Guidelines for clinical evaluation of chronic kidney disease in early stages : AMED research on regulatory science of pharmaceuticals and medical devices.

BACKGROUND: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5-1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. METHODS: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. RESULTS: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. CONCLUSION: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors.

Interpretations of SARS-CoV-2 IgM and IgG antibody titers in the seroepidemiological study of asymptomatic healthy volunteers.

INTRODUCTION: The usefulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests in asymptomatic individuals has not been well validated, although they have satisfied sensitivity and specificity in symptomatic patients. In this study, we investigated the significance of IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects. METHODS: From June 2020, we recruited 10,039 participants to the project named the University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS), and measured iFlash-SARS-CoV-2 IgM and IgG (YHLO IgM and IgG) titers in the collected serum. For the samples with increased IgM or IgG titers, we performed additional measurements using Elecsys Anti-SARS-CoV-2 Ig (Roche total Ig) and Architect SARS-CoV-2 IgG (Abbott IgG) and investigated the reactivity to N, S1, and receptor binding domain (RBD) proteins. RESULTS: After setting the cutoff value at 5 AU/mL, 61 (0.61%) were positive for YHLO IgM and 104 (1.04%) for YHLO IgG. Few samples with elevated YHLO IgM showed reactivity to S1 or RBD proteins, and IgG titers did not increase during the follow-up in any samples. The samples with elevated YHLO IgG consisted of two groups: one reacted to S1 or RBD proteins and the other did not, which was reflected in the results of Roche total Ig. CONCLUSIONS: In SARS-CoV-2 seroepidemiological studies of asymptomatic participants, sufficient attention should be given to the interpretation of the results of YHLO IgM and IgG, and the combined use of YHLO IgG and Roche total Ig might be more reliable.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)-related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non-haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients. METHODS: The study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phase 5 (2012-2015). The outcome was erythropoiesis-stimulating agent hyporesponsiveness (ESA-hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA-hypo and FGF23 was estimated using multivariable-adjusted logistic generalized estimating equation regression models. RESULTS: Patients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin-corrected calcium, phosphorus, PTH, 25(OH)-vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA-hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA-hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively. CONCLUSION: The lowest and highest levels of FGF23 were associated with higher odds of ESA-hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA-hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Diagnostic accuracy of urine dipstick for proteinuria category in Japanese workers.

BACKGROUND: Urine dipstick tests are often used to evaluate proteinuria during health checkups. We examined the dipstick's accuracy in assessing the proteinuria levels among Japanese workers. METHODS: We assessed subjects aged ≥ 18 years who had a health checkup at the University of Tokyo in 2016 or 2017 (n = 5383). Proteinuria was stratified by urine protein-to-creatinine ratio (PCR): A1, < 150 mg/gCre; A2, 150-499 mg/gCre; and A3, ≥ 500 mg/gCre. The accuracy of a dipstick result of ± or higher to detect a PCR level of ≥ A2 was examined. We compared changes in dipstick results and PCR level in 136 subjects evaluated twice with a median interval of 119 days. RESULTS: The subjects' mean age was 40 years, and half were women. The dipstick results were - in 94.9%, ± in 4.1%, and ≥ 1 + in 1.0%. The PCR level was A1, A2, A3 in 98.6%, 1.2%, and 0.2% of the subjects, respectively. The sensitivity, specificity, and positive and negative predictive values of a ± or higher dipstick result to detect A2 or higher were 66.2%, 95.6%, 17.5%, and 99.5%, respectively. Among the 136 subjects examined twice, 134 (98.5%) had no change in PCR level (A1 in all cases) despite a decrease or increase in dipstick results. CONCLUSION: Urine dipstick results of ± or above had a high specificity but low sensitivity and positive predictive value to detect PCR proteinuria of A2 or higher. Confirmation by quantitative protein measurement should be recommended for individuals at high risk of chronic kidney disease.

Comparison between the clinical characteristics of patients with adrenal incidentalomas and those with hypertension-associated adrenal tumors in a single center in Japan.

