Publications by authors named "Yoshitaka Isaka"

298 Publications

Variability in estimated glomerular filtration rate and patients' outcomes in a real-world heart failure population.

ESC Heart Fail 2021 Sep 23. Epub 2021 Sep 23.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Aims: The prognostic significance of renal function variability has not been fully elucidated in heart failure (HF). This multicentre, prospective cohort study aimed to evaluate the usefulness of visit-to-visit variability in estimated glomerular filtration rate (eGFR) for predicting patients' outcomes in a real-world HF population.

Methods: A total of 564 patients who had survived HF hospitalization were randomly assigned with a 2:1 ratio to derivation and validation cohorts, and they were then followed after discharge. Using the data for 6 months after discharge, each patient's visit-to-visit eGFR variability (EGV) was estimated. In the derivation cohort, Cox regression analyses were performed to assess the association of EGV with a subsequent composite event (death and HF hospitalization). In the validation cohort, the predictive performance was compared among Cox regression models with EGV, those with B-type natriuretic peptide (BNP) and those with eGFR.

Results: In the derivation cohort (376 patients), median age, left ventricular ejection fraction (LVEF), BNP and eGFR at discharge were 72 years, 53.3%, 134.8 pg/mL and 58.7 mL/min/1.73 m , respectively. During a median follow-up of 2.2 years, higher EGV was associated with an increased risk of the composite event (adjusted hazard ratio [per standard deviation increase in log-transformed EGV], 1.5; 95% confidence interval, 1.1-2.0). A similar finding was observed in a stratified analysis by LVEF. In the validation cohort (188 patients), better model fit, discrimination, reclassification and calibration were observed for EGV than for 6-month averaged BNP or eGFR for predicting the composite event when added to HF risk prediction models. Adding EGV to models with BNP or eGFR improved model discrimination and reclassification.

Conclusions: EGV predicts HF outcomes regardless of LVEF. Risk prediction models with EGV have good performance in real-world HF patients. The study findings highlight the clinical importance of observing visit-to-visit fluctuations in renal function in this population.
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http://dx.doi.org/10.1002/ehf2.13557DOI Listing
September 2021

Renoprotection by long-term low-dose tolvaptan in patients with heart failure and hyponatremia.

ESC Heart Fail 2021 Sep 23. Epub 2021 Sep 23.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

Aims: In previous randomized controlled trials, the use of tolvaptan (TLV) at a fixed dose of 30 mg/day for 1 year did not provide renal benefits in patients with heart failure (HF). This retrospective, cohort study examined the renoprotective effects of long-term, flexible-dose, and lower-dose TLV use.

Methods And Results: Tolvaptan users were defined as patients receiving TLV for at least 180 consecutive days or those who continued it until death, any cardiac events, or renal replacement therapy even if it was taken for <180 days. Of a total of 584 HF patients, 78 TLV users were identified. The median age, baseline B-type natriuretic peptide, and estimated glomerular filtration rate (eGFR) were 71 years, 243 pg/mL, and 54 mL/min/1.73 m , respectively. During follow-up (median, 461 days), TLV use (median average dose, 7.5 mg/day) was associated with frequent dose reductions of loop diuretics (incidence rate ratio [IRR], 1.5; 95% confidence interval [CI], 1.1-2.2), particularly in patients with serum sodium ≤135 mEq/L (IRR, 2.9; 95% CI, 1.5-5.7) (P  = 0.04). In a mixed effects model, propensity score (PS)-matched TLV users had higher eGFRs over time than PS-matched never-users (P < 0.01). The entire cohort analyses (N = 584) yielded similar results. The renal benefit of TLV in terms of annualized eGFR slope was more pronounced in patients with lower sodium levels (P  = 0.03). This effect modification was extinguished when patients who underwent a loop diuretic dose reduction during the follow-up period were excluded from the analysis.

Conclusions: Long-term, flexible-dose, and low-dose TLV use was associated with better renal function, particularly in hyponatremic HF, possibly due to its loop diuretic dose-sparing effect in the long term.
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http://dx.doi.org/10.1002/ehf2.13507DOI Listing
September 2021

Demographic, clinical characteristics and treatment outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulonephritis in Japan: A retrospective analysis of data from the Japan Renal Biopsy Registry.

PLoS One 2021 14;16(9):e0257397. Epub 2021 Sep 14.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on immunofluorescence findings in kidney biopsies has provided insights into these two distinct diseases. C3G is further classified into dense deposit disease and C3 glomerulonephritis (C3GN) based on electron micrographic findings. Although these diseases have poor outcomes, limited Japanese literature confined to small, single-center cohorts exist on these diseases. We retrospectively analyzed 81 patients with MPGN type I and III from 15 hospitals in the Japan Renal Biopsy Registry to compare demographic, clinical characteristics and treatment outcomes of patients with IC-MPGN to those with C3GN. Of the 81 patients reviewed by immunofluorescence findings in kidney biopsies, 67 patients had IC-MPGN and 14 patients had C3GN. Age at diagnosis and systolic and diastolic pressure were higher and proteinuria and impaired renal function were significantly more prevalent in patients with IC-MPGN than those with C3GN. About 80% of the patients in both groups were treated with immunosuppressive therapy. At last follow-up (median 4.8 years), complete remission rate of proteinuria was significantly higher in patients with C3GN (64.3%) than in those with IC-MPGN (29.9%; P = 0.015). The renal survival rate was lower in patients with IC-MPGN when compared to C3GN (73.1% vs. 100%; log-rank, P = 0.031). Systolic blood pressure and renal function at baseline were independent predictors of progression to end-stage kidney disease. The overall prognosis of patients with C3GN is more favorable than for patients with IC-MPGN.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257397PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439563PMC
September 2021

Focal segmental glomerulosclerosis histologic variants and renal outcomes based on nephrotic syndrome, immunosuppression, and proteinuria remission.

