Clinical Impacts of Allograft Biopsy in Renal Transplant Recipients 10 Years or Longer After Transplantation.

We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.

Breakfast Frequency and Smoking Initiation in University Students: A Retrospective Cohort Study.

Smoking causes various health problems. Limited studies have reported a clinical effect of skipping breakfast on smoking initiation among adolescents. This retrospective cohort study aimed to assess the dose-dependent association between skipping breakfast and smoking initiation in university students. This study included 17,493 male and 8880 female students aged 18-22 years at a national university in Japan. The association between breakfast frequency (eating every day and skipping occasionally, often, and usually) and smoking initiation was evaluated using Cox proportional hazards models adjusted for clinically relevant factors. Smoking initiation was observed in 2027 (11.6%) male and 197 (2.2%) female students over the median observational period of 3.0 and 3.1 years. Skipping breakfast was significantly associated with smoking initiation in a dose-dependent fashion in male students (the adjusted hazard ratios [95% confidence interval] of eating breakfast every day and skipping occasionally, often, and usually: 1.00 [reference], 1.30 [1.15, 1.46], 1.47 [1.21, 1.79], and 1.77 [1.40, 2.25], respectively). Female students skipping breakfast occasionally and often were more vulnerable to smoking initiation than those who ate breakfast every day (1.00 [reference], 1.86 [1.24, 2.78], 2.97 [1.66, 5.32], and 1.76 [0.55, 5.64], respectively). Breakfast frequency may be useful to identify university students at risk of smoking initiation who need improvement in their health literacy.

Endogenous activation of peroxisome proliferator-activated receptor-α in proximal tubule cells in counteracting phosphate toxicity.

Increased dietary phosphate consumption intensifies renal phosphate burden. Several mechanisms for phosphate-induced renal tubulointerstitial fibrosis have been reported. Considering the dual nature of phosphate as both a potential renal toxin and an essential nutrient for the body, kidneys may possess inherent protective mechanisms against phosphate overload, rather than succumbing solely to injury. However, there is limited understanding of such mechanisms. To identify these mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) analysis of the kidneys of control and dietary phosphate-loaded (Phos) mice at a time point when the Phos group had not yet developed tubulointerstitial fibrosis. scRNA-seq analysis identified the highest number of differentially expressed genes in the clusters belonging to proximal tubular epithelial cells (PTECs). Based on these differentially expressed genes, in silico analyses suggested that the Phos group activated peroxisome proliferator-activated receptor-α (PPAR-α) and fatty acid ß-oxidation (FAO) in the PTECs. This activation was further substantiated through various experiments, including the use of an FAO activity visualization probe. Compared with wild-type mice, Ppara knockout mice exhibited exacerbated tubulointerstitial fibrosis in response to phosphate overload. Experiments conducted with cultured PTECs demonstrated that activation of the PPAR-α/FAO pathway leads to improved cellular viability under high-phosphate conditions. The Phos group mice showed a decreased serum concentration of free fatty acids, which are endogenous PPAR-α agonists. Instead, experiments using cultured PTECs revealed that phosphate directly activates the PPAR-α/FAO pathway. These findings indicate that noncanonical metabolic reprogramming via endogenous activation of the PPAR-α/FAO pathway in PTECs is essential to counteract phosphate toxicity.NEW & NOTEWORTHY This study revealed the activation of peroxisome proliferator-activated receptor-α and fatty acid ß-oxidation in proximal tubular epithelial cells as an endogenous mechanism to protect the kidney from phosphate toxicity. These findings highlight noncanonical metabolic reprogramming as a potential target for suppressing phosphate toxicity in the kidneys.

Short sleep duration and smoking initiation in university students: a retrospective cohort study.

PURPOSE: The aim of this study was to clarify an association between short sleep duration and smoking initiation. METHODS: Participants eligible for this retrospective cohort study were university students who were admitted to a single national university in Japan between 2007 and 2015. Baseline sleep duration and smoking status were measured using general questionnaires at health checkups at admission. During a 6-year observation period, smoking initiation was assessed using general questionnaires at annual health checkups. Cox proportional hazards models adjusted for clinically relevant factors were used to assess the association between sleep duration and smoking initiation. RESULTS: Of 17,493 men, including 540, 5,568, 8,458, 2,507, and 420 men with sleep duration of < 5, 5-6, 6-7, 7-8, and ≥ 8 h, respectively, smoking initiation was observed in 16.1%, 12.5%, 11.2%, 10.0%, and 11.7%, respectively, during a median observation period of 3.0 years. Men with shorter sleep duration were at a higher risk of smoking initiation (adjusted hazard ratio 1.49 [95% confidence interval 1.19-1.85], 1.11 [1.01-1.22], 1.00 [reference], 0.92 [0.80-1.06], and 1.00 [0.75-1.34], respectively). Of 8,880 women, including 267, 3,163, 4,220, and 1,230 women with sleep duration of < 5, 5-6, 6-7, and ≥ 7 h, respectively, smoking initiation was observed in 4.9%, 2.3%, 2.0%, and 2.2%, respectively, during a median observation period of 3.0 years. A similar dose dependent association was ascertained in women (2.50 [1.39-4.49], 1.18 [0.86-1.62], 1.00 [reference], and 1.22 [0.79-1.89], respectively). CONCLUSION: This study clarified that university students with short sleep duration were vulnerable to smoking initiation.

