristic (ROC) curve analysis) was 3.0 (area under the curve (AUC) 0.747; 95% CI 0.669–0.825; sensitivity 84.1%; specificity 60.5%) (Figure 10). Because all AUCs were less than 0.5, it was impossible to determine cutoffs for the other four symptom categories.

[0081]

[0082] 2.5. Predictive power of NLR for two categories of symptoms in patients initiating hemodialysis

[0083] Multiple logistic regression analysis of neurological and gastrointestinal symptoms revealed that NLR significantly predicted the occurrence of these types of symptoms. For neurological symptoms (Table 2), p < 0.001; odds ratio (OR) 32.030; CI 6.412–160.0), and for gastrointestinal symptoms (Table 3), p < 0.001; OR 1.583; CI 1.298–1.930. However, multiple logistic regression analysis did not identify any factors that significantly predicted the presence of the other four uremic symptom categories (data not shown).

[0084]

[0085] P value*OROR95% confidence interval [CI]Sub-upper age (years)0.1460.9560.9001.016eGFR(ml / min / 1.73m 2)0.210 0.7850.5371.146BUN(mg / dL)0.922 0.998 0.9681.030tCO2 (mmol / L)0.397 1.076 0.9091.274NLR<0.00132.0306.412160.0eGFR: Estimated glomerular filtration rate; BUN: Blood urea nitrogen; NLR: Neutrophil-to-lymphocyte ratio; tCO2: Total CO2.

[0086] P value*OROR95% confidence interval [CI] Lower upper age (years) 0.6960.9950.9731.019eGFR(ml / min / 1.73m 2 )0.5921.0430.8941.217BUN(mg / dL) 0.0660.9880.9751.001tCO2 (mmol / L)0.8850.9950.9301.065NLR<0.0011.5831.2981.930eGFR: Estimated Glomerular Filtration Rate; BUN: Blood Urea Nitrogen; NLR: Neutrophil-Lymphocyte Ratio; tCO2: Total CO2.

Claims

1. A method for providing information for deciding whether to initiate replacement therapy, comprising the step of determining the neutrophil to lymphocyte ratio in a sample isolated from an individual.

2. A method for providing information for determining the initiation of new replacement therapy, according to claim 1, wherein the sample is tissue, whole blood, plasma, serum or blood.

3. A method for providing information for determining whether to initiate renal replacement therapy, further comprising a step of determining whether to initiate renal replacement therapy when the neutrophil to lymphocyte ratio is 3 to 8 in claim 1.

4. A method for providing information for deciding to initiate renal replacement therapy, further comprising a step of determining to initiate renal replacement therapy when the current neutrophil-to-lymphocyte ratio is 1.5 to 5 times higher than the neutrophil-to-lymphocyte ratio 6 months ago, in claim 1.

5. A method for providing information for deciding to initiate renal replacement therapy, wherein the renal replacement therapy according to claim 1 is selected from the group consisting of hemodialysis, peritoneal dialysis, and renal transplantation.

6. A composition for diagnosing end-stage renal disease for determining the initiation of renal replacement therapy, comprising a substance for detecting the ratio of neutrophils to lymphocytes among white blood cells in the blood.

7. A kit for diagnosing end-stage renal disease comprising the composition for diagnosing end-stage renal disease of claim 6.

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