Published papers

The "preconditioning effect" in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.

Aims/Introduction: The mechanisms of the renoprotective effects of sodium-glucose cotransporter 2 inhibitors are unknown. This study aimed to explore the effect and mechanism of tofogliflozin on urinary albumin by administration, withdrawal, and re-administration. Materials and Methods: Individuals with type 2 diabetes mellitus and stage 2 or 3 diabetic nephropathy were enrolled. Tofogliflozin was administered for 24 weeks, withdrawn for 12 weeks (withdrawal period), and re-administered for 24 weeks. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR). The secondary endpoints included hemoglobin A1c (HbA1c), hepatic biomarkers, lipid profiles, physical examinations, and blood counts. Results: A total of 47 individuals were enrolled. UACR significantly decreased throughout the observation period. It also significantly decreased, increased, and again decreased during the period of the 1st administration, withdrawal, and re-administration, respectively. HbA1c, body weight, waist circumference, and systolic blood pressure also showed the same tendency. Aspartate aminotransferase and alanine aminotransferase significantly decreased throughout the observation period, but did not increase during the withdrawal period. Conclusions: Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects.

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

There are limited data on the nighttime blood pressure (BP)-lowering effect of esaxerenone and its effect on N-terminal pro b-type natriuretic peptide (NT-proBNP), a predictor of cardiovascular risk, according to different dipping patterns of nocturnal BP. This was a post hoc analysis of a multicenter, open-label, long-term phase 3 study of esaxerenone, a new highly selective mineralocorticoid receptor blocker, in patients with essential hypertension. Patients were classified by dipping pattern (extreme dippers, dippers, non-dippers, risers). Mean changes in BP, changes in dipping pattern, mean NT-proBNP levels, and percentage of patients with normal NT-proBNP levels (<55 pg/mL) at baseline and Weeks 12 and 28 were evaluated. Nighttime systolic BP decreased in all dipping pattern groups at Week 28, with the riser group showing the greatest change (-25.5 mmHg). A significant shift in dipping pattern and riser/non-dipper pattern changes to dipper/extreme dipper pattern were found from baseline to Week 28 (p < 0.0001). The prevalence of the riser pattern decreased from 14.4% to 9.8%, and that of the non-dipper pattern from 44.7% to 39.2%. The decrease in NT-proBNP from baseline to Week 28 was statistically significant in risers, non-dippers, dippers, and extreme dippers (p < 0.001, respectively). At baseline, the proportion of patients with NT-proBNP <55 pg/mL was lowest in risers versus the other dipping pattern types, but after reductions in NT-proBNP in all groups to Week 28, these differences disappeared. Long-term administration of esaxerenone may be a useful treatment option for nocturnal hypertension, especially in patients with a riser pattern.

Amiodarone is an effective antiarrhythmic drug. However, it is associated with changes in thyroid function in euthyroid patients due to its high iodine content and intrinsic drug effects. Studies have been conducted in iodine-deficient and iodine-sufficient countries; however, data from countries with excessive iodine intake are lacking. Thus, this study aimed to evaluate the effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients. Japanese adults aged ≥18 years who were treated with amiodarone for at least 90 consecutive days were included in this retrospective chart review. Patients with abnormal thyroid function test results at baseline were excluded. Serial changes in thyroid function tests at baseline and at days 30, 90, 180, 270, and 360 were analyzed using a mixed-effects model for repeated measures. In total, 46 patients with a mean age of 63.7 years were evaluated. The mean TSH level significantly increased from 1.62 μIU/mL at baseline to 3.43, 2.75, 2.84, 2.78, and 2.65 μIU/mL at days 30, 90, 180, 270, and 360, respectively. The mean free T4 level significantly increased from 1.3 ng/dL at baseline to 1.4, 1.5, 1.5, 1.5, and 1.5 ng/dL at days 30, 90, 180, 270, and 360, respectively. The mean free T3 level significantly decreased from 2.8 pg/mL at baseline to 2.4, 2.3, 2.3, 2.4, and 2.4 pg/mL at days 30, 90, 180, 270, and 360, respectively. In conclusion, significant changes in thyroid function persisted not only in the acute phase but also in the chronic phase of long-term amiodarone treatment.

BACKGROUND Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

BACKGROUND: Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. METHODS: CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. RESULTS: IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. CONCLUSIONS: Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.

Objective: Diminished physical capacity is common and progressive in patients undergoing dialysis, who are also prone to deficiency in carnitine, which plays a pivotal role in maintaining skeletal muscle and cardiac function. The present study aimed to evaluate the association of carnitine profile with exercise parameters in patients with incident dialysis. Design and Methods: This was a single-center cross-sectional study including 87 consecutive patients aged 20-90 years who were initiated on dialysis in Keio University Hospital between December 2019 and December 2022 and fulfilled the eligibility criteria. Exercise parameters were evaluated via cardiopulmonary testing (CPX) using the electronically braked STRENGTH ERGO 8 ergometer, whereas the carnitine profile was assessed by determining serum free carnitine (FC), acylcarnitine (AC) levels and AC/FC ratio. Results: The mean cohort age was 62.1 ± 15.2 years, with male and hemodialysis predominance (70% and 73%, respectively). AC/FC was 0.46 ± 0.15, and CPX revealed peak oxygen consumption (VO2) of 13.9 ± 3.7 (mL/kg/min) with percent-predicted peak VO2 of 53.6% ± 14.7% and minute ventilation (VE)/carbon dioxide output (VCO2) slope of 35.1 ± 8.0. Fully-adjusted multivariate linear regression analysis showed that AC/FC was significantly associated with decreased peak VO2 (β, -5.43 [95% confidence interval (CI), -10.15 to -0.70]) and percent-predicted peak VO2 (β, -19.98 [95% CI, -38.43 to -1.52]) and with increased VE/VCO2 slope (β, 13.76 [95% CI, 3.78-23.75]); FC and AC did not exhibit similar associations with these parameters. Moreover, only AC/FC was associated with a decreased peak work rate (WR), percent-predicted WR, anaerobic threshold, delta VO2/delta WR, and chronotropic index. Conclusion: In patients on incident dialysis, exercise parameters, including those related to both skeletal muscle and cardiac function, were strongly associated with AC/FC, a marker of carnitine deficiency indicating altered fatty acid metabolism. Further studies are warranted to determine whether carnitine supplementation can improve exercise capacity in patients on incident dialysis.

Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.