Systemic inflammatory responses and nutritional status are useful prognostic factors in gastric cancer patients. Since oral hypofunction causes undernutrition, we cross-sectionally investigated whether nutritional biomarkers were affected by the occlusal supporting zone status.P = .033, P = .00097, P = .04, respectively; Mann-Whitney U test). PNI values were lower in group C with poor occlusal support zones than in group A with stable occlusal support zones.In 114 gastric cancer patients, the gastric cancer stage, body mass index, albumin levels, total lymphocyte counts, cholesterol levels, C-reactive protein levels, and 4 nutritional biomarkers - the Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio, prognostic nutrition index (PNI), and controlling nutritional status (CONUT) - were evaluated. Oral conditions were assessed by determining the number of remaining teeth. The occlusal supporting status was based on the Eichner classification. Patients were assigned into 3 groups per their occlusal status, and mean values were compared using the Kruskal-Wallis test. The mean age and body mass index were 72.2 ± 8.5 (50-89) years and 22.0 ± 3.6 (14.8-33.4), respectively. There were 42, 39, 23, and 10 patients in stages I, II, III, and IV, respectively. The mean number of remaining teeth was 18.1 ± 9.5. According to the Eichner classification, there were 45, 42, and 27 patients in groups A, B, and C, respectively. The GPS and neutrophil-lymphocyte ratio values and CONUT frequencies between groups A and C were significantly different (Occlusal supporting zone reductions were undernutrition associated. Eichner Class C patients with few occlusal supporting zones had poor GPS, PNI, and CONUT values and were undernourished. The immune and nutritional statuses of patients have been reported to be associated with postoperative outcomes in malignant tumors.-6 The nutritional status of patients with cancer is often evaluated by physical examination and blood biochemical findings such as albumin (ALB). Patients with gastric cancer who are immunocompromised due to pre-operative malnutrition or systemic inflammatory responses often have delayed wound healing, develop complications, and have increased mortality rates.-12 The nutritional status and systemic inflammatory responses in patients with cancer are considered to be useful prognostic factors.-15 Therefore, various biomarkers that reflect the inflammatory state, nutritional status, and immunocompetence of patients have been reported as valuable prognostic factors.-20Gastric cancer is one of the most lethal forms of cancer worldwide, with an estimated 951,600 new cases and 723,100 deaths in 2012. People with chewing difficulties eventually consume less nutritious foods such as vegetables, fruits, meats, and grains.-23 Hence, a decrease in oral cavity function results in a poor pre-operative nutritional status during gastric cancer surgery, with the possibility of an increase in the occurrence of postoperative complications.Pre-operative undernutrition is due to multiple biological, physiological, and pathological factors, one of which is decreased oral function. Oral dysfunction, which causes undernutrition, includes impaired masticatory ability due to tooth loss, dry oral mucosa, and infection. Such conditions affect food choices and result in a reduced quality of life, development of severe complications, and increased mortality rates. A change in food selection is often observed with a decline in masticatory efficiency due to tooth loss and malocclusion.Although there have been studies that investigated how a decrease in the number of teeth and impaired masticatory function affect nutritional status, studies that determine the association between nutritional status before gastrointestinal cancer surgery and oral conditions of patients are few. Currently, it is uncertain whether the intraoral state of the patient affects either blood cells or plasma components, and to determine these effects would require a novel evaluation approach. In the present cross-sectional study, we investigated whether some biomarkers , pre-operative nutritional markers in patients with gastric cancer, would differ according to the occlusal support zone status. From this assessment, we determined how the occlusion support zone status is associated with various biomarkers in the blood.This cross-sectional study enrolled 145 patients who were pathologically diagnosed with primary gastric cancer and underwent a dental examination before surgery at the Nagoya Ekisaikai Hospital between September 2014 and March 2019. Of these patients, 31 who had recurrent cancer, metabolic diseases , or incomplete data were excluded. In the present study, 114 patients (85 men and 29 women) were included.Gastric cancer was diagnosed by consensus among skilled physicians. While assessing gastric cancer, the onset site and cancer stage was determined based on the results of endoscopy, computed tomography, and magnetic resonance imaging performed at the department of gastrointestinal surgery. The body mass index (BMI) of each patient was also calculated. Blood samples were collected on admission, during the pre-surgical examination (within 1 month before surgery). From these blood samples, ALB levels, total lymphocyte counts, and C-reactive protein (CRP) levels were measured. Based on these pre-operative blood test results, the severity of inflammation was assessed.,25 NLR,,27 CONUT,,29 and PNI,,18 as described in Tables We evaluated 4 kinds of nutritional biomarkers. The biomarkers evaluated were GPS,3)]PNI = [10 × serum ALB level (g/dL)] + [0.005 × total peripheral lymphocyte count , mild disorder (2-4), moderate disability (5-8), and severe disability (>8). The Eichner classification is a method used to evaluate occlusion support zone status based on the remaining teeth. The zone is defined as a site supporting occlusion. In a healthy dentition composed of opposing tooth pairs in the right and left premolar and molar regions, occlusion is supported by 4 occlusal supporting zones. The Eichner index categorizes the occlusal status into 3 main groups . The number of remaining teeth and Eichner classification are so objective that they can be regarded as very reliable.Oral conditions were assessed by 2 dentists who were blinded to patients’ nutritional status in the present study. In the oral examination, the remaining teeth excluding residual dental roots were counted, and the occlusal support zone status was assessed according to the Eichner classification.In