Novel therapeutic strategies targeting abnormal T-cell signaling in systemic lupus erythematosus.

Therapeutic strategies for autoimmune diseases have been based on the use of glucocorticoids and immunosuppressive agents that broadly suppress immune responses. Therefore, organ damage from long-term use and infections due to immunocompromised status have been significant issues. Safer immunosuppressants and biological agents are now available, but there is still an urgent need to develop specific drugs to replace glucocorticoids. T-lymphocytes, central players in immune responses, could be crucial targets in the treatment of autoimmune diseases. Extensive research has been conducted on the phenotypic changes of T-cells in systemic lupus erythematosus, which has led to the discovery of various therapeutic strategies. In this comprehensive review, we discuss novel treatment approaches and target molecules with expected effectiveness in humans and mice, based on research for lymphocytes involved in autoimmune diseases, especially T-cells in SLE.

Association between urinary uric acid excretion and kidney outcome in patients with CKD.

Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15-60 mL/min/1.73 m2. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13-2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.

Development of a three-dimensional HPLC system for the determination of serine, threonine and allo-threonine enantiomers in the plasma of patients with chronic kidney disease.

A highly-selective three-dimensional high-performance liquid chromatographic (3D-HPLC) system was developed for the determination of serine (Ser), threonine (Thr) and allo-threonine (aThr) enantiomers in human plasma to screen the new biomarker of chronic kidney disease (CKD). d-Ser has been reported to be the candidate biomarker of CKD, however, multiple biomarkers are still required. Therefore, Ser analogs of hydroxy amino acids are the focus in the present study. For the sensitive analysis, the amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole and detected by their fluorescence. The 3D-HPLC system consisted of a reversed-phase column (Singularity RP18, 1.0 × 250 mm), an anion-exchange column (Singularity AX, 1.0 × 150 mm) and a Pirkle-type chiral stationary phase (Singularity CSP-013S, 1.5 × 250 mm). The developed method was validated and applied to the human plasma samples obtained from 15 healthy volunteers and 165 CKD patients. The concentrations of the d-forms were 1.13-2.26 (Ser), 0.01-0.03 (Thr) and 0.04-0.10 µM (aThr) for the healthy volunteers and 0.95-19.0 (Ser), 0-0.57 (Thr) and 0.04-1.02 µM (aThr) for the CKD patients. The concentrations and the %d values of all the target d-amino acids were increased along with the decreasing of renal function and further investigation for clinical applications are expected.

Living Arrangements Predict Frequent Alcohol Consumption Among University Students: A Retrospective Cohort Study.

PURPOSE: This study aimed to confirm the clinical impact of living arrangements on incidence of frequent alcohol consumption in university students. DESIGN: A retrospective cohort study. SETTING: A national university in Japan. SUBJECTS: 17,774 university students. MEASURES: The association between living arrangements on admission and the incidence of frequent alcohol consumption (≥4 days/week) was assessed using multivariable-adjusted Cox proportional-hazards models. RESULTS: Among 5,685, 692, and 5,151 male students living with family, living in the dormitory, and living alone, 5.0%, 6.2%, and 5.8% reported frequent alcohol consumption during the median observational period of 3.0 years, respectively. Living in the dormitory and living alone were identified as significant predictors of frequent alcohol consumption (multivariable-adjusted hazard ratios: 1.00 [reference], 1.39 [1.01-1.92], and 1.21 [1.03-1.42], respectively). On the contrary, living arrangements were not associated with the incidence of frequent alcohol consumption among of 6,091 female students, partly because of low incidence of frequent alcohol consumption (2.3%, 1.4%, and 2.6%, respectively). CONCLUSIONS: Living arrangements predicted frequent alcohol consumption among male university students, whereas not among female university students.