In the largest retrospective study of adrenal incidentalomas (AIs) in Japan between 1999 and 2004, adrenal tumors detected during secondary hypertension (HT) screening were included. The characteristics of patients with adrenal tumors detected during HT screening may differ from those of patients with AIs. This study aimed to compare the characteristics of patients with AIs with those of patients with adrenal tumors detected during HT screening. We retrospectively analyzed patients referred to our division for detailed examination of adrenal tumors between April 2009 and April 2017. When the purposes of imaging tests included HT screening, we defined adrenal tumors as HT associated, otherwise as strictly defined AIs. We reviewed data on age, sex, purpose and modality of imaging, location of tumor, tumor diameter, and hormonal evaluation. We identified 104 patients with HT-associated adrenal tumors and 413 with AIs. Patients with HT-associated adrenal tumors were younger (54.2 years vs. 61.7 years, p < 0.001) and had smaller tumor diameters (1.3 cm vs. 1.9 cm, p < 0.001), lower prevalence of nonfunctioning tumors (24.0% vs. 67.6%, p < 0.001), and higher prevalence of primary aldosteronism (58.7% vs. 4.8%, p < 0.001) than those with AIs. There were no differences in terms of tumor location and prevalence of subclinical Cushing's syndrome, Cushing's syndrome, and pheochromocytoma (18.3% vs. 16.0%, 7.7% vs. 8.0%, and 2.9% vs. 4.6%, respectively). In conclusion, patients with HT-associated tumors were younger and had a smaller tumor with higher prevalence of primary aldosteronism than those with AIs.

Serum total iron-binding capacity and iron status in patients with non-dialysis-dependent chronic kidney disease: A cross-sectional study in Vietnam.

BACKGROUND AND OBJECTIVES: We performed this study to evaluate serum iron and ferritin concentrations, serum total iron-binding capacity (TIBC), and proportion of overall iron deficiency among patients with non-dialysisdependent chronic kidney disease (ND-CKD). METHODS AND STUDY DESIGN: A hospital-based cross-sectional observational study was conducted on 175 adult patients with stage 3-5 chronic kidney disease (CKD) by using 51 healthy age-sex-matched Vietnamese adults as the control group. We next examined the prevalence of anemia and determined the serum iron and ferritin concentrations and TIBC. Anemia in CKD was defined as hemoglobin levels <13 g/dL in men and <12 g/dL in women. Transferrin saturation (TSAT, %) was calculated as (serum iron x 100)/TIBC. Functional iron deficiency was defined as serum ferritin >100 ng/mL and TSAT <20%, and absolute iron deficiency was defined as serum ferritin <100 ng/mL and TSAT <20%. Overall iron deficiency was defined as the presence of either absolute or functional iron deficiency. RESULTS: Anemia prevalence in our study was approximately 88.6% with a mean hemoglobin concentration of 9.71±2.26 g/dL. The median serum TIBC was lower in the CKD group (50.4 µmol/L) than in the control group (66.0 µmol/L; p<0.001). The proportion of overall iron deficiency was 44.0%. TIBC had a diagnostic value for overall iron deficiency (area under the ROC curve=0.81; p<0.001). CONCLUSIONS: Anemia and iron deficiency are common in Vietnamese patients with NDCKD. TIBC had diagnostic value for overall iron deficiency.

Longitudinal change in blood pressure and risk of end-stage renal disease in a community-based cohort in Okinawa.

BACKGROUND: The appropriate blood pressure target to prevent end-stage renal disease (ESRD) is controversial. METHODS: We examined the association between systolic blood pressure (SBP) changes and ESRD incidence in 69,575 participants from the Okinawa general population aged ≥ 20 years who underwent health check-ups in 1993 and more than once in 1994-1996. ESRD incidence was identified using dialysis registry until 2011. Cox proportional hazards model was used to estimate hazard ratio (95% confidence interval) with confounding factor adjustment. RESULTS: At baseline, 29.9%, 22.1%, 20.6%, and 27.5% of subjects had SBP < 120, 120-129, 130-139, and ≥ 140 mmHg, respectively. Only 405 subjects developed ESRD. After 1 year, SBP was lowered, unchanged, and elevated in 20.8%, 54.3%, and 24.9% of subjects, respectively. Compared to the subjects with SBP < 120 mmHg both at baseline and the second measurement, there was no significant risk of ESRD in those who had SBP < 130 mmHg both at baseline and 1-3 years and or those with baseline SBP 130-139 mmHg and 1- to 3-year SBP < 140 mmHg. Subjects with baseline SBP 120-129 mmHg and 1- and 2-year SBP ≥ 130 mmHg were not significant (1.51 [0.86-2.66] and 1.73 [0.95-3.15], respectively) but 3-year SBP ≥ 130 mmHg had a significant ESRD risk (2.37 [1.23-4.56]). Subjects with baseline SBP ≥ 130 mmHg and 1- to 3-year SBP ≥ 140 mmHg had significant ESRD risk. CONCLUSION: Subjects with SBP < 130 mmHg at baseline and 1-3 years showed no significant risk of developing ESRD, in the general population.