patients using dentures, their dentures were examined by a dentist. The occlusal supporting zones were assessed for the contact between opposite tooth pairs.2 tests, except when expected cells were found to be less than 5, in which case, Fisher exact test was employed. The Shapiro-Wilk test was used to assess the distribution of pre-operative NLR and PNI values, and the normality was confirmed at a 5% significance level. Because NLR and PNI were not normally distributed (P = .000003493 and .02542), the 3 groups were compared using the Kruskal-Wallis test, which is a non-parametric test. In addition, Steel-Dwass multiple comparison tests were performed to determine which of the 3 groups showed differences in NLR and PNI. All statistical analyses were performed with EZR , which is a graphical user interface for R . More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. Based on the effect size observed in our study, the estimated sample size was 44 patients per group for a total of 88 patients. Sample size estimates were based on the following: standard deviation within groups 5.0, alevel, 0.5 and power of 80%.The number of cases during the study period determined the sample size. We also examined whether the values of the 4 biomarkers differed among the 3 Eichner Classes A, B, and C. We considered whether there was a difference in GPS and CONUT frequencies between the 3 Eichner groups. Categorical data (GPS and CONUT) were analyzed using χThis cross-sectional study was approved by the Nagoya Ekisaikai Hospital Ethics Committee . The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines for reporting observational studies and the Declaration of Helsinki. Informed consent was obtained from the patient for the purpose of publication.None of the markers of systemic and oral conditions was normally distributed. Patients were classified into 3 groups according to the occlusal support zone status based on the Eichner classification to compare each marker. Table P = .01), indicating significant differences among the 3 groups. The ALB levels were 3.9 ± 0.45, 3.68 ± 0.5, and 3.43 ± 0.7 in groups A, B, and C, respectively (P = .002), indicating significant differences among the 3 groups . Even among patients with the same number of remaining teeth, if the number of occlusal supporting zones differs, their nutritional status may be differently affected. Thus, differences in nutritional biomarkers were analyzed according to the Eichner classification. The nutritional biomarkers are shown in Table P = .0179), indicating significant differences among the 3 groups. In addition, multiple comparisons revealed no difference in GPS levels between groups A and B, and between groups B and C , but significant differences were observed between groups A and C (P = .033) (Mann-Whitney U test) , indicating no significant difference among the 3 groups  values were 2.7 ± 1.3, 3.0 ± 1.9, and 4.2 ± 4.8 in groups A, B, and C, respectively (P = .0048), indicating significant differences among the 3 groups. In addition, multiple comparisons revealed no difference in either ALB levels or PNI between groups A and B, and between groups B and C , but significant differences were observed between groups A and C (P = .00097) (Mann-Whitney U test). These results revealed that PNI values were lower in group C with poor occlusal support than in group A with stable occlusal support , indicating significant differences among the 3 groups. In addition, multiple comparisons revealed no difference in GPS levels between groups A and B, and between groups B and C , but significant differences were observed between groups A and C (P = .04) (Mann-Whitney U test) , cell counts , and ratios of these values. Each nutrient rating system has its intrinsic characteristics. There are limitations to the use of a single index; thus, we chose appropriate nutritional indexes and evaluated them based on the disease stage and the therapeutic option employed.In patients with poor pre-operative nutritional status, the relative risks of postoperative complications and in-hospital death are considered to be increased by 2 to 4 folds. Cell-mediated immunity is most affected by undernutrition. Undernourished people exhibit atrophy of the thymus, reduced peripheral T cell counts, reduced CD4/CD8 ratios (CD4 dominant), and atrophy of lymph nodes, spleen, and gut-associated lymphoid tissue, which is the immune tissue of the intestinal tract. Atrophy of gut-associated lymphoid tissue reduces the immunity of the intestinal mucosa and causes gastrointestinal infection. In addition, severe malnutrition reduces immunoglobulin levels. On the other hand, neither neutrophil nor peripheral B lymphocyte count decreases, but the phagocytic capacity, bactericidal capacity, and complement production are reduced. Whereas, the progression of periodontal disease and the presence of dental caries cause odontogenic infectious diseases and an increase in CRP. However, between the 3 Eichner groups, a significant difference was not found in CRP levels. The effect on GPS had little impact on teeth and chronic odontogenic infectious diseases in this examination, while for effect on GPS category, the ALB was thought to be more important. Systemic inflammatory responses are assessed as changes in biochemical data that result from activation of the immune system by the presence of tumors and secretion of IL-6 and other proinflammatory cytokines.-44The GPS was the index reported in non-small lung cell cancer by Macmillan, and the GPS combines CRP and ALB and evaluates blood protein moieties primarily. The GPS has been reported in various cancer studies to be a prognostic marker. The poor prognosis case shows systemic inflammatory such as the GPS Category 2 and 3 and undernutrition. The CRP level of patients with cancer reflects IL-6 levels in the blood, and a persistent increase in IL-6 levels suggests inflammation of the carcinoma tissue. Lymphocytes are used as an indicator of immunity. The lymphocytes are related to tumor immunity and act for a tumor restrainingly.,47 Whereas neutrophils increase due to inflammation and induce the production of chemokines and cytokine, the produced chemokines and cytokines enhance the growth, invasion, and neovascularization of tumors. Therefore, tumor growth is closely associated with inflammation.,49 NLR, which evaluates CRP and ALB ratios, is reported as an oncological prognostic marker similar to GPS. A significant difference was not found in this examination between the 3 Eichner groups. NLR is considered to