A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Tacrolimus use and renal function in pregnancy with lupus nephritis: Analysis of post-marketing surveillance data in Japan.

OBJECTIVES: Tacrolimus may be administered to pregnant women with lupus nephritis in Japan if considered therapeutically beneficial, but supporting data are limited. We assessed the safety and effectiveness of tacrolimus before, during, and after pregnancy in women with lupus nephritis receiving tacrolimus. METHODS: This was an ad hoc analysis of data from a post-marketing surveillance study of tacrolimus in patients with lupus nephritis in Japan. Pregnancy outcomes, nephritis status, and adverse events were assessed for up to 2 years postpartum. RESULTS: Data were available for 23 births in 21 patients (two patients had two births each). Tacrolimus for lupus nephritis was continued during 11 births in nine patients (during and after pregnancy) and discontinued in 12 patients (when pregnancy was known or when approaching delivery). Renal function was generally maintained in patients who gave birth while receiving tacrolimus; however, there were cases of increased urine protein and decreased renal function over 2 years. There were no unexpected adverse events/safety concerns. CONCLUSIONS: These data from clinical practice suggest that tacrolimus is a valid treatment option for lupus nephritis in fertile women in Japan and, with careful monitoring, pregnant women with lupus nephritis may continue their tacrolimus treatment.

Early development of pearlside Maurolicus stehmanni off south-eastern Brazil.

The pearlside Maurolicus stehmanni is one of the most abundant mesopelagic fishes off south-eastern Brazil and plays a key role in the regional ecosystem. However, its early life history remains poorly understood. This study examined the M. stehmanni early life stages, from eggs to juveniles, including all developmental changes in external morphology. Larvae are simple in morphology and lack specialized larval structures. Notochord flexion begins at ~5.15 mm body length (BL) and larvae ≥5.95 mm BL are flexed. The relative growth of seven measured larval characters (head length, body depth, snout length, eye diameter, pre-dorsal length, pre-ventral length and pre-anal length) have transition points (allometric inflexion points), indicating biphasic growth patterns which are likely related to shifts in habitat use, feeding and behaviour. Larval development is similar to that of other Maurolicus species. The relatively fast development of the fins, photophores, swimbladder and pigmentation suggests a precocious adoption of a micronektonic lifestyle in the mesopelagic environment.

Comparison of the predictive ability of albuminuria and dipstick proteinuria for mortality in the Japanese population: the Yamagata (Takahata) study.

BACKGROUND: Albuminuria and proteinuria are known risk factors for premature death. This study compared the ability of albuminuria and proteinuria to predict mortality in a community-based population. METHODS: We evaluated the urinary albumin creatinine ratio (ACR) and proteinuria by dipstick at a baseline survey and examined the association between the 7-year mortality and three categories (albuminuria [ACR ≥ 30 mg/g], trace proteinuria, and ≥[1+] proteinuria) in 3446 Japanese subjects at a local health check. RESULTS: Albuminuria, ≥trace proteinuria, and ≥(1+) proteinuria were identified in 514 (14.9 %), 290 (8.4 %), and 151 (4.4 %) subjects, respectively. There were 138 deaths during the follow-up period, including 41 cardiovascular deaths. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in ACR and proteinuria levels (log-rank P < 0.01). The mortality rate (deaths per 1000 person-year) was higher in subjects with albuminuria (12.8), ≥trace proteinuria (12.6), and ≥(1+) proteinuria (16.2) than in all subjects (6.9). A Cox proportional hazard model analysis showed that all three categories were significant predictors of all-cause mortality in the unadjusted model, although after adjustment for possible confounders, a significant association was observed only with albuminuria. Albuminuria, but not proteinuria, was a significant predictor of cardiovascular mortality in both the unadjusted and adjusted models. CONCLUSION: Albuminuria had a high prevalence and was strongly associated with mortality, as compared with proteinuria by dipstick, suggesting that albuminuria might be a superior predictor of poor prognosis in the Japanese population.

Serum uric acid levels and mortality in the Japanese population: the Yamagata (Takahata) study.

