Graphical Abstract Highlights d KAT5-mediated DNA damage repair is essential for podocyte maintenance d KAT5 is decreased in diabetic nephropathy podocytes d Impaired DNA damage repair may be associated with altered DNA methylation status d KAT5 may be a therapeutic target for diabetic nephropathy SUMMARY Altered DNA methylation plays an important role in the onset and progression of kidney disease. However, little is known about how the changes arise in disease states. Here, we report that KAT5-mediated DNA damage repair is essential for the maintenance of kidney podocytes and is associated with DNA methylation status. Podocyte-specific KAT5-knockout mice develop severe albuminuria with increased DNA double-strand breaks (DSBs), increased DNA methylation of the nephrin promoter region, and decreased nephrin expression. Podocyte KAT5 expression is decreased, whereas DNA DSBs and DNA methylation are increased in diabetic nephropathy; moreover, KAT5 restoration by gene transfer attenuates albuminuria. Furthermore, KAT5 decreases DNA DSBs and DNA methylation at the same nephrin promoter region, which indicates that KAT5-mediated DNA repair may be related to DNA methylation status. These results suggest a concept in which an environment of DNA damage repair, which occurs with decreased KAT5, may affect DNA methylation status.

Background The potential effects of aerobic and resistance training in patients with severe chronic kidney disease (CKD) are not fully elucidated. This study investigated the effects of a home‐based exercise programme on physical functioning and health‐related quality of life (HRQOL) in patients with Stage 4 CKD, equivalent to estimated glomerular filtration rate of 15–30 mL/min/1.73 m2. Methods Forty‐six patients with Stage 4 CKD (median age, 73 years; 33 men) were randomly assigned to exercise (n = 23) and control (n = 23) groups. Exercise group patients performed aerobic exercise at 40–60% peak heart rate thrice weekly and resistance training at 70% of one‐repetition maximum twice weekly at home for 6 months. Control patients received no specific intervention. Primary outcomes were distance in incremental shuttle walking test and HRQOL assessed using the Kidney Disease Quality of Life—Short Form questionnaire. Secondary outcomes included kidney function assessed with combined urea and creatinine clearance, urinary biomarkers, and anthropometric and biochemical parameters associated with CKD. Results Improvement in incremental shuttle walking test was significantly greater in the exercise group compared with controls (39.4 ± 54.6 vs. −21.3 ± 46.1; P < 0.001). Among Kidney Disease Quality of Life domains, significant mean differences were observed between the exercise group and the control group in work status, quality of social interaction, and kidney disease component summary outcomes (12.76 ± 5.76, P = 0.03; 5.97 ± 2.59, P = 0.03; and 4.81 ± 1.71, P = 0.007, respectively). There were greater reductions in natural log (ln)‐transformed urinary excretion of liver‐type fatty acid‐binding protein, ln serum C‐reactive protein, and acylcarnitine to free carnitine ratio in the exercise group compared with controls, with significant between‐group differences of −0.579 ± 0.217 (P = 0.008), −1.13 ± 0.35 (P = 0.003), and −0. 058 ± 0.024 (P = 0.01), respectively. Conclusions Our 6 month home‐based exercise programme improved aerobic capacity and HRQOL in patients with Stage 4 CKD, with possible beneficial effects on kidney function and CKD‐related parameters.