mirror a balance between the innate and adaptive immune mechanisms. The NLR can reflect the initial innate immune mechanisms (involving cells such as neutrophils and macrophages that provide a non-specific response), which triggers the adaptive immune mechanisms  that result in periodontal destruction. In cases of high NLR values, periodontitis becomes more severe. It is reported that NLR is useful for clinical evaluations of periodontitis. A mouth cleaning state is good in Eichiner A where many residual teeth are present in, and the inflammatory reaction is poor. Additionally, there is no effect as we raise CRP because Eichner C has few residual teeth causing odontogenic infectious diseases. The difference was not found in such a situation. Whereas there are many patients that a lot of residual teeth have a good mouth cleaning state in Eichner A. Also, Eichner C has few residual teeth and does not reach it before we greatly change CRP even if periodontal disease is severe because there are few teeth causing inflammation. A difference was not found in such a situation. PNI and CONUT are indexes that are dependent on the evaluation of lymphocyte counts, ALB, and cholesterol. It has been reported that it has a poor prognosis in a low level of PNI and the extensive malnutrition category of CONUT. The lymphocytes have antitumor immunity eligibility. The lymphocytes commit a tumor restrainingly and have antitumor immunocompetence. The half-life in the blood of cholesterol 8 days, shorter than 21 days for ALB, and reflects malnutrition subtly.-23,50 Significant differences were found between the 3 groups and PNI and CONUT proved to the more reflective of undernutrition in group C than in group A. Wakai et al reported that as the number of teeth decreases, people consume fewer vegetables but their total calorie intake increases with an increase in the consumption of carbohydrate such as rice, and other confectionaries. If the occlusion status is poor, carbohydrates and glucose play key dietary roles. Simultaneously, there is a reduced intake of neutral fat or proteins. As a result, these indexes are thought to worsen.NLR is a nutrient rating system using blood cells (neutrophils and lymphocytes). Lymphocytes have been used as one of the nutritional evaluation indexes for a long time. It was impossible to control all of these potential variables in the present study. Furthermore, to determine whether dentures functioned well, factors that can influence outcomes such as the levels of technical skills of dentists, designs of dentures, the difficulty of cases, skills of dental technicians who fabricate dentures, perfection levels of dentures, and the actual use of dentures, should be assessed. However, there are no standardized methods to assess these factors, and only a few studies have reported the evaluation of these factors. These factors should be assessed in future studies. Because the present study is a cross-sectional study, no causal relationship could be determined. Thus, we cannot state that the number of teeth or occlusal status directly affects nutritional status. Our results are based on the experience with a small number of patients at single institution. Therefore, the generality of our findings are proven for more further studies.The present study has several limitations. Nutritional status is affected by many factors. This study was conducted as a retrospective, exploratory observational study of single center. There are many complex factors that influence the nutritional status of occlusion. In order to better understand its manifestation, more cases need to be accumulated. It is difficult to recognize the causes of changes in masticatory function in the elderly. These changes may be caused by aging, sensory or physiological changes, disease, or drug-related processes. The biomarkers examined in this study are calculated based on the measurement of ALB levels and blood cell counts. They are decreased by dehydration, increased vascular permeability associated with vascular endothelial damage and systemic inflammation, and liver dysfunction. Chemotherapy can also affect nutritional biomarkers by decreasing ALB levels and blood cell counts associated with drug toxicity. The biomarkers are likely to be frequently variable, when patients do pre-operative chemotherapy or those with severe inflammation or autoimmune diseases. We should be consider carefully about the patients. In addition to oral findings such as prosthodontic treatment with dentures and conditions of the remaining teeth, other factors including socioeconomic strata, income levels, and acquired behavioral patterns are also very important.An early transition to oral intake is essential in the treatment of gastric cancer. The reasons for this are not only that oral intake is the best enteral nutrition, but also that eating through the mouth is an important activity, which is associated with human dignity and affects quality of life. In addition to the problems of undernutrition, prolonged lack of oral intake leads to a disuse hypofunction of the eating and swallowing muscles. Thus, a delayed start of oral intake due to complications, such as postoperative ruptured suture, should be avoided, and efforts should be made to precisely diagnose and improve pre-operative undernutrition. Given the importance of the function of the remaining teeth for nutrient intake and the unduly significant effects of impaired masticatory function on nutritional status, dentists and dental hygienists in a nutrition support team play an important role in maintaining and improving oral function, which is important for nutrient intake. For example, the oral cavity should be kept clean, and the periodontal condition should be maintained. In addition, patients with occlusal disharmony may be undernourished, as an underlying condition, even if they are satisfied with denture use. Thus, occlusal disharmony is suggested to be a possible factor for the consideration of preoperative nutritional supplementation. Based on this study, there are 2 conclusions that can be drawn regarding malnutrition and inflammation in patients with gastric cancer patients with oral health conditions: There are direct effects of occlusal abnormalities on dietary intake, and there is indirect action of systemic inflammatory conditions such as odontogenic infectious diseases on acute protein synthesis.Further studies on oral health and its role in malnutrition and inflammation are warranted. A long-term prospective study and intervention study are