BACKGROUND: Serum uric acid level is regulated by gender, dietary habit, genetic predisposition, and renal function, and is associated with the development of renal and cardiovascular diseases. This study prospectively investigated the association between serum uric acid levels and mortality in a community-based population. METHODS: Three thousand four hundred and eighty-seven subjects regardless of the antihyperuricemic medication (45 % male; mean age 62 years old) from the Takahata town in Japan participated in this study and were followed up for 8 years (median 7.5 years). We examined the association between serum uric acid levels at baseline and the all-cause and cardiovascular mortality, respectively, in this population. RESULTS: One hundred seventy-nine subjects died during the follow-up period, with 49 deaths attributed to cardiovascular causes. Kaplan-Meier analysis revealed that the all-cause mortality was significantly higher along with the increase in serum uric acid levels at baseline among female (Log-rank P < 0.01), but not male subjects (P = 0.97). Cox-proportional hazard model analysis with adjustment for possible confounders including age, renal function, and comorbidities revealed that hyperuricemia (uric acid ≥7.0 mg/dL) was an independent risk factor for all-cause and cardiovascular mortality, respectively, in female [hazard ratio (HR) 5.92, 95 % confidence interval (CI) 2.10-14.6 for all-cause mortality, and HR 10.7, 95 % CI 1.76-50.2 for cardiovascular mortality], but not male subjects. CONCLUSION: Hyperuricemia was an independent risk for all-cause and cardiovascular mortality in female, but not among the male subjects in a community-based population.

A slight increase within the normal range of serum uric acid and the decline in renal function: associations in a community-based population.

BACKGROUND: Hyperuricemia is a risk factor for adverse renal outcomes in patients with chronic kidney disease. This study investigated the effect of uric acid on renal function in a community-based population. METHODS: We used a nationwide database of 165 847 subjects (aged 29-74, male 40%) who participated in the annual 'Specific Health Check and Guidance in Japan' checkup between 2008 and 2010; we examined the relationship between serum uric acid levels at baseline and 2-year change in the estimated glomerular filtration rate (eGFR) obtained by using the Japanese equation. RESULTS: After adjusting for possible confounders, the eGFR change was inversely correlated with uric acid at baseline. In the multivariable analysis, the decline in eGFR was significantly more rapid in subjects with the slight increase in uric acid (males ≥5.7 mg/dL, females ≥4.4 mg/dL), and the risk for incidental renal insufficiency (eGFR <60 mL/min/1.73 m(2)) was increased at uric acid of ≥6.3 mg/dL in males and ≥5.5 mg/dL in females, compared with the lowest quintile. The multiple linear regression analysis revealed that the effect of uric acid on eGFR changes was significant, especially in females, those with proteinuria and diabetes and those without alcohol consumption. CONCLUSION: This study showed that serum uric acid is independently associated with a more rapid decline of eGFR and incident renal insufficiency, and that a slight increase within the normal range of serum uric acid might be a risk for renal damage in the general population.

A microarray analysis of urinary microRNAs in renal diseases.

BACKGROUND: MicroRNAs (miRNAs), a family of endogenous small non-coding RNAs, are associated with the development of renal diseases. To clarify whether urinary miRNAs (UmiRNAs) can be used for the evaluation of renal disease, we examined the profiles of UmiRNAs in various renal diseases. METHODS: We extracted miRNAs from urine specimens of 5 healthy controls and 71 patients with renal diseases, and we examined the correlation between clinical and histological parameters and the profile of UmiRNAs by microarray analysis. RESULTS: The urinary concentration of miRNAs increased in patients with renal disease compared with healthy controls, and the levels correlated with urinary protein and the degree of glomerular sclerosis. The microarray analysis detected 83-137 distinct UmiRNAs. We observed 80-99 % of the miRNAs in both the healthy controls and the renal disease patients. The majority of UmiRNAs displayed higher signal intensity in renal disease patients than in healthy controls, including 39 miRNAs exhibiting signal intensities 100 times greater than in healthy controls. A different pattern of UmiRNAs was observed in each type of renal disease. A comparison of renal tissue and UmiRNAs revealed that the sample profiles were similar and that their signal intensity was significantly correlated. CONCLUSION: This study demonstrated that UmiRNAs are correlated with renal pathological changes and that the profile of UmiRNAs presented different patterns corresponding to the type of renal disease. These results suggest that UmiRNAs can potentially be used as novel biomarkers for renal diseases.

Rapid decline in renal function after acute myocardial infarction.