Nephrol Dial Transplant 2021 Sep 9. Epub 2021 Sep 9.

Department of Internal Medicine, JR Sendai Hospital, Miyagi, Japan.

Background: The associations of focal segmental glomerulosclerosis (FSGS) histologic variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age.

Methods: Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression, and proteinuria remission (PR, proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression, and PR with outcomes were examined for each variant.

Results: The distribution of variants was 48% (n = 145) FSGS not otherwise specified (NOS), 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular, and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants (hazard ratio adjusted for histologic variant and potential confounders [adjusted HR]: 0.19 [95% confidence interval (CI), 0.10-0.34]). NS was marginally associated with better outcome compared with non-NS (adjusted HR: 0.50 [95% CI, 0.25-1.01].

Conclusions: FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.
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http://dx.doi.org/10.1093/ndt/gfab267DOI Listing
September 2021

Quantitative Analyses of Foot Processes, Mitochondria, and Basement Membranes by Structured Illumination Microscopy Using Elastica-Masson- and Periodic-Acid-Schiff-Stained Kidney Sections.

Kidney Int Rep 2021 Jul 1;6(7):1923-1938. Epub 2021 May 1.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

Introduction: Foot process effacement and mitochondrial fission associate with kidney disease pathogenesis. Electron microscopy is the gold-standard method for their visualization, but the observable area of electron microscopy is smaller than light microscopy. It is important to develop alternative ways to quantitatively evaluate these microstructural changes because the lesion site of renal diseases can be focal.

Methods: We analyzed elastica-Masson trichrome (EMT) and periodic acid-Schiff (PAS) stained kidney sections using structured illumination microscopy (SIM).

Results: EMT staining revealed three-dimensional (3D) structures of foot process, whereas ponceau xylidine acid fuchsin azophloxine solution induced fluorescence. Conversion of foot process images into their constituent frequencies by Fourier transform showed that the concentric square of (1/4)-(1/16) in the power spectra (PS) included information for normal periodic structures of foot processes. Foot process integrity, assessed by PS, negatively correlated with proteinuria. EMT-stained sections revealed fragmented mitochondria in mice with mitochondrial injuries and patients with tubulointerstitial nephritis; Fourier transform quantified associated mitochondrial injury. Quantified mitochondrial damage in patients with immunoglobulin A (IgA) nephropathy predicted a decline in estimated glomerular filtration rate (eGFR) after kidney biopsy but did not correlate with eGFR at biopsy. PAS-stained sections, excited by a 640 nm laser, combined with the coefficient of variation values, quantified subtle changes in the basement membranes of patients with membranous nephropathy stage I.

Conclusions: Kidney microstructures are quantified from sections prepared in clinical practice using SIM.
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http://dx.doi.org/10.1016/j.ekir.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258503PMC
July 2021

Association of Time-Updated Anion Gap With Risk of Kidney Failure in Advanced CKD: A Cohort Study.

Am J Kidney Dis 2021 Jul 16. Epub 2021 Jul 16.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

Rationale & Objective: High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD.

Study Design: Retrospective cohort study.

Setting & Participants: 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap.

Exposure: High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile).

Outcome: KFRT and death.

Analytical Approach: Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding.

Results: The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m. Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P < 0.001). This association was stronger in patients with a baseline eGFR of <30 mL/min/1.73 m (P for interaction = 0.05). High anion gap was also associated with a higher mortality rate (HR, 5.56 [95% CI, 2.95-10.5]; P < 0.001). Sensitivity analyses with different definitions of high anion gap showed similar results.

Limitations: Observational study design and selection bias due clinical indications for measuring anion gap.

Conclusions: Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.022DOI Listing
July 2021

Recurrent membranous nephropathy with a possible alteration in the etiology: a case report.

BMC Nephrol 2021 Jul 6;22(1):253. Epub 2021 Jul 6.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Background: Phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major pathogenic antigens for membranous nephropathy (MN). It has been reported that THSD7A-associated MN has a higher prevalence of comorbid malignancy than PLA2R1-associated MN. Here we present a case of MN whose etiology might change from idiopathic to malignancy-associated MN during the patient's clinical course.

Case Presentation: A 68-year-old man with nephrotic syndrome was diagnosed with MN by renal biopsy. Immunohistochemistry showed that the kidney specimen was negative for THSD7A. The first course of corticosteroid therapy achieved partial remission; however, nephrotic syndrome recurred 1 year later. Two years later, his abdominal echography revealed a urinary bladder tumor, but he did not wish to undergo additional diagnostic examinations. Because his proteinuria increased consecutively, corticosteroid therapy was resumed, but it failed to achieve remission. Another kidney biopsy was performed and revealed MN with positive staining for THSD7A. PLA2R1 staining levels were negative for both first and second biopsies. Because his bladder tumor had gradually enlarged, he agreed to undergo bladder tumor resection. Pathological examination indicated that the tumor was THDS7A-positive bladder cancer. Subsequently, his proteinuria decreased and remained in remission.