necessary to completely evaluate the association among systemic inflammation in oral health, malnutrition, and gastric cancer. Patients with gastric cancer who are eligible for surgery need to undergo a variety of screening tests. One of them includes dental evaluation. Pre-operative dental examinations are one of the most important tests to assess nutritional status. The pre-operative oral evaluation should assess the occlusal status in addition to the oral cleaning status, presence of moving teeth, and prevent postoperative pneumonia. For patients with poor occlusion, it is necessary to re-evaluate nutritional management, consult with nurses, physicians in charge, and dietitians, and if necessary, consider requesting Nutrition Support Team intervention.The association between the nutritional biomarkers and dental conditions of patients with gastric cancer with different occlusal statuses was examined. Decreases in the occlusal supporting zones were correlated with undernutrition. Patients with fewer occlusal supporting zones had lower ALB levels and PNI, and GPS and CONUT levels were found to be reduced in undernourished patients. The Eichner C group was inferior to other groups in GPS, PNI, and CONUT. The occlusion status affects humoral ingredients such as ALB. This study emphasizes an important role of oral health in improving malnutrition in gastric cancer. Furthermore, it shows that it predicts the decrease of a nutrient in gastric cancer and the caloric intake that the oral cavity appearing by the loss of teeth is in bad health. Furthermore, oral functional decline due to the tooth missing shows that we predict a decrease in the nutrition of patients with gastric cancer and systemic inflammatory reaction.We would like to thank Editage Science Communications for English language editing and publication support.Conceptualization: Atsushi Abe.Data curation: Moeko Momokita.Formal analysis: Hiroaki Hsegawa.Investigation: Akari Tsunoda.Methodology: Atsushi Abe, Atsushi Nakayama.Project administration: Atsushi Abe.Resources: Hiroki Hayashi, Atsushi Nakayama.Supervision: Hiroshi Furuta.Validation: Yu Ito.Visualization: Hiroaki Hsegawa.Writing - original draft: Atsushi Abe.Writing - review & editing: Atsushi Abe.


The National Kidney Foundation recently proposed a ≥ 30% decrease in urinary albumin–to–creatinine ratio (UACR) over 0.5–2 years as a surrogate endpoint for chronic kidney disease (CKD) progression in individuals with baseline UACR > 30 mg/g. This historical cohort study aimed to determine the applicability of a decrease in UACR, within as little as 1 year, as a surrogate endpoint for Japanese individuals with type 2 diabetes mellitus (T2D).A total of 5067 individuals with T2D were divided into three groups based on 1-year change in UACR: ≥ 30% decrease (UACR decreased group), < 30% decrease and < 30% increase (UACR unchanged group), or ≥ 30% increase (UACR increased group). The primary endpoint was a composite of a ≥ 30% decline in estimated glomerular filtration rate (eGFR) or the initiation of kidney replacement therapy, whichever occurred first.2 were 68.1%, 22.1%, and 75.5%, respectively. During a median follow-up of 6.8 years, 926 individuals (18.3%) reached the composite endpoint. Adjusted hazard ratios (vs. the UACR unchanged group) for the UACR decreased and increased groups were 0.758  and 1.304 , respectively.At baseline, the proportions of individuals with normoalbuminuria, microalbuminuria, and eGFR ≥ 60 mL/min/1.73 mThese findings support the use of 1-year changes in UACR as a surrogate endpoint for the progression of CKD and the implementation of a ≥ 30% decrease in UACR as a positive efficacy endpoint in Japanese individuals with T2D and early-stage kidney disease. Urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are essential for the diagnosis and staging of chronic kidney disease (CKD). We previously reported that a higher UACR at baseline was associated with a faster decline in subsequent eGFR in a historical cohort study of 5449 Japanese individuals with diabetes . In a moHowever, the NKF meta-analyses included limited data from the Japanese population, necessitating further investigation to determine the applicability of these recommendations to the Japanese context. In our very recent study , we repoThis single-center historical cohort study was designed in adherence to the tenets of the Declaration of Helsinki. The Ethics Committee of Tokyo Women’s Medical University approved the protocol , waiving the need for informed consent as this was a historical cohort study rather than a prospective interventional study. All participants were provided with the option to opt out through the website of Tokyo Women’s Medical University.n = 48), malignant diseases (n = 152), history of unilateral nephrectomy (n = 7), biopsy-proven diagnosis of non-diabetic kidney disease (n = 2), and acute kidney injury or post-renal failure (n = 2). We also excluded 3344 individuals who had no UACR measurement between 0.5 and 1.5 years after the index date (n = 3100), experienced a kidney outcome within 1 year after the index date (n = 181), had no serum creatinine measurements ≥ 1 year after the index date (n = 56), and had missing data on smoking status or height at the index date (n = 7). If multiple UACR measurements were available between 0.5 and 1.5 years after the index date, we selected the measurement closest to 1 year. Ultimately, 5067 individuals were eligible for inclusion in this study. Among them, 3497 individuals (69.0%) were also subjects in our recent cohort study examining the association between 3-year changes in UACR and the subsequent composite outcome of eGFR halving or initiation of KRT, and their index dates coincided with those in the present study [Initially, individuals with T2D who visited the Diabetes Center of Tokyo Women’s Medical University from August 1, 2003 to January 31, 2017, were identified from the hospital database and electronic medical charts. Among these, we included a total of 8,622 individuals who were aged ≥ 18 years, had not undergone kidney replacement therapy (KRT), and had measurements of body mass index, blood pressure, glycated hemoglobin (HbA1c), lipid parameters, serum creatinine, and UACR all obtained on the same day. If multiple measurements for variables were available within the study period, the earliest measurement was designated as the index date. We excluded individuals with the following conditions at the index date: pregnancy  = 194 × age (years)−0.287 × serum creatinine level (mg/dL)−1.094 × 0.739 , as proposed by the Japanese Society of Nephrology [The first morning urine was used to measure UACR. eGFR was calculated using the following formula: eGFR . Continuous data are expressed as arithmetic mean ± standard deviation or median and interquartile range (IQR), as appropriate. Categorical data are expressed as number (%). A two-tailed 2-transformed change in UACR modeled using the multivariable-adjusted restricted cubic spline function, where four knots were placed at the 5th, 35th, 65th, and 95th percentile levels. The following 14 variables were incorporated as covariates in the model: sex, age, presence of cardiovascular diseases, smoking history (current or ever), use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, body mass index, systolic and diastolic blood pressure, HbA1c, triglycerides (log-transformed), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, eGFR, and UACR (log-transformed) at the index date.The cumulative incidence function and the multivariable Fine and Gray subdistribution hazard model were used, considering death as a competing event . Change 2, respectively. The median UACR was 13.5 mg/g (IQR 6.7–47.5 mg/g). Among the participants, 75.5% had eGFR ≥ 60 mL/min/1.73 m2. The proportions of individuals with normoalbuminuria and microalbuminuria were 68.1% and 22.1%, respectively.The baseline characteristics of the 5,067 individuals at the index date are shown in Table During a median observation period of 1.02 years (IQR 0.88–1.17 years), 1313 individuals experienced a decrease in UACR (the UACR decreased group), 2061 individuals had unchanged UACR (the UACR unchanged group), and 1693 individuals had an increase in UACR (the UACR increased group). Other clinical characteristics and the main laboratory data for each UACR group are also summarized in Table During a median follow-up of 6.8 years (IQR 3.6–10.7 years), 926 individuals (18.3%) reached the composite kidney event endpoint, including 908 who experienced a ≥ 30% decline in eGFR and 18 who initiated KRT ; that for the UACR increased group was 1.304  (Table The adjusted hazard ratio (HR) for the composite kidney event in the UACR decreased group versus the UACR unchanged group was 0.758 (95% CI, 0.636–0.905; Similar trends to those of the overall analysis were observed in the sensitivity analysis of 1117 individuals with microalbuminuria.The association of UACR fold change with the composite kidney event outcome was generally linear Fig. A. On theWhen individuals were classified according to baseline albuminuria, the incidence of composite kidney events in the UACR decreased individuals was lower than that in the UACR increased individuals in all the three groups classified Fig. .Fig. 5DiThe results of the current cohort study not only confirmed our recently published data but also provide additional findings demonstrating a positive correlation between a decrease in UACR and kidney events—even over a shorter timeframe of approximately 1 year. The findings suggest that changes in UACR over 1 year can be used as a reliable surrogate marker for evaluating the efficacy of interventions in this population. Consistent results were observed when analyzing a subgroup of participants exhibiting microalbuminuria, indicating the robustness of the trend.Traditionally, initiation of KRT and doubling of serum creatinine levels have been established as efficacy endpoints in clinical studies involving individuals with CKD. However, these endpoints generally require long-term observation and large sample sizes, limiting eligibility to individuals with late-stage CKD. Recently, the Scientific Workshop sponsored by the NKF proposed a ≥ 30% or a ≥ 40% decline in eGFR as an efficacy endpoint in addition to the conventional kidney events . A similThe initiation of interventional therapy for individuals with early-stage CKD is believed to be more efficient in ensuring the prevention or delay of the transition to end-stage kidney disease. The establishment of surrogate endpoints specifically targeting this population is thus urgently required. To address this, the workshop sponsored by the NKF performed meta-analyses using cohorts and interventional studies, aiming to identify alternative efficacy endpoints applicable to clinical studies involving individuals with early-stage CKD , 6. TheiIn our recent study , we demo2/year over 2–3 years was also associated with a reduced risk of subsequent kidney events. This suggests that the reduction in eGFR slope could serve as a positive efficacy endpoint [2/year, which is less than the minimum threshold of eGFR slope recommended by the NKF workshop. Given these observations from the finerenone study, caution is required when using eGFR slope as an efficacy endpoint if the early decline in eGFR caused by medications is included in the assessment.Further analyses from the NKF workshop demonstrated that a reduction in eGFR slope by 0.5–1.0 mL/min/1.73 mendpoint , 17. It endpoint –20. Consendpoint , 21–24. endpoint . SubsequThis study has several limitations that should be acknowledged. First, the findings may have limited generalizability to all Japanese individuals with T2D, as the study was conducted at a single center, introducing selection bias. Therefore, caution should be exercised when extrapolating the results to other populations. Second, the lack of information on medication use, including SGLT2 inhibitors and MRAs during both the baseline UACR observation period and subsequent follow-up period, is a notable limitation. These medications could potentially have had an impact on the observed results. Third, UACR values at the index date and end of the observation period were determined based on a single measurement, which may have led to improper categorization because of the day-to-day variability in albumin excretion , 25. WhiThis historical cohort study, conducted in Japanese individuals with T2D, provides evidence that changes in UACR over a period of approximately 1 year were significantly associated with a long-term kidney prognosis, i.e., a composite of ≥ 30% decline in eGFR and KRT initiation, independently of clinical parameters including baseline UACR and other clinical characteristics. These findings support the use of the change in UACR over a 1-year period as a surrogate endpoint for assessing kidney events in clinical studies involving individuals with early-stage CKD and diabetes. Furthermore, the results support the recommendation of a ≥ 30% decrease in UACR as a positive efficacy endpoint for evaluating interventions in Japanese individuals with T2D and early-stage CKD.