AIM: To investigate the long term effects of cardiac events on renal function, a prospective study of patients with acute myocardial infarction was conducted. METHODS: A total of 137 patients with acute myocardial infarction were followed for 1 year. The change of estimated glomerular filtration rate (eGFR) in cardiac patients was compared with that in background-matched controls, and the factors associated with eGFR changes were analyzed. RESULTS: The eGFR decrease was much larger after myocardial infarction, from 73.7 ± 1.9 ml/min/1.73 m2 (mean ± SEM) at baseline to 64.7 ± 1.7 at 1 year, (p < 0.001), compared with that of controls (from 72.8 ± 1.2 to 72.1 ± 1.3, p = 0.305). Multiple regression analysis showed that eGFR change was associated negatively with age, baseline eGFR, proteinuria, and positively with the administration of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, but not the severity of cardiac damage and comorbidities. Longitudinal analysis 1 year before and 2 years after myocardial infarction showed that eGFR decrease was larger during baseline and 6 months after the event (-7.0 ± 1.0). CONCLUSIONS: Renal decline was rapid after myocardial infarction and was affected by clinical characteristics of patients. Careful follow-up of renal function is recommended to prevent the progression of renal and cardiac disease.

The association between serum uric acid and renal damage in a community-based population: the Takahata study.

BACKGROUND: Hyperuricemia is a risk factor for end-stage renal disease. This study examined the association between serum uric acid and renal damage in a community-based population. METHODS: In this study 3126 subjects without renal insufficiency were recruited at baseline and were followed for one year. The urinary albumin-creatinine ratio (UACR) and ß2-microglobulin-creatinine ratio (UBCR) in morning spot urine samples were used as indices of either glomerular (UACR) or tubular (UBCR) damage. RESULTS: The mean value of serum uric acid (mg/dL) was 5.8 ± 1.3 (SD) in men and 4.5 ± 1.1 in women. In cross-sectional analysis the increased serum uric acid levels were accompanied by higher UACR values in both men and women (P < 0.01). In contrast, UBCR values were reduced when uric acid levels increased in both men and women (P < 0.01). Multivariate analysis revealed that albuminuria (UACR ≥ 30 mg/g) was significantly associated with increased uric acid (≥7 mg/dL for men, ≥6 mg/dL for women). High UBCR (≥300 µg/g) was negatively associated with uric acid in men, but not in women, after adjustment for possible confounders. In longitudinal analysis in 1388 subjects multiple linear regression analysis showed that uric acid at baseline was an independent factor for one-year increase of UACR [coefficient 4.80 (95 % confidence interval 0.40-9.33) (mg/g) per 1 mg/dL increase in uric acid, P = 0.033]. CONCLUSION: This study showed that serum uric acid concentration was positively associated with UACR, suggesting that uric acid may be related to glomerular damage in a community-based population.

Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study.

BACKGROUND: Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study. METHODS: This study included 3,445 registered Japanese subjects (mean age 62.6 years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR) ≥30 mg/g in the morning spot urine. RESULTS: Subjects with albuminuria (n = 514, 14.9 %) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n = 2931, 85.1 %). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P < 0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4 %; log-rank test, P < 0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95 % confidence interval [CI] 1.12-2.56 and HR 2.27, 95 % CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (≥300 mg/g). CONCLUSIONS: Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful.

Hartmann-Hahn 2D-map to optimize the RAMP-CPMAS NMR experiment for pharmaceutical materials.

Cross polarization-magic angle spinning (CPMAS) is the most used experiment for solid-state NMR measurements in the pharmaceutical industry, with the well-known variant RAMP-CPMAS its dominant implementation. The experimental work presented in this contribution focuses on the entangled effects of the main parameters of such an experiment. The shape of the RAMP-CP pulse has been considered as well as the contact time duration, and a particular attention also has been devoted to the radio-frequency (RF) field inhomogeneity. (13)C CPMAS NMR spectra have been recorded with a systematic variation of (13)C and (1)H constant radiofrequency field pair values and represented as a Hartmann-Hahn matching two-dimensional map. Such a map yields a rational overview of the intricate optimal conditions necessary to achieve an efficient CP magnetization transfer. The map also highlights the effects of sweeping the RF by the RAMP-CP pulse on the number of Hartmann-Hahn matches crossed and how RF field inhomogeneity helps in increasing the CP efficiency by using a larger fraction of the sample. In the light of the results, strategies for optimal RAMP-CPMAS measurements are suggested, which lead to a much higher efficiency than constant amplitude CP experiment.

Phase Ib study of durvalumab (MEDI4736) in combination with carbon-ion radiotherapy and weekly cisplatin for patients with locally advanced cervical cancer (DECISION study): study protocol for a prospective open-label single-arm study.

INTRODUCTION: Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects. OBJECTIVE: We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer. METHODS AND ANALYSIS: This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study.