Conclusions: This case suggests that the etiology of MN might be altered during the therapeutic course. Intensive screening for malignancy may be preferable in patients with unexpected recurrence of proteinuria and/or change in therapy response.
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http://dx.doi.org/10.1186/s12882-021-02457-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258946PMC
July 2021

Mean corpuscular hemoglobin concentration: an anemia parameter predicting cardiovascular disease in incident dialysis patients.

J Nephrol 2021 Jul 2. Epub 2021 Jul 2.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Background: Hemoglobin levels usually decline before dialysis initiation. The influence of overhydration on anemia progression and iron sequestration is poorly documented. Furthermore, clinical implications of anemia at dialysis initiation remain to be elucidated.

Methods: This multicenter retrospective cohort study enrolled incident dialysis patients. The patients were stratified by tertiles of overhydration rate (OH-R) defined by (BW - DW)/DW*100 (BW: body weight just before dialysis initiation, DW: dry weight). Time courses (6 months before, to 1 month after, dialysis initiation) of hemoglobin, C-reactive protein (CRP), and iron sequestration index (ISI) were examined using mixed effects models. We used Cox models to identify anemia parameters predicting subsequent cardiovascular disease (CVD).

Results: Among the 905 enrolled patients, hemoglobin levels gradually decreased before dialysis initiation and rapidly increased thereafter. An inverse V-shaped time course was observed for CRP and ISI with an increase during dialysis initiation. Patients with a higher OH-R showed lower hemoglobin levels along with higher CRP and ISI levels before dialysis initiation. Mean corpuscular hemoglobin concentration (MCHC) was more stable before dialysis initiation than were mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Low MCHC (< 32 g/dL) was independently associated with the incidence of nonatherosclerotic CVD. Patients with low MCHC tended to have increased left ventricular wall thickness and left atrial diameter.

Conclusions: Progression of anemia before dialysis among overhydrated patients may mainly occur through hemodilution and iron sequestration partly induced by inflammation. Low MCHC reflects left atrial overload and left ventricular hypertrophy and hence may predict nonatherosclerotic CVD.
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http://dx.doi.org/10.1007/s40620-021-01107-wDOI Listing
July 2021

Cyclosporine A Treatment of Proteinuria in a New Case of MAFB-Associated Glomerulopathy without Extrarenal Involvement: A Case Report.

Nephron 2021 11;145(4):445-450. Epub 2021 May 11.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The MAFB gene encodes an important basic leucine zipper transcription factor that functions in glomerular podocytes, macrophages, and osteoclasts. Recently, MAFB was identified as the gene that was responsible for causing nephropathy with focal segmental glomerulosclerosis (FSGS) with multicentric carpotarsal osteolysis (MCTO) or Duane retraction syndrome (DRS). Here, we describe a patient with nephropathy associated with FSGS who exhibited a novel stop-gain variant in the MAFB gene (NM_005461:c.590C>A (p.Ser197Ter)). The patient's father exhibited proteinuria with FSGS with possible DRS, whereas the patient exhibited nephropathy with FSGS and nearly normal eye movement and hearing function, as well as intact bone structure in the extremities. Conventional oral steroids or immunosuppressive drugs have not demonstrated effectiveness for patients with nephropathy who exhibit pathogenic variants in MAFB, except for a patient with nephropathy with FSGS and MCTO who experienced attenuated proteinuria within the subnephrotic range in response to cyclosporine A (CyA) treatment for at least 4 years. Thus, we attempted administration of CyA in our patient. Unexpectedly, the patient demonstrated good and rapid responses to CyA, including a partial reduction in proteinuria from approximately 2.0 g/g Cr to proteinuria within the subnephrotic range (0.27 g/g Cr) after 13 months of observation. Our findings suggest that CyA may be a suitable treatment option for patients with nephropathy with FSGS who exhibit pathogenic MAFB variants.
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http://dx.doi.org/10.1159/000516248DOI Listing
May 2021

Optimal Protein Intake in Pre-Dialysis Chronic Kidney Disease Patients with Sarcopenia: An Overview.

Authors:
Yoshitaka Isaka

Nutrients 2021 Apr 6;13(4). Epub 2021 Apr 6.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.