Atrial fibrillation (AF) is prevalent in individuals with essential hypertension (HTN). Masked hypertension occurs in up to 15% of the general population and is associated with adverse clinical outcome. The aim of the current study was to evaluate the prevalence of masked hypertension in apparently normotensive individuals with lone AF. A cross sectional analytical study performed at the Rabin Medical Center included all patients > 18 years who visited the emergency department (ED) in the years 2018–2021 with idiopathic AF, had normal blood pressure (BP) values during their ED visit and did not have a history of hypertension or current use of anti-hypertensives. Ambulatory blood pressure monitoring (ABPM) was performed in all eligible patients within 30 days from ED visit. Data collected included information from the ED visit and data extracted from the monitoring device. A total of 1258 patients were screened for eligibility, of which 40 were included in the analysis. The average age was 53.4 ± 16 years, 28 patients (70%) were males. Overall, 18 individuals (46%) had abnormal BP values according to the 2017 ACC/AHA guidelines for the diagnosis of hypertension. Of these, 12 had abnormal 24-h BP average (≥ 125/75 mmHg), one had isolated daytime abnormal average (≥ 130/80 mmHg) and 11 had isolated night time abnormal average (≥ 110/65 mmHg). Masked hypertension is prevalent in patients with lone AF without a diagnosis of HTN and performing ABPM in such individuals should be strongly considered. Masked hypertension is a condition in which blood pressure is within normal limits during office measurements but is elevated on ambulatory blood pressure monitoring. This condition is reported to occur in up to 30% of hypertensives7 and is associated with similar adverse clinical outcomes as hypertension diagnosed on office measurements10. Masked hypertension has been reported to affect atrial remodeling11 but its association with the occurrence of atrial fibrillation has not been reported. Although the reliability of ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension in patients with AF has been questioned12, it is still a legitimate method for diagnosing hypertension in patients with AF. The prevalence of masked hypertension in the general population is about 10–15%13. Different studies have found that the prevalence is similar in different populations. In the American population the estimated prevalence of masked hypertension in the years 2005–2010 was 12.3%6. In Israel a study published in 2005 reported 11% prevalence of masked hypertension14.Atrial fibrillation (AF) is prevalent in individuals with essential hypertensionThe aim of the current study is to evaluate the prevalence of masked hypertension in individuals with lone AF in order to determine whether an active search for masked hypertension should be performed in those with lone AF.This study was a cross sectional analytical study, single center, non-interventional study performed in the Rabin Medical Center emergency department (ED), one of the largest ED in Israel.Patients > 18 years old with lone AF who presented to the Beilinson hospital emergency department (ED) from March 2018 to June 2021 were identified. All patients with a previous diagnosis of hypertension were excluded as well as patients chronically treated with anti-hypertensive medications such as Angiotensin-converting-enzyme inhibitors (ACEi), Angiotensin receptor blockers (ARBs), diuretics, nitrates, alpha and beta blockers and other drugs that may affect blood pressure.Patients in which BP measurements were higher than 140/90 mmHg (or stage 2 hypertension based on the ACC/AHA guideline) during the ED visits were excluded. We chose to include individuals with BP 130/80–140/90 mm Hg given that non-office-based measurement may reasonably be higher in the ED. However, in addition to the main analysis, we also performed an additional analysis in which patients with stage 1 hypertension were also excluded.Blood pressure measurement in the emergency department was performed using PHILIPS SureSigns VSi blood pressure monitoring device, which is an automatic electronic device.The diagnosis of AF was based on 12-lead ECG performed in the emergency department (ED). Lone AF was defined as AF without structural heart disease or other condition triggering the event, and therefore patients with AF attributable to cardiac disease, pulmonary disease, metabolic/endocrine conditions, medications, substance abuse, anemia, alcohol, electrolyte abnormalities or acid/base disorders were excluded. Pregnant women were also excluded and patients who were treated for AF in the ED with agents such as calcium channel blockers or beta blockers  were excluded due to the possible effect of these medications on BP values. Patients treated with antiarrhythmic therapy during the ED visit, which included mainly amiodarone and propafenone were included.15 during the ABPM examination.Patients who fulfilled eligibility criteria underwent 24-h ambulatory blood pressure monitoring (ABPM) within 30 days from ED visit, regardless of the decision to hospitalize or discharge the patient. The monitoring was performed using Oscar 2™ Ambulatory Blood Pressure Monitor from SunTech Medical®. Prior to the examination, a resting ECG was performed in all patients. If elevated BP values was identified, the primary care physician was notified to continue follow-up and treatment accordingly. From the screening process until the 24 h ABPM examination the patient continued to take his regular medications as well as medication prescribed due to the new diagnosis of AF (e.g. anticoagulants). The study information was collected from different sources such as the medical records, the hospital visit during the connection to the device and from extraction of the output of the “Holter” examination. The data collected included information from the admission such as demographic variables, co-morbidities, vital signs, ECG results, symptoms and laboratory on admission, medications, hospitalization or discharge information and the medications prescribed for the treatment of AF. The data regarding the 24 h ABPM output was 24 h, daytime and nighttime blood pressure measurements, duration of examination, symptoms during the examination and any special activity of the patient during the test. The definition of masked hypertension in this study was any abnormal blood pressure measurement according to the 2017 ACC/AHA guidelines for the