Diabetes and hypertension have become the primary causes of chronic kidney disease worldwide. However, there are no established markers for early diagnosis or predicting renal prognosis. Here, we investigated the expression profiles of DNA repair and DNA methylation factors in human urinederived cells as a possible diagnostic or renal prognosis-predicting marker. A total of 75 subjects, aged 63.3 ± 1.9 years old, were included in this study. DNA and RNA were extracted from 50 mL of urine samples. We evaluated DnA double-strand breaks (DSBs) by the quantitative long distance-PCR method and performed real-time RT-PCR analysis to analyze the expression of renal cell-specific markers, DNA DSB repair factor KAT5, DNA methyltransferases DNMTs, and demethylation enzymes tets. in patients with hypertension and diabetes, DnA DSBs of the nephrin gene increased with decreased urine KAT5/nephrin expression, consistent with our previous study (Cell Rep 2019). In patients with hypertension, DNA DSBs of the AQP1 gene were increased with elevated urine DNMTs/ AQP1 and TETs/AQP1 expression. Moreover, urine DNMTs/AQP1 expression was significantly correlated with the annual eGFR decline rate after adjustment for age, baseline eGFR, the presence of diabetes and the amount of albuminuria, suggesting a possible role as a renal prognosis predictor. The prevalence of chronic kidney disease (CKD) has increased globally and become recognized as a worldwide health problem 1. Specifically, the number of CKD caused by diabetes or hypertension is constantly growing along with rapid aging of the world population. The DNA damage repair system is indispensable for maintaining genome integrity, and accumulation of DNA damage is linked to aging and age-related diseases. Recently, we have reported a possible association of KAT5 (lysine acetyltransferase 5, Tip60)-mediated DNA damage repair and DNA methylation changes in kidney glomerular podocytes 2. KAT5, a repair factor of DNA double-strand breaks (DSBs), is crucial for podocyte maintenance, and deletion of podocyte KAT5 caused an increase in DNA DSBs together with increased DNA methylation and expression of DNA methyltransferase 1 (DNMT1) and DNMT3B. Reduced KAT5 expression was observed in the glomeruli of diabetic nephropathy in mouse models and humans. However, the association of KAT5 expression with DNA DSB levels and kidney disease progression has not been clarified. A kidney biopsy is an invasive procedure that is not often performed in patients with an early stage of hypertension or diabetes. In addition, many histological findings of hypertensive nephrosclerosis and diabetic kidney disease are common and coexist; therefore, it is hard to determine which pathophysiology plays a dominant role in patients with both hypertension and diabetes. Urine examinations are noninvasive procedures, and because they identify changes in gene expression in urine-derived cells 3-6 , they may be particularly useful for the noninvasive assessment of kidney condition and prediction of renal outcomes in early ...

Aims: Remote monitoring (RM) can improve management of chronic diseases. We evaluated the impact of RM in automated peritoneal dialysis (APD) in a simulation study. Materials and methods: We simulated 12 patient scenarios with common clinical problems and estimated the likely healthcare resource consumption with and without the availability of RM (RM+ and RM– groups, respectively). Scenarios were evaluated 4 times by randomly allocated nephrologist-nurse teams or nephrologist-alone assessors. Results: The RM+ group was assessed as having significantly lower total healthcare resource consumption compared with the RM– group (36.8 vs. 107.5 total episodes of resource consumption, p = 0.002). The RM+ group showed significantly lower “unplanned hospital visits” (2.3 vs. 11.3, p = 0.005), “emergency room visits” (0.5 vs. 5.3, p = 0.003), “home visits” (0.5 vs. 5.8, p = 0.016), “exchanges over the telephone” (18.5 vs. 57.8, p = 0.002), and “change to hemodialysis” (0.5 vs. 2.5, p = 0.003). Evaluations did not differ between nephrologist-nurse teams vs. nephrologist-alone assessors. Conclusion: RM can be expected to reduce healthcare resource consumption in APD patients.

Accumulation of DnA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DnA DSBs with altered DnA methylation in murine models of kidney disease. However, DSBs and DnA methylation in human kidneys was not adequately investigated. this study was a cross-sectional observational study to evaluate the glomerular DnA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance pcR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DnA methylation level in igA nephropathy. podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of pcR product of the nephrin gene, which indicate podocyte DnA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGfR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in igA nephropathy. Various stresses, including UV radiation, chemicals, reactive oxygen species (ROS), DNA replication errors and mechanical stress, cause DNA damage 1. Although various types of DNA damage have been reported, DNouble-strand breaks (DSBs) are biologically important because of the repair difficulty 2. Accumulation of DNA damage is linked to aging and age-related diseases, such as cancer. Recent studies reported that increased DNA damage and reduced DNA repair capacity also play roles in the pathogenesis of cardiovascular and metabolic diseases 3. Angiotensin II and aldosterone are key factors in kidney disease that cause DNA damage, such as DSBs, and DNA base modification, such as 8-OHdG 4,5. However, the association of DNA DSBs in human kidneys with clinical parameters and pathological findings has not been adequately elucidated. Previous in vitro studies suggested that DNA DSBs and their repair processes induced altered DNA methylation 6-8. We recently investigated the association of DNA DSBs with altered DNA methylation status in glomerular podocytes using murine models of diabetic nephropathy 9. Increased DNA DSBs in podocytes due to both decreased levels of the DNA repair factor KAT5 and increased DNA damage induced by high-glucose conditions increased DNA methylation in the nephrin promoter region. However, the association of DNA DSBs with DNA methylation status in human kidneys was not investigated. IgA nephropathy is the most common glomerulonephritis in many countries, especially countries in Asia...