Multi-factors, such as anorexia, activation of renin-angiotensin system, inflammation, and metabolic acidosis, contribute to malnutrition in chronic kidney disease (CKD) patients. Most of these factors, contributing to the progression of malnutrition, worsen as CKD progresses. Protein restriction, used as a treatment for CKD, can reduce the risk of CKD progression, but may worsen the sarcopenia, a syndrome characterized by a progressive and systemic loss of muscle mass and strength. The concomitant rate of sarcopenia is higher in CKD patients than in the general population. Sarcopenia is also associated with mortality risk in CKD patients. Thus, it is important to determine whether protein restriction should be continued or loosened in CKD patients with sarcopenia. We may prioritize protein restriction in CKD patients with a high risk of end-stage kidney disease (ESKD), classified to stage G4 to G5, but may loosen protein restriction in ESKD-low risk CKD stage G3 patients with proteinuria <0.5 g/day, and rate of eGFR decline <3.0 mL/min/1.73 m/year. However, the effect of increasing protein intake alone without exercise therapy may be limited in CKD patients with sarcopenia. The combination of exercise therapy and increased protein intake is effective in improving muscle mass and strength in CKD patients with sarcopenia. In the case of loosening protein restriction, it is safe to avoid protein intake of more than 1.5 g/kgBW/day. In CKD patients with high risk in ESKD, 0.8 g/kgBW/day may be a critical point of protein intake.
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http://dx.doi.org/10.3390/nu13041205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067427PMC
April 2021

Correcting anemia and native vitamin D supplementation in kidney transplant recipients: a multicenter, 2 × 2 factorial, open-label, randomized clinical trial.

Transpl Int 2021 07 15;34(7):1212-1225. Epub 2021 Jun 15.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

Anemia and vitamin D deficiency are associated with allograft failure, and hence, are potential therapeutic targets among kidney transplant recipients (KTRs). We conducted a multicenter, two-by-two factorial, open-label, randomized clinical trial to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among KTRs (CANDLE-KIT). We enrolled 153 patients with anemia and >1-year history of transplantation across 23 facilities in Japan, and randomly assigned them to either a high or low hemoglobin target (>12.5 vs. <10.5 g/dl) and to either cholecalciferol 1000 IU/day or control. This trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034). Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (i.e., -1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m ; P = 0.021), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. In conclusion, aggressive anemia correction showed a potential to preserve allograft kidney function.
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http://dx.doi.org/10.1111/tri.13885DOI Listing
July 2021

Intra-body dynamics of D-serine reflects the origin of kidney diseases.

Clin Exp Nephrol 2021 Aug 25;25(8):893-901. Epub 2021 Mar 25.

KAGAMI Project, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.

Introduction: D-Serine, present only in trace amounts in humans, is now recognized as a biomarker of chronic kidney disease (CKD). CKD is heterogeneous in its original kidney diseases, whose diagnoses require kidney biopsy. In this study, we examined whether the intra-body dynamics of D-serine, indexed by its blood and urinary levels, reflects the origin of kidney diseases.

Methods: Patients with six kinds of kidney disease undergoing kidney biopsy were enrolled in a single center. Levels of D- and L-serine were measured using two-dimensional high-performance liquid chromatography. The associations between the origin of kidney diseases and the intra-body dynamics of D-serine were examined using multivariate cluster analyses.

Results: Unlike the non-CKD profile, patients with CKD showed broadly-distributed profiles of intra-body dynamics of D-serine. The plasma level of D-serine plays a key role in the detection of kidney diseases, whereas a combination of plasma and urinary levels of D-serine distinguished the origin of CKD, especially lupus nephritis.

Conclusion: Intra-body dynamics of D-serine have the potential to predict the origin of kidney diseases. Monitoring of D-serine may guide specific treatments for the origin of kidney diseases.
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http://dx.doi.org/10.1007/s10157-021-02052-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260539PMC
August 2021

Incidence and factors associated with prescribing renin-angiotensin-system inhibitors in adult idiopathic nephrotic syndrome: A nationwide cohort study.

J Clin Hypertens (Greenwich) 2021 05 1;23(5):999-1007. Epub 2021 Mar 1.

Department of Clinical Epidemiology, Graduate School of Medicine, Fukushima Medical University, Fukushima, Japan.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are prescribed as conservative or adjunctive therapies for adult idiopathic nephrotic syndrome. However, studies on real-world practice patterns are scarce. This study aimed to examine the prevalence and incidence of ACEI/ARB prescription and their associated factors. This nationwide cohort study included adult Japanese patients with idiopathic nephrotic syndrome including minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and others. The outcomes were the prevalence of ACEI/ARB prescription at baseline (date of renal biopsy or date of immunosuppressant initiation) and at 2 months after baseline. Of the 326 eligible patients, 122 (37.4%) had already been prescribed ACEIs/ARBs. Of the remaining 204 patients, 67 (32.7%) were newly prescribed within the 2-month period. MN/FSGS (vs. MCD, adjusted odds ratio [AOR]: 4.96 [95% confidence interval {CI} 2.53-9.72] and 3.95 [95% CI 1.61-9.66], respectively), higher age (per 1-yr increase, AOR: 1.02 [95% CI 1.00-1.04]), other hypertensive agents (AOR: 2.18 [95% CI 1.21-3.92]), antidiabetic drug (AOR: 6.57 [95% CI 1.77-24.4]) were associated with a higher prevalence of ACEI/ARB prescription. MN (vs. MCD, AOR: 6.00 [95% CI 2.57-14.0]) and higher baseline systolic blood pressure (SBP) (per 10-mmHg increase, AOR: 1.36 [95% CI 1.09-1.70]) were associated with a higher incidence of ACEI/ARB prescription. On average, incidence of ACEI/ARB prescription increased from 19.2% to 40.8% as baseline SBP increased from 100 to 140 mmHg. Thus, Japanese nephrologists are likely to prescribe ACEIs/ARBs for nephrotic patients with MN or high baseline SBP, even below the hypertensive range.
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http://dx.doi.org/10.1111/jch.14224DOI Listing
May 2021

THOC4 regulates energy homeostasis by stabilizing mRNA during prolonged starvation.