Correction to: Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome.

The original article can be found online.

Association of dialysis with in-hospital disability progression and mortality in community-onset stroke.

AIM: End-stage renal disease is associated with increased risk of cerebrovascular disease, but the effect on post-stroke clinical outcomes has not been thoroughly investigated. METHODS: Using the Japanese Diagnosis Procedure Combination database, which includes administrative claims and discharge abstract data, we examined the association between risk factors including dialysis therapy and in-hospital disability progression or mortality in patients with community-onset stroke. We extracted data of patients aged ≥ 20 years old who were admitted to the hospital within 3 days after onset of stroke between July 2010 and March 2013. The disability level was divided into modified Rankin Scale (mRS) 0-1, 2-3, 4-5, and 6 (death). Disability progression was defined as an increase in disability level. Odds ratios for in-hospital disability progression and mortality were calculated using logistic regression models. RESULTS: Of 435 403 patients, 7562 (1.7%) received dialysis therapy. The median length of stay was 21 and 20 days for patients with and without dialysis, respectively. During the hospital stay, disability progressed in 100 402 (23.1%) patients and 45 919 (10.5%) died. Patients on dialysis had a higher prevalence of disability progression (26.8%) and mortality (13.1%) compared to those without dialysis (23.0% and 10.5%, respectively). Dialysis was associated with an increased risk of in-hospital disability progression (odds ratio, 1.56; 95% confidence interval, 1.47-1.66) and mortality (odds ratio 1.70; 95% confidence interval, 1.57-1.84). These risks were comparable among subtypes of stroke. CONCLUSIONS: Dialysis was associated with an increased risk of in-hospital disability progression and mortality among patients with community-onset stroke, regardless of stroke subtype.

Distribution and Characteristics of Hypouricemia within the Japanese General Population: A Cross-Sectional Study.

Background and objectives: There is insufficient epidemiological knowledge of hypouricemia. In this study, we aimed to describe the distribution and characteristics of Japanese subjects with hypouricemia. Materials and Methods: Data from subjects who underwent routine health checkups from January 2001 to December 2015 were analyzed in this cross-sectional study. A total of 246,923 individuals, which included 111,117 men and 135,806 women, met the study criteria. The participants were divided into quartiles according to their serum uric acid (SUA) levels. We subdivided the subjects with hypouricemia, which was defined as SUA level ≤ 2.0 mg/dL, into two groups and compared their characteristics, including their cardiovascular risks. Results: The hypouricemia rates were 0.46% overall, 0.21% for the men and 0.66% for the women (P < 0.001). The number of the subjects with hypouricemia showed two distributions at SUA levels of 0.4⁻1.1 mg/dL (lower hypouricemia group), which included a peak at 0.7⁻0.8 mg/dL, and at SUA levels of 1.4⁻2.0 mg/dL (higher hypouricemia group). The men in the higher hypouricemia group had lower body mass indexes (BMI) and triglyceride (TG) levels and had higher fasting blood glucose levels than those in the lower hypouricemia group. The women in the higher hypouricemia group were younger; had lower BMI, total protein, TG, total cholesterol and low-density lipoprotein cholesterol levels; and had higher estimated glomerular filtration rates levels compared to those in the lower hypouricemia group. Conclusions: The characteristics of the individuals in the lower and higher hypouricemia groups differed significantly, indicating different pathophysiologies within each group.