diagnosis of hypertensionFurthermore, as part of the ABPM examination, a calculation of %dipping was performed, and was defined as the proportional reduction in nighttime BP compared with daytime BP. Non-dippers were patients whose BP failed to decrease by at least 10% during sleep. A calculation of systolic and diastolic BP load during 24 h, daytime and nighttime, defined as the proportion of time that the systolic and diastolic BP were elevated respectively, was also performed. Morning surge was defined as the difference between the nighttime BP and the mean early morning BPs. Abnormal morning surge was considered above 23 mmHg.All patients’ data were anonymized following data collection to prevent possible identification of the patients whose medical records were reviewed. The study was approved by the Rabin Medical Center institutional review board and all methods were performed in accordance with the relevant guidelines and regulations. All the participants provided written informed consent.The prevalence of masked hypertension in the study population was compared with the known prevalence of masked hypertension in the general population in Israel. Another goal of this study was to compare patients with AF and masked hypertension and patients with AF without masked hypertension, in order to characterize the clinical and demographic parameters of patients with AF and risk of masked hypertension.In addition, all patients were followed for 1 year following performance of the 24 h ABPM for any new diagnoses of hypertension or hospitalization. Diagnosis of hypertension were usually based on clinic and home measuring of blood pressure.Blinding is not relevant in this type of study and since the study is not interventional there are no adverse effects expected.The statistical analysis for this paper was generated using SAS Software, Version 9.4. Continuous variables were presented by Mean ± Std, Categorical variables were presented by . Normality of continuous variables was assessed graphically. T Test was used to compare the value of normally distributed continuous variables between study groups, Wilcoxon was used for non-normal continuous variables and Fisher’s exact was used to compare the value of categorical variables between study groups. In addition to the main analysis, we made a stratification analysis according to BMI above 25 and MBI 25 or lower. A multivariable analysis was constructed according to univariable analysis by entering variables that were statistically significant in the univariable analysis, as well as age and gender. Two-sided p values less than 0.05 were considered statistically significant.A total of 1258 patients were screened for eligibility. Of them, 1218 patients were excluded and the reasons for exclusion are presented in Fig. The baseline characteristics of the study cohort excluding patients with BP > 130/80 mmHg on admission is presented in Table 15. Of these, 12 patients (31%) had abnormal 24-h BP average (≥ 125/75 mmHg), one patient (3%) had isolated daytime abnormal average (≥ 130/80 mmHg), 11 patients (28%) had isolated night time abnormal average (≥ 110/65 mmHg) and six patients (15%) had combined day time & night time abnormal average. 21/39 patients were normotensives (53.8%). In the analysis excluding patients with BP > 130/80 mmHg during the ED visit based on the ACC/AHA guideline, 8/25 patients (32%) were diagnosed with masked hypertension. To note that also according to the mitigating criteria of the 2018 ESC/ESH guidelines for the management of arterial hypertension13, the prevalence of masked HTN in our total cohort was high and was found in 11 patients (28.2%).From extraction of the 24 h ABPM examination, 18 individuals (46.2%) had abnormal BP values according to the 2017 ACC/AHA guidelines for the diagnosis of hypertensionNon-dipping and blood pressure load are present in Table From the total cohort, 15 patients 38%) were non-dippers, 12 patients (31%) were extreme dippers, one patient (3%) was a reverse dipper, and only 10 patients (26%) were normal dippers. Unfortunately, to one patient the data regarding dipping was missing. From the normal dippers, three patients had a diagnosis of masked HTN and the rest were normotensives. The median of nighttime systolic blood pressure load was 26% and 6% in the hypertensive and normotensive groups respectively, P < 0.001  had a BMI greater than 25. Of them, 14 individuals (66%) had masked HTN and 7 patients (33%) were normotensives, P = 0.01. These results are present in Table 4% had a In a multivariable analysis for age, gender and body mass index, only high BMI was associated with the risk for masked hypertension, HR of 1.45 (CI of 1.09–1.93) Table .Table 6MAfter a follow-up period of 1 year, five patients in the masked HTN group had a confirmed diagnosis of hypertension compared to no patients in the normotensives group, P = 0.03. In the cohort of patients excluding patients with BP > 130/80 mmHg on admission, two patients in the masked HTN group had a confirmed diagnosis of hypertension after 1 year, compared to no patients in the normotensives group, P = 0.08.The prevalence of masked hypertension in our cohort of patients with lone AF and without a diagnosis of hypertension was 46.2%. This prevalence is significantly higher than the figures previously reported and is true for both the 2017 ACC/AHA and the 2018 ESC/ESH guidelines for the management of arterial hypertension.The decision to include BP values in the range of 130/80–140/90 mmHg (excluding stage 2 hypertension according to the ACC/AHA guideline) in the main analysis was based on the assumption that non-office-based measurement may reasonably be higher in the ED and according to all guidelines, hypertension is usually diagnosed based on several elevated BP measurements and an elevated BP on a single occasion, particularly during visit to ED, cannot be used to diagnose this condition. Furthermore, often, patients with mildly elevated BP values during the ED visit (130/80–140/90 mmHg) are not followed-up as these elevated values are attributed to the stressful situation of being in the ED. Although this was not the purpose of the study, we do believe that continued follow-up of these patients is essential particularly in those with atrial fibrillation. The high prevalence of masked hypertension even after excluding patients with stage 1 hypertension during the ED visit (32%) serves as additional evidence for the importance of performing ABPM to all patients with atrial fibrillation, even when BP values are