J Cell Sci 2021 03 22;134(6). Epub 2021 Mar 22.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

TFEB, a basic helix-loop-helix transcription factor, is a master regulator of autophagy, lysosome biogenesis and lipid catabolism. Compared to posttranslational regulation of TFEB, the regulation of mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to mRNA and stabilized it after transcription by maintaining poly(A) tail length. We further found that this mode of regulation was conserved in and was essential for TFEB-mediated lipid breakdown, which becomes over-represented during prolonged starvation. Taken together, our findings reveal the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function of TFEB in mediating autophagy and lipid metabolism.
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http://dx.doi.org/10.1242/jcs.248203DOI Listing
March 2021

The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study.

Am J Transplant 2021 09 6;21(9):3043-3054. Epub 2021 Mar 6.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m (95% CI; -0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m (95% CI, -0.02 to 3.7) in the placebo group, with no significant between-group difference (-0.7 mL/min/1.73 m [95% CI; -3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m (P <0.05, between-group difference; -4.3 mL/min/1.73 m [95% CI; -7.3 to -1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs. Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN000020597 (please refer to the links below). UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023776.
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http://dx.doi.org/10.1111/ajt.16530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518814PMC
September 2021

Clinical characteristics of COVID-19 infection in a dialysis center during a nosocomial outbreak.

Clin Exp Nephrol 2021 Jun 8;25(6):652-659. Epub 2021 Feb 8.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Blood purification therapy is a treatment method, wherein many patients gather in the same space to receive regular treatments, possibly increasing the risk of contracting the coronavirus disease 2019 (COVID-19) through contact, droplet, and aerosol. We experienced a nosocomial outbreak and evaluated the clinical characteristics of COVID-19 infection in patients undergoing blood purification therapy.

Methods: We retrospectively analyzed 28 patients who underwent blood purification therapy at the dialysis center of our hospital from April 2, 2020, to April 29, 2020. Logistic regression analysis was performed to identify clinical factors related to COVID-19 for 18 patients who were tested using real-time reverse transcriptase-polymerase chain reaction (RT-PCR).

Results: Of the 28 patients, seven were COVID-19 positive, as confirmed by RT-PCR. The median age was 77 years, 22 patients were male (79%), four patients had acute kidney injury (14%), and six patients were bedridden (21%). All infected patients had been admitted to the wards where the nosocomial outbreak had occurred. Logistic regression analysis revealed that being bedridden (odds ratio 13.33, 95% confidence interval 1.05-169.56, p < 0.05) was significantly related to COVID-19 infection. However, the Charlson comorbidity index, receiving dialysis in the same room, and adjacency of the dialysis bed to COVID-19-positive patients before the confirmation of infection did not reveal any significant relationship.

Conclusion: Bedridden patients admitted to nosocomial infection wards were associated with COVID-19 infection, and transmission within the dialysis center was not observed. More rigorous infection control measures need to be implemented for bedridden patients undergoing blood purification therapy.
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http://dx.doi.org/10.1007/s10157-021-02025-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869077PMC
June 2021

Optimal Phosphate Control Related to Coronary Artery Calcification in Dialysis Patients.

J Am Soc Nephrol 2021 03 5;32(3):723-735. Epub 2021 Feb 5.

Department of Biostatistics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges.

Methods: We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment.

Results: The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1; =0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants ( value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores.

Conclusions: Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis.

Clinical Trial Registry Name And Registration Number: Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.
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http://dx.doi.org/10.1681/ASN.2020050598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920180PMC
March 2021

Dermatologist and Patient Perceptions of Treatment Success in Alopecia Areata and Evaluation of Clinical Outcome Assessments in Japan.

Dermatol Ther (Heidelb) 2021 Apr 10;11(2):433-447. Epub 2021 Jan 10.

Medical Development Unit, Eli Lilly Japan K.K., Kobe, Japan.

Introduction: The content validity and treatment success thresholds of clinical outcome assessments (COAs) for alopecia areata (AA)-including the Alopecia Areata-Investigator Global Assessment™ (AA-IGA™), Scalp Hair Assessment Patient-Reported Outcome™ (PRO), and clinician-reported outcome (ClinRO) and PRO measures for eyebrows, eyelashes, eye irritation, and nails-were established in interviews with dermatologists and patients in North America. This study aimed to confirm the content validity and treatment success thresholds of these measures with clinicians and patients in Japan.

Methods: Qualitative interviews were conducted in Japan with dermatologists with AA expertise and adults with AA who experienced ≥ 50% scalp hair loss. Interviews included concept elicitation and cognitive interview questions. Data were analyzed using thematic and framework techniques.

Results: Seven dermatologists and 15 patients participated. Scalp hair loss was the most important sign/symptom of AA and the greatest treatment priority. Dermatologists and patients understood the AA-IGA™, Scalp Hair Assessment PRO™, and other COAs, and found these measures to be appropriate, relevant, and clinically meaningful. Dermatologists and patients confirmed that achieving ≤ 20% scalp hair loss (AA-IGA™/Scalp Hair Assessment PRO™ categories 0 or 1) indicated treatment success for patients with ≥ 50% scalp hair loss. Categories 0 or 1 on the other COAs represented treatment success.