Association of Serum Triglycerides With Arterial Stiffness in Subjects With Low Levels of Low-Density Lipoprotein Cholesterol.

BACKGROUND: The independent role of serum triglyceride (TG) levels as a cardiovascular risk factor is still not elucidated. We aimed to investigate if the effect of TG on arterial stiffness is influenced by the serum level of low-density lipoprotein cholesterol (LDL-C). Methods and Results: We studied 11,640 subjects who underwent health checkups. They were stratified into 4 groups according to LDL-C level (≤79, 80-119, 120-159, and ≥160 mg/dL). Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). In each group, univariate and multivariete logistic regression analyses were performed to investigate the association between high TG (≥150 mg/dL) and high baPWV (>1,400 cm/s). In the univarite analysis, high TG was significantly associated with high baPWV in LDL-C <79 mg/dL (OR, 3.611, 95% CI, 2.475-5.337; P<0.0001) and 80-119 mg/dL (OR, 1.881; 95% CI, 1.602-2.210; P<0.0001), but not in LDL-C 120-159 mg/dL and ≥160 mg/dL. In the multivariate analysis, high TG was significantly associated with high baPWV in LDL-C ≤79 mg/dL (OR, 2.558; 95% CI, 1.348-4.914; P=0.0040) and LDL-C 80-119 mg/dL (OR, 1.677; 95% CI, 1.315-2.140; P<0.0001), but not in LDL-C 120-159 mg/dL and ≥160 mg/dL. CONCLUSIONS: High TG and increased arterial stiffness showed an independent relationship in a Japanese general population with LDL-C ≤119 mg/dL. TG-lowering therapy might be an additional therapeutic consideration in these subjects.

Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study.

BACKGROUND: Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. METHODS: Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. RESULTS: Subjects had a mean ± SD age, 55.59 ± 14.69 years; eGFR, 80.15 ± 21.15 ml/min/1.73 m2. Among the subjects recruited, 15.81% had a low eGFR (<60 ml/min/1.73 m2) and 36.1/100,000 person years developed ESRD. Cox proportional hazards models adjusted for baseline characteristics showed that the risk of ESRD tended to be high with high rates of decrease in %eGFR changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. CONCLUSIONS: %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population.

Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes. METHODS: We conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course. RESULTS: The most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%. CONCLUSIONS: The common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS.

Urinary N-acetyl-ß-glucosaminidase and estimated Glomerular filtration rate may identify patients to be treated with immuno-suppression at diagnosis in idiopathic membranous nephropathy.

AIM: The clinical course of idiopathic membranous nephropathy (IMN) varies from spontaneous remission of nephrotic syndrome (NS) to end-stage renal disease (ESRD). The aim of the study was baseline identification of patients with high risk of progression for which immunosuppressive therapy is mandatory. METHODS: Eighty-six IMN subjects were followed for a median of 69 months (range 6-253). Receiver operating characteristic curve and Cox proportional hazards model were used to evaluate prognostic factors for progression, defined as ESRD or estimated glomerular filtration rate (eGFR) reduction ≥50% of baseline. RESULTS: Among all, 24 subjects had progression. Area under the ROC curve of N-acetyl-ß-glucosaminidase/creatinine ratio (NAG/C) were significantly higher than proteinuria/24 h (0.770 and 0.637 respectively, P = 0.018). In Cox proportional hazards regression analysis, NAG/C and eGFR were independent predictors of progression. Compared to lowest tertile of NAG/C (<9.4 UI/gC) or highest tertile of eGFR (≥88 mL/min per 1.73m2 ), the multivariable-adjusted hazard ratio of highest tertile of NAG/C (≥19.2) was 18.97 (95%CI, 1.70-211.86) and lowest tertile of eGFR (<59) was 11.58 (95%CI, 2.02-66.29). Subjects with high NAG/C or low eGFR (high-risk, n = 43) had greater progression rate compared to moderate to low NAG/C and high eGFR (low-risk, n = 43) with or without NS at baseline (Log-rank test P = 0.001 and 0.006, respectively). In NS subjects (n = 65), high-risk group progression rate was significantly higher (91% vs. 29%, P = 0.003) and remission rate significantly lower (0% vs. 42%, p < 0.001) in non-immunosuppressed compared to steroids and cyclophosphamide treated patients; no significant differences were observed in low-risk group. CONCLUSION: Idiopathic membranous nephropathy subjects with high NAG/C and low eGFR have greater risk of progression, and immunosuppressive treatment is suggested at diagnosis.