entirely within normal limits even under stressful conditions, such as during an ED visit.16. Another study evaluated patients aged ≥ 75 years with non-valvular AF and found that masked uncontrolled morning hypertension was very prevalent in these patients17.Interestingly, a recently published study examining the risk of new-onset AF in patients with masked uncontrolled hypertension found that the risk is approximately doubled for patients with controlled HTN18. Given the high prevalence of masked hypertension in our population of patients with lone AF without a diagnosis of HTN, we believe that ABPM in such individuals should be strongly considered, for identification and early treatment of HTN. Early diagnosis of hypertension may significantly diminish cardiovascular risk, as has been shown in several previous studies19. Since masked hypertension is difficult to diagnose and since it is impractical to perform ABPM to the entire population, it is crucial to identify populations at risk for this condition, in which ABPM is cost-effective. The fact that masked hypertension was extremely prevalent in individuals with atrial fibrillation in our cohort may serve as preliminary evidence for performing ABPM in all individuals with AF. It seems that AF is prevalent in patients with masked hypertension due to the fact that elevated BP leads to left ventricular hypertrophy, left atrial enlargement and this probably increases the risk of atrial arrythmias. This has been previously reported for patients with overt hypertension21 and therefore it is not surprising that it would be true for patients with masked hypertension.ABPM is an important diagnostic tool for the diagnosis of masked hypertension in the general population and it is also a useful tool for follow-up of treated patients22, that assessed ambulatory blood pressure in 4121 subjects and found that masked hypertension was more common according to the awake-sleep blood pressure method.In our cohort, 41% had abnormal night-time BP average. This finding of abnormal nocturnal BP among masked hypertensives is consistent with another study from Israel23. Non-dipping is the failure of BP to drop during sleep by at least 10 percent and it is associated with risk for development of heart failure, stroke and cardiovascular complications28, and with the risk of progression of nephropathy among patients with diabetes and with decline in renal function among patients with chronic kidney disease32. Moreover, in our cohort, only 26% of individuals were normal dippers. Finally, 37% of the patients in our cohort had abnormal morning surge, which was found to be associated with adverse cardiovascular outcome in elderly dippers33.In our cohort, a very high rate of non-dippers was found (38%). According to the literature, normal BP fall between daytime and the nighttime is approximately 15 percentIn a sub-analysis according to BMI, an association was found between masked HTN and overweight. Overall, 66% of patients with BMI above 25 had masked HTN, P = 0.01. Also according to multivariable analysis for age, gender and body mass index, only high BMI was associated with the risk for masked hypertension. Therefore, it seems that ABPM is especially warranted to individuals with AF who also have BMI > 25, in which masked hypertension is particularly common.34. Young healthy males are expected to benefit significantly from the identification of masked hypertension as they have a long-life expectancy. Thus, the occurrence of AF in such individuals should alert the clinician to the possibility of masked hypertension, as identification of this condition in young healthy adults would be expected to significantly improve cardiovascular outcomes if BP would be identified and treated appropriately. It is important to note that in our cohort, comorbidities were equally prevalent in those with and without masked hypertension. This in contrast to previous studies in which masked hypertension was more prevalent in individuals with diabetes mellitus30, chronic kidney disease31 and obstructive sleep apnea35. This highlights the fact that ABPM should be performed in patients with AF, irrespective of comorbidities.In our cohort, the average age was relatively young, and most individuals were males without comorbidities. These findings are consistent with previous studies in which masked hypertension was more common among males36.This study has several limitations. The first is the small sample size, which is due to the strict criteria used for screening and exclusion of patients who were discharged from the ED with beta blockers or calcium channel blockers, which was the main reason for exclusion. In our opinion, it was crucial to exclude such individuals because these medications may have caused a decrease in BP, leading to misidentification of these patients as normotensive. It is evident that it is difficult to identify patients according to our strict exclusion criteria but it seems that the large percentage of patients who had masked hypertension should not be influenced from the sample size. A second limitation stems from a selection bias and the homogeny of the study population. Only patients with lone AF without a diagnosis of hypertension were included and therefore the conclusions of this manuscript apply to this population. Yet, considering the large number of patients diagnosed with masked hypertension, it would be logical to assume that older individuals with more comorbidities would have a higher prevalence of masked hypertension. Additional limitation is that BP measurements in the ED were made using automated BP measurement technique, rather than auscultatory methods, which are considered more precise and are the preferred method for measuring blood pressure in patients with AF. Since most BP measurements performed in the ED are performed using automated BP devices, we believe that this information represents real world data by which patients with masked hypertension will be identified in the ED. In addition, several studies have already validated the reliability of BP monitoring devices in individuals with AFThis study has clinical significance because it is one of the first studies to evaluate the prevalence of masked hypertension in patients with AF. The results certainly support performing ABPM to all patients with new onset AF, irrespective of comorbidities. Whether early identification and treatment of masked hypertension in these patients will lead to improved cardiovascular outcomes, requires long-term large-scale studies.