BACKGROUND: A cluster of proinflammatory cytokines plays an important role in the development of various renal diseases, and the expression of these cytokines is genetically modified. To examine the association between polymorphisms of proinflammatory cytokine genes and albuminuria, a cross-sectional study was conducted in the general population. METHODS: Single nucleotide polymorphisms (SNPs) in six proinflammatory cytokine genes, including interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, CC chemokine ligand 1 (CCL1) and monocyte chemoattractant protein-1 (MCP-1), were genotyped in 2927 Japanese subjects. Urine albumin-creatinine ratio (UACR) was measured in morning spot urine samples. RESULTS: Albuminuria (UACR ≥ 30 mg/g) was significantly associated with the A/A + A/G genotype at rs2069852 in the IL-6 gene (P = 0.01) and the A/A genotype at rs228269 in the CCL1 gene (P = 0.002). Multivariate analysis with adjustment for traditional risk factors showed that these genotypes independently predicted albuminuria [odds ratio (OR) 1.782, 95% confidence interval (CI) 1.171-2.712, P = 0.007 for the A/A + A/G genotype at rs2069852 in IL-6, and OR 1.432, 95% CI 1.128-1.770, P = 0.003 for the A/A genotype at rs228269 in CCL1]. The prevalence of albuminuria and the UACR were increased along with the increase of risk genotypes. CONCLUSIONS: This study revealed that SNPs in the IL-6 and CCL1 genes were associated with albuminuria, and the combination of these genotypes had an additive effect on the prevalence and severity of albuminuria. This indicates that genetic factors influencing inflammatory responses may affect the development of renal injury in the Japanese general population.

The association between renal tubular damage and rapid renal deterioration in the Japanese population: the Takahata study.

BACKGROUND: Injury to renal tubules plays an important role in the development of various renal diseases; however, the prevalence and significance of renal tubular damage in the general population are unclear. To clarify this point, we conducted a community-based study, using urinary ß(2)-microglobulin as a marker of tubular damage. METHODS: The subjects studied were 3,444 Japanese over the age of 40 years. The urinary ß(2)-microglobulin-creatinine ratio (UBCR) was assessed in morning spot urine samples. RESULTS: In this population, the distribution of the UBCR among these subjects was skewed towards higher values and a high UBCR (≥300 µg/g) was identified in 438 (12.7%) subjects. However, overlap with macroalbuminuria and renal insufficiency [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2)] was observed in only 25 (5.7%) and 58 (13.2%) of these subjects, respectively. Multivariate analysis indicated that a high UBCR was positively associated with aging, hypertension, macroalbuminuria and increased urinary sodium excretion. A 5-year longitudinal analysis in 899 subjects indicated a greater decline in eGFR in parallel with the increase in baseline UBCR. After adjustment for possible confounders, a high UBCR was an independent risk factor for rapid decline in eGFR [<-10 mL/min/1.73 m(2); odds ratio 1.79 (95% confidence interval 1.07-2.99), P = 0.026]. CONCLUSION: This study showed that renal tubular damage was common and was an independent risk factor for renal deterioration in the Japanese population. More attention should be paid to occult renal tubular damage in order to prevent end-stage renal disease.

The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study.

Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals >40 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (>0.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3±15.6 (n=1886), A/T: 82.0±15.5 (n=652) and A/A: 87.4±21.4 ml min(-1) per 1.73m(2) (n=66); mean±s.d., P=0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR <90 ml min(-1) per 1.73m(2); odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05-2.94, P=0.033). These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population.

In a non-diabetic Japanese population, the combination of macroalbuminuria and increased urine beta 2-microglobulin predicts a decline of renal function: the Takahata study.