Observation period for changes in proteinuria and risk prediction of end-stage renal disease in general population.

AIM: Proteinuria is known to be an independent risk factor of end-stage renal disease (ESRD). But the associations between changes in dipstick proteinuria and the risk of ESRD in the general population and its appropriate observation period to predict incident ESRD are unknown. METHODS: We assessed the changes in dipstick proteinuria in 69 021 participants aged ≥20 years who participated in health check-ups from 1993 and more than once until 1996 in Okinawa, Japan. Development of ESRD until 2011 was identified using dialysis registry. Cox proportional hazards model and receiver operating characteristic (ROC) curve were used. RESULTS: At baseline, proteinuria (±) and ≥(1+) were observed in 2.4% and 1.2% of total subjects. 1.5% of subjects had decreased and 9.4% of subjects had increased their proteinuria level after 2 years. After adjustment for confounding factors, hazard ratios (95% confidence interval) of ESRD for subjects with proteinuria change ≤ - 1, +1, +2, +3, and +4 level during 2 years compared to subjects with no change were 0.89 (0.43-1.87), 3.18 (2.21-4.60), 8.01 (5.55-11.55), 11.17 (6.59-19.95), and 16.59 (5.95-46.25), respectively. Heterogeneity existed between changes in proteinuria level during 1 or 3 years and the risk of ESRD among baseline proteinuria. Area under the ROC curve (95%CI) to predict ESRD by increase in proteinuria level during 1, 2, and 3 years were 0.650 (0.623-0.679), 0.779 (0.751-0.808), and 0.778 (0.748-0.808), respectively. CONCLUSIONS: The changes in dipstick proteinuria were an independent predictor of ESRD in the general population. Changes in proteinuria over 2 years may be appropriate for the risk prediction of ESRD.

Serum 1,25-dihydroxyvitamin d and the development of kidney dysfunction in a Japanese community.

BACKGROUND: Recent evidence indicates that vitamin D deficiency is associated with an increased risk of renal impairment, but studies addressing the influence of vitamin D deficiency on the development of chronic kidney disease (CKD) in the general Asian population have been few. METHODS AND RESULTS: A total of 2,417 community-dwelling individuals without CKD stage 3-5 aged ≥40 years were followed for 5 years (mean age, 60 years; women, 59.1%). The cumulative incidence of CKD stage 3-5, defined as estimated glomerular filtration rate (eGFR) <60ml·min(-1)·1.73m(-2), and the rate of decline in eGFR according to quartile of serum 1,25-dihydroxyvitamin D (1,25(OH)2D), were estimated. During follow-up, 378 subjects experienced CKD stage 3-5. The age- and sex-adjusted incidence of CKD stage 3-5 increased significantly with decreasing serum 1,25(OH)2D (P for trend <0.001). Compared with the highest quartile, the multivariate-adjusted odds ratio for the development of CKD stage 3-5 was 1.90 in the lowest quartile and 1.74 in the second lowest quartile, after adjusting for confounding factors. Additionally, lower serum 1,25(OH)2D was significantly associated with a greater change in eGFR (-0.10ml·min(-1)·1.73m(-2)·year(-1) per 10-pg/ml decrement in serum 1,25(OH)2D). CONCLUSIONS: Lower serum 1,25(OH)2D is a significant risk factor for the development of CKD stage 3-5 in the general Asian population.

[Cross-cultural validated adaptation of dysfunctional voiding symptom score (DVSS) to Japanese language and cognitive linguistics in questionnaire for pediatric patients].