Conclusion: This study confirmed the content validity and treatment success thresholds of the AA-IGA™, Scalp Hair Assessment PRO™, and other ClinRO and PRO measures for AA in Japan. These findings were aligned with interview results in North America and support the use of these measures in AA treatment studies.
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http://dx.doi.org/10.1007/s13555-020-00477-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019002PMC
April 2021

Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney.

Sci Rep 2021 01 8;11(1):73. Epub 2021 Jan 8.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Kidney development requires the coordinated growth and differentiation of multiple cells. Despite recent single cell profiles in nephrogenesis research, tools for data analysis are rapidly developing, and offer an opportunity to gain additional insight into kidney development. In this study, single-cell RNA sequencing data obtained from embryonic mouse kidney were re-analyzed. Manifold learning based on partition-based graph-abstraction coordinated cells, reflecting their expected lineage relationships. Consequently, the coordination in combination with ForceAtlas2 enabled the inference of parietal epithelial cells of Bowman's capsule and the inference of cells involved in the developmental process from the S-shaped body to each nephron segment. RNA velocity suggested developmental sequences of proximal tubules and podocytes. In combination with a Markov chain algorithm, RNA velocity suggested the self-renewal processes of nephron progenitors. NicheNet analyses suggested that not only cells belonging to ureteric bud and stroma, but also endothelial cells, macrophages, and pericytes may contribute to the differentiation of cells from nephron progenitors. Organ culture of embryonic mouse kidney demonstrated that nerve growth factor, one of the nephrogenesis-related factors inferred by NicheNet, contributed to mitochondrial biogenesis in developing distal tubules. These approaches suggested previously unrecognized aspects of the underlying mechanisms for kidney development.
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http://dx.doi.org/10.1038/s41598-020-80154-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794461PMC
January 2021

Electrocardiogram findings at the initiation of hemodialysis and types of subsequent cardiovascular events.

Hypertens Res 2021 05 4;44(5):571-580. Epub 2021 Jan 4.

Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The prognostic value of electrocardiograms (ECGs) has been reported in predialysis patients but not in incident hemodialysis patients with overhydration and electrolyte disturbances, both of which potentially affect ECG results. We performed a retrospective multicenter cohort study involving incident hemodialysis patients and examined whether ECG parameters immediately before hemodialysis initiation can predict subsequent cardiovascular disease (CVD) using Cox proportional hazards models. We explored potential effect modifications by several electrolytes on the predictive power of ECG abnormalities. Among the 618 enrolled patients, 16%, 10%, 46%, and 22% showed a PR interval ≥ 200 ms, QRS interval ≥120 ms, QTc interval ≥ 450/460 ms (male/female), and left ventricular hypertrophy (LVH) by voltage criteria, respectively. Over a median 3-year follow-up, 19% and 16% of the patients developed atherosclerotic and nonatherosclerotic CVD, respectively. The Cox regression model results revealed that the sum of the number of abnormalities in PR, QRS, and QT intervals was a significant risk factor for nonatherosclerotic CVD (hazard ratios (HRs) [95% confidence interval (CI)]: 1.58 [1.24-2.01] per number of abnormalities). The predictive value of LVH for atherosclerotic CVD was attenuated over time. At up to 36 months, although the proportional hazards assumption was met, LVH was significantly associated with atherosclerotic CVD (HR [95% CI]: 1.89 [1.15-3.11]). The adjusted HR was particularly high (HR [95% CI]: 4.02 [1.68-9.60]) among patients who were in the lowest tertile of serum magnesium levels (P for interaction = 0.04). PR, QRS, and QT prolongation additively predicted nonatherosclerotic CVD, while LVH predicted atherosclerotic CVD in the short term.
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http://dx.doi.org/10.1038/s41440-020-00592-zDOI Listing
May 2021

Efficacy of aerobic exercise on the cardiometabolic and renal outcomes in patients with chronic kidney disease: a systematic review of randomized controlled trials.

J Nephrol 2021 02 2;34(1):155-164. Epub 2021 Jan 2.

Department of Nephrology, Saitama Medical University, Iruma-gun, Saitama, Japan.

Background: Several randomized controlled trials (RCTs) have demonstrated the cardiometabolic effects of aerobic exercise in the general population and in patients with cardiovascular diseases. However, the efficacy of aerobic exercise in patients with chronic kidney disease (CKD) remains to be elucidated.

Methods: RCTs comparing aerobic exercise with no aerobic exercise in patients with CKD not requiring kidney replacement therapy were identified through PubMed using RobotAnalyst, a web-based software system that combines text-mining and machine learning algorithms for organizing references. Cardiometabolic and renal outcomes of interest included body mass index (BMI); systolic blood pressure (SBP); hemoglobin A1c (HbA1c), total cholesterol (TCHO), low- and high- density lipoprotein cholesterol (LDLC and HDLC, respectively), and urinary protein (UP) levels/concentration; peak oxygen uptake (Vopeak); and glomerular filtration rate (GFR) at the end of the follow-up period. The standardized mean difference (SMD) of each outcome was estimated using the DerSimonian-Laird random-effect model with inverse-variance weighting.