BACKGROUND: Glomerular and tubular damage are important factors in the development of renal insufficiency. However, the interaction of these factors is largely unknown in the non-diabetic Japanese population. To clarify the relationship between renal insufficiency and both glomerular and tubular damage, we conducted a community-based study using albuminuria and urine beta 2-microglobulin as markers of glomerular and tubular damages, respectively. METHODS: Subjects of this study were 2816 non-diabetic individuals >40 years old in Takahata, Japan. The urine albumin-creatinine ratio (UACR) and urine beta 2-microglobulin-creatinine ratio (UBCR) were assessed from single spot urine. The glomerular filtration rate (eGFR) was estimated using the abbreviated MDRD equation with a Japanese coefficient. RESULTS: The prevalence of albuminuria (UACR >20 mg/ g in men and >30 mg/g in women), increased UBCR (>300 microg/g) and renal insufficiency (eGFR <60 mL/ min/1.73 m(2)) were 21.0%, 12.5% and 21.7%, respectively, and there was only a small overlap between the three. The mean eGFR was significantly lower in subjects with macroalbuminuria (UACR >200 mg/g in men and >300 mg/g in women) and increased UBCR. No urinary abnormalities were observed in 71.7% of the 611 subjects with renal insufficiency, and were more common in young, women and the non-hypertensive population. The 1-year decline of eGFR was greatest in subjects with an overlap of macroalbuminuria and increased UBCR. CONCLUSIONS: This study indicated that only a small part of renal insufficiency accompanied increased urine albumin or beta 2-microglobulin in the non-diabetic Japanese population. The combination of macroalbuminuria and increased urine beta 2-microglobulin might predict faster renal deterioration.

High variability of albuminuria in nondiabetic population: the Takahata Study.

BACKGROUND: Albuminuria is a risk factor for renal and cardiovascular events and shows a quick change reflecting vascular status. The aim of this study is to examine the frequency and related factors of the short-term change of albuminuria in nondiabetic Japanese population. METHODS: The study subjects were 1,378 individuals (mean age 63.9 years) who attended community-based health checkup in 2004 and 2005 in Takahata town. Albuminuria was evaluated by urine albumin creatinine ratio in morning urine and was categorized into four stages (low normal, high normal, and micro- and macroalbuminuria). RESULTS: At baseline, the prevalence of subjects with low normal, high normal, and micro- and macroalbuminuria was 62.3, 17.3, 18.7, and 1.7%, respectively. During 1 year, progression and remission of albuminuria stages were observed in 23.1 and 14.5% of total subjects, respectively. Both progression and remission of albuminuria were frequently detected at every stage, especially in high normal albuminuria (29% in progression and 39% in remission, respectively). On multivariate analysis, the changes of albuminuria were associated with older age, blood pressures, total protein, estimated glomerular filtration rate (GFR), and urine sodium excretion at baseline, start of antidiabetic drugs, changes in body weight (+/-1 kg), hemoglobin (+/-1 g/dl), and urine sodium excretion (+/-50 mEq/day). CONCLUSION: This study revealed that albuminuria showed high variability associated with age and small changes in modifiable risk factors during 1 year. In the treatment and risk analysis of subjects with albuminuria, the effect of these factors should be considered.

Persistent fever and destructive arthritis caused by dialysis-related amyloidosis: A case report.

RATIONALE: Dialysis-related amyloidosis (DRA) can present rheumatic manifestations in patients on long-term hemodialysis. Typical articular symptoms with DRA involve carpal-tunnel syndrome, effusion in large joints, spondyloarthropathy, or cystic bone lesions, which are usually with non-inflammatory processes. PATIENT CONCERNS: A 64-year-old man on hemodialysis for >30 years was admitted because of intermittent fever, polyarthritis, and elevated serum C-reactive protein (CRP) level, which was continuous for 2 years. Several antibiotics were ineffective for 3 months before his admission. On physical examination, joint swelling was observed at bilateral wrists, knees, ankles, and hip joints. Laboratory tests revealed elevation of serum inflammatory markers and ß2-microglobulin (ß2-MG). Synovial fluid showed predominant infiltration of polymorphonuclear leukocytes and the increase of ß2-MG level. DIAGNOSIS: Significant deposition of ß2-MG with inflammatory cell infiltration was found in biopsied samples from synovium, skin, and ileum. INTERVENTIONS: We decided to switch to the hemodialysis column with membrane that can effectively absorb ß2-MG in circulation. OUTCOMES: The relief of symptoms and a decrease of CRP level by changing the membrane lead to the final diagnosis of DRA. LESSONS: Our case demonstrates that DRA arthropathy can be inflammatory and destructive, and also develop systemic inflammatory signs and symptoms. In such cases, aggressive absorption of ß2-MG in circulation might help the amelioration of symptoms.

Adolescent PR3-ANCA-positive hypertrophic pachymeningitis: A case report and review of the literature.

RATIONALE: Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. PATIENT CONCERNS: A 14-year-old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. DIAGNOSIS: PR3-ANCA-positive HP. INTERVENTIONS: She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. OUTCOME: The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. LESSONS: PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital.

Genetic variations of the ABC transporter gene ABCC3 in a Japanese population.

An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.