PURPOSE: Validated questionnaire for evaluation of pediatric lower urinary tract symptoms (LUTS) is of a great need. We performed cross-cultural validated adaptation of Dysfunctional Voiding Symptom Score (DVSS) to Japanese language, and assessed whether children understand and respond to questionnaire correctly, using cognitive linguistic approach. METHODS: We translated DVSS into two Japanese versions according to a standard validation methodology: translation, synthesis, back-translation, expert review, and pre-testing. One version was written in adult language for parents, and the other was written in child language for children. Pre-testing was done with 5 to 15-year-old patients visiting us, having normal intelligence. A specialist in cognitive linguistics observed the response by children and parents to DVSS as an interviewer. When a child could not understand a question without adding or paraphrasing the question by the parents, it was defined as 'misidentification'. RESULTS: We performed pretesting with 2 trial versions of DVSS before having the final version. The pre-testing for the first trial version was done for 32 patients (male to female ratio was 19 : 13). The pre-testing for the second trial version was done for 11 patients (male to female ratio was 8 : 3). In DVSS in child language, misidentification was consistently observed for representation of time or frequency. We completed the formal validated translation by amending the problems raised in the pre-testing. CONCLUSION: The cross-cultural validated adaptation of DVSS to child and adult Japanese was completed. Since temporal perception is not fully developed in children, caution should be taken for using the terms related with time or frequency in the questionnaires for children.

Erythropoiesis-stimulating agent hyporesponsiveness was associated with worse survival of hemodialysis patients independent of the serum ferritin level.

INTRODUCTION: Ferritin level and erythropoiesis-stimulating agent (ESA) responsiveness are each associated with hemodialysis patient survival. We assessed interrelationships between these two vs. survival. METHODS: Patients in the Japan Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-2018) were included. All-cause mortality associations were assessed with progressive adjustment to evaluate covariate influence. RESULTS: During follow-up (median 2.6 years), 773 of 5154 patients died. After covariate adjustment, the mortality hazard ratio (HR) was 0.99 (95% CI: 0.81, 1.20) for low serum ferritin and 1.12 (CI: 0.89, 1.41) for high serum ferritin. By contrast, mortality risk with elevated ESA resistance index (ERI) persisted after covariate adjustment (HR 1.44, CI [1.17-1.78]). The serum ferritin and ERI interaction was not significant; p > 0.96 across all models. CONCLUSIONS: Japanese hemodialysis patients with high ERI experienced worse survival independent of serum ferritin levels, highlighting the importance of identifying and mitigating ESA hyporesponsiveness among dialysis patients.

Angiopoietin-like protein 2 is associated with chronic kidney disease in a general Japanese population: the Hisayama Study.

BACKGROUND: Angiopoietin-like protein 2 (Angptl2) is an adipokine that promotes inflammation and endothelial dysfunction of the vessels. The aim of this study was to investigate the relationship between serum Angptl2 level and chronic kidney disease (CKD). METHODS AND RESULTS: A total of 3,169 community-dwelling subjects aged ≥40 years were divided into quintiles by Angptl2 level. CKD was defined as the presence of albuminuria (urine albumin-creatinine ratio ≥30.0mg/g) or decreased estimated glomerular filtration rate (eGFR <60ml·min(-1)·1.73m(-2)). The odds ratio (OR) for the presence of CKD was calculated using a logistic regression model. The overall prevalence of CKD was 37.5%. The age- and sex-adjusted ORs for the presence of CKD increased with higher serum Angptl2 level. This trend remained significant after adjusting for known cardiovascular risk factors (<2.01ng/ml: OR, 1.00 (reference); 2.01-2.48ng/ml: OR, 1.67, 95% confidence interval [CI]: 1.24-2.24; 2.49-2.99ng/ml: OR, 1.70, 95% CI: 1.27-2.28; 3.00-3.65ng/ml: OR, 1.78, 95% CI: 1.32-2.39; ≥3.66ng/ml: OR, 1.79, 95% CI: 1.32-2.43; P-value for trend=0.001). Multivariate-adjusted ORs for the presence of albuminuria increased significantly with elevated serum Angptl2 (P-value for trend=0.004), while there was no evidence of a significant relationship between serum Angptl2 level and decreased eGFR (P-value for trend=0.08). CONCLUSIONS: Elevated serum Angptl2 is associated with the likelihood of CKD in the general population.