Results: A total of 15 trials, including 622 patients, were included. Their follow-up periods were 3-4, 6-12, and > 12-months in 7 (46.7%), 7 (46.7%), and 1 (6.7%) trial(s), respectively. Meta-analyses showed that aerobic exercise significantly decreased BMI (SMD, -0.19 [95% confidence interval, -0.38, -0.00]) and SBP (-0.75 [-1.24, -0.26]) and increased Vopeak (0.54 [0.29, 0.78]); however, no significant association was observed in HbA1c, TCHO, HDLC, LDLC, GFR, and UP. Meta-regression models suggested that aerobic exercise was more likely to improve Vopeak in patients with younger age, no diabetes, and lower BMI.

Conclusion: Aerobic exercise of 3-12 months' duration improved obesity, high blood pressure, and low exercise capacity in overweight/obese patients with CKD, but it had no significant effect on GFR and proteinuria. Well-designed large RCTs with a longer follow-up period are needed to evaluate the efficacy of aerobic exercise in patients with CKD.
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http://dx.doi.org/10.1007/s40620-020-00865-3DOI Listing
February 2021

Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy.

Nephrol Dial Transplant 2020 Dec 24. Epub 2020 Dec 24.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN.

Methods: Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion.

Results: Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria.

Conclusions: uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.
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http://dx.doi.org/10.1093/ndt/gfaa298DOI Listing
December 2020

Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin.

Am J Physiol Endocrinol Metab 2021 02 7;320(2):E179-E190. Epub 2020 Dec 7.

Department of Metabolic Medicine, Graduate School of Medicine and Faculty of Medicine, Osaka University, Suita, Japan.

Adiponectin (APN) is a circulating protein specifically produced by adipocytes. Native APN specifically binds to T-cadherin, a glycosylphosphatidylinositol-anchored protein, mediating the exosome-stimulating effects of APN in endothelial, muscle, and mesenchymal stem cells. It was previously reported that APN has beneficial effects on kidney diseases, but the role of T-cadherin has not been clarified yet. Here, our immunofluorescence study indicated the existence of both T-cadherin and APN protein in pericytes, subsets of tissue-resident mesenchymal stem/progenitor cells positive for platelet-derived growth factor receptor β (PDGFRβ), surrounding peritubular capillaries. In an acute renal ischemia-reperfusion (I/R) model, T-cadherin-knockout (Tcad-KO) mice, similar to APN-KO mice, exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability than wild-type mice. In addition, in response to I/R-injury, the renal PDGFRβ-positive cell area increased in wild-type mice, but opposingly decreased in both Tcad-KO and APN-KO mice, suggesting severe pericyte loss. Mouse primary pericytes also expressed T-cadherin. APN promoted exosome secretion in a T-cadherin-dependent manner. Such exosome production from pericytes may play an important role in maintaining the capillary network and APN-mediated inhibition of renal tubular injury. In summary, our study suggested that APN protected the kidney in an acute renal injury model by binding to T-cadherin. In the kidney, T-cadherin-associated adiponectin protein existed on peritubular capillary pericytes. In an acute renal ischemia-reperfusion model, deficiency of adiponectin or T-cadherin exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability, accompanied by severe pericyte loss. In vitro, adiponectin promoted exosome secretion from mouse primary pericytes in a T-cadherin-dependent manner. Adiponectin plays an important role in maintaining the capillary network and amelioration of renal tubular injury by binding to T-cadherin.
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http://dx.doi.org/10.1152/ajpendo.00393.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260375PMC
February 2021

Frequency of Breakfast, Lunch, and Dinner and Incidence of Proteinuria: A Retrospective Cohort Study.

Nutrients 2020 Nov 19;12(11). Epub 2020 Nov 19.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2-D11 Yamadaoka, Suita, Osaka 565-0871, Japan.

Although multiple studies have revealed a close association of skipping breakfast with cardiometabolic diseases, few studies have reported its association with chronic kidney disease (CKD). Furthermore, there is scant reporting on the clinical impacts that skipping lunch and dinner has on cardiometabolic diseases and CKD. This retrospective cohort study, including 5439 female and 4674 male workers of a national university in Japan who underwent annual health checkups between January 2005 and March 2013, aimed to assess an association of frequencies of breakfast, lunch, and dinner with incidence of proteinuria (dipstick urinary protein ≥1+). The incidence of proteinuria was observed in 763 (14.0%) females and 617 (13.2%) males during the median 4.3 and 5.9 years of the observational period, respectively. In females, skipping breakfast as well as skipping dinner, but not lunch, were associated with the incidence of proteinuria (adjusted hazard ratios of breakfast frequency of "every day", "sometimes", and "rarely": 1.00 (reference), 1.35 (1.09-1.66), and 1.54 (1.22-1.94), respectively; those of dinner frequency of "every day" and "≤sometimes": 1.00 (reference) and 1.31 (1.00-1.72), respectively). However, no association was observed in male workers. Skipping breakfast and skipping dinner were identified as risk factors of proteinuria in females, but not in males.
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http://dx.doi.org/10.3390/nu12113549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699477PMC
November 2020

Recurrence of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Deposits with a Striated Ultrastructure.

Nephron 2020 23;144 Suppl 1:43-48. Epub 2020 Nov 23.

Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.

A 64-year-old man with nephrotic syndrome was admitted to another hospital where his renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) with monoclonal immunoglobulin (Ig) G, subclass 1, κ light chain (IgG1κ) deposition on immunofluorescence (IF). Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) was suspected due to monoclonal IgG1κ deposits and the absence of hematological abnormalities. However, the typical PGNMID phenotype was not observed by electron microscopy. Instead, an organized and striated muscle-like structure was observed in the subendothelial space. Since a 2-year treatment with immunosuppressants did not improve his proteinuria, a second biopsy was performed at our hospital. It showed an MPGN-like phenotype; however, monoclonal Ig deposits on IF were no longer observed. One year after the second biopsy, he developed ESRD. Thus, he underwent living kidney transplantation from his wife. Allograft biopsy was performed as proteinuria was observed 3 months after transplantation, which again showed an MPGN-like phenotype with monoclonal IgG1κ deposits. The observed electron-dense deposits were similar to those in the native biopsies. Accordingly, the patient was diagnosed with recurrent MPGN. Adding methylprednisolone pulse therapy to conventional immunosuppressants did not improve the patient's renal function or proteinuria. He died of Legionella pneumonia 8 months after transplantation. Considering the patient's histological findings of MPGN with monoclonal IgG1κ deposits and early recurrence of glomerulonephritis after transplantation, he was diagnosed with PGNMID with novel electron-dense deposits.
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http://dx.doi.org/10.1159/000512330DOI Listing
November 2020

Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity.

Cardiovasc Drugs Ther 2021 04 18;35(2):381-397. Epub 2020 Nov 18.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Purpose: Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency.

Methods: In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT.

Results: OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A.

Conclusion: Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.
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http://dx.doi.org/10.1007/s10557-020-07111-9DOI Listing
April 2021

Dietary casein, egg albumin, and branched-chain amino acids attenuate phosphate-induced renal tubulointerstitial injury in rats.

Sci Rep 2020 11 4;10(1):19038. Epub 2020 Nov 4.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Dietary phosphate intake is closely correlated with protein intake. However, the effects of the latter on phosphate-induced organ injuries remain uncertain. Herein, we investigated the effects of low (10.8%), moderate (23.0%), and high (35.2%) dietary casein and egg albumin administration on phosphate-induced organ injuries in rats. The moderate and high casein levels suppressed renal tubulointerstitial fibrosis and maintained mitochondrial integrity in the kidney. The serum creatinine levels were suppressed only in the high casein group. Phosphate-induced muscle weakness was also ameliorated by high dietary casein. The urinary and fecal phosphate levels in the early experiment stage showed that dietary casein did not affect phosphate absorption from the intestine. High dietary egg albumin showed similar kidney protective effects, while the egg albumin effects on muscle weakness were only marginally significant. As the plasma branched-chain amino acid levels were elevated in casein- and egg albumin-fed rats, we analyzed their effects. Dietary supplementation of 10% branched-chain amino acids suppressed phosphate-induced kidney injury and muscle weakness. Although dietary protein restriction is recommended in cases of chronic kidney disease, our findings indicate that the dietary casein, egg albumin, and branched-chain amino acid effects might be reconsidered in the era of a phosphate-enriched diet.
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http://dx.doi.org/10.1038/s41598-020-76228-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643071PMC
November 2020

Prevalences of hyperuricemia and electrolyte abnormalities in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB).

PLoS One 2020 15;15(10):e0240402. Epub 2020 Oct 15.

Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan.

Background: The Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD.

Methods: In total, 35,508 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively.

Results: Logistic regression analysis showed that prevalence of hyperuricemia was associated with CKD stages G3b (adjusted odds ratio [95% confidence interval]: 2.12 [1.90-2.37]), G4 (4.57 [3.92-5.32]), and G5 (2.25 [1.80-2.80]). The respective prevalences of hyponatremia, hypercalcemia, hyperphosphatemia, and narrower difference between serum sodium and chloride concentrations were elevated in patients with CKD stages G3b, G4, and G5, compared with those prevalences in patients with CKD stage G3a. The prevalences of hyperkalemia were 8.3% and 11.6% in patients with CKD stages G4 and G5, respectively. In patients with CKD stage G5, the proportions of patients with optimal ranges of serum uric acid, potassium, corrected calcium, and phosphate were 49.6%, 73.5%, 81.9%, and 56.1%, respectively.

Conclusions: We determined the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD using data from a nationwide cohort study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561156PMC
December 2020

Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observed in patients with rheumatoid arthritis treated with baricitinib.

RMD Open 2020 10;6(3)

Division of Rheumatology, Department of Medicine, Albany Medical College, Albany, New York, USA.

Objective: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.

Methods: Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).

Results: Mean absolute neutrophil counts decreased (-1.36×10/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×10/L) within 1 month, then decreased to baseline (weeks 12-24). Mean platelet counts increased at week 2 (+51×10/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (-0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).

Conclusions: Moderate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.
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http://dx.doi.org/10.1136/rmdopen-2020-001370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722368PMC
October 2020

LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.

Nat Cell Biol 2020 10 28;22(10):1252-1263. Epub 2020 Sep 28.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
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http://dx.doi.org/10.1038/s41556-020-00583-9DOI Listing
October 2020
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