Publications by authors named "Takashi Wada"

360 Publications

Correction to: Renal complications in coronavirus disease 2019: a systematic review.

Inflamm Regen 2021 Jul 23;41(1):24. Epub 2021 Jul 23.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.

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http://dx.doi.org/10.1186/s41232-021-00171-wDOI Listing
July 2021

Validation of the risk factors for primary control of early T-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma by transoral surgery: a prospective observational study.

Int J Clin Oncol 2021 Jul 21. Epub 2021 Jul 21.

Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: We had previously identified the following risk factors for insufficient control of early T-stage head and neck cancer by transoral surgery (TOS): (1) tumor thickness > 7 mm on enhanced computed tomography (CT), and (2) poor differentiation in pathological examination. We subsequently used a different patient cohort to validate the usefulness of these factors in determining the need for adaptation of TOS.

Study Setting: A prospective observational study METHODS: Patients who received TOS as a definitive treatment between April 1, 2016 and September 30, 2020 were included. Primary control rates (by single TOS and TOS alone) in relation to the above-mentioned risk factors were calculated. Overall (O), recurrence-free (RF), and disease-free (DF) survival (S) outcomes were evaluated. A combination analysis based on the number of risk factors was also performed.

Results: Patients with tumor thickness > 7 mm had a 2.88-fold [95% confidence interval (CI) 1.01-8.51] higher risk of incomplete primary resection by single TOS, while patients who showed poor differentiation on pathological assessments had a 13.14-fold (95% CI 3.66-47.14) higher risk of insufficient primary control by TOS alone. The 3 year OS, RFS, and DFS rates were 99%, 83%, and 63%, respectively. Patients with both risk factors had a 93.00-fold (95% CI 4.99-1732.00) higher risk of incomplete primary control by TOS alone.

Conclusions: Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, primary control by TOS alone may not be achieved in patients with both risk factors, that is, tumor thickness > 7 mm as measured by enhanced CT and poor differentiation on pathological examination.
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http://dx.doi.org/10.1007/s10147-021-01992-yDOI Listing
July 2021

The relationship between the modified National Institute of Health activity and chronicity scoring system, and the long-term prognosis for lupus nephritis: A retrospective single-center study.

Lupus 2021 Jul 20:9612033211034234. Epub 2021 Jul 20.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Background: The revision of International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification guidelines for lupus nephritis (LN) was suggested by a working group, who recommended a modified National Institute of Health (NIH) activity and chronicity scoring system to evaluate active and chronic LN lesions. However, whether this approach was useful for estimating long-term prognosis for LN patients is unclear.

Methods: We conducted a retrospective cohort study in Japanese subjects with biopsy-proven LN, between 1977 and 2018. Pathologic lesions were evaluated based on ISN/RPS 2003 classifications and the modified NIH scoring system. Patients were grouped by activity index (low, 0-5; moderate, 6-11; high, 12-24), and chronicity index (low, 0-2; moderate, 3-5; high, 6-12). The primary outcome was a composite of end-stage kidney disease (ESKD) or all-cause death, and the secondary outcome was ESKD alone.

Results: Sixty-six subjects with a median age of 31 years were included. During median follow-up (11.5 years), 15 patients reached the primary outcome: 10 had ESKD, four had died, and one had ESKD and died. Kaplan-Meier analysis showed that the cumulative primary outcome incidence increased with a higher chronicity index (log-rank trend  < 0.001). From multivariable survival analysis, moderate (hazard ratio [HR] 6.17, 95% confidence interval [CI] 1.14 to 33.20;  = 0.034) and high chronicity indices (HR 20.20, 95% CI 1.13 to 359.82;  = 0.041) were risk factors for the primary outcome.

Conclusion: Moderate and high chronicity indices were associated with an increased ESKD risk for LN.
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http://dx.doi.org/10.1177/09612033211034234DOI Listing
July 2021

Renal, Cardiovascular and Safety Outcomes of Canagliflozin in Patients with Type 2 Diabetes and Nephropathy in East and Southeast Asian Countries: Results from the CREDENCE Trial.

J Diabetes Investig 2021 Jul 1. Epub 2021 Jul 1.

The George Institute for Global Health, UNSW, Sydney, Australia.

Aim: The sodium-glucose cotransporter 2 inhibitor canagliflozin reduced kidney failure and cardiovascular events in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. We conducted a post-hoc analysis to evaluate the efficacy and safety of canagliflozin in a subgroup of participants in East and Southeast Asian (EA) countries who are at high risk of renal complications.

Methods: Participants with an estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m and urinary albumin-creatinine ratio of >300 to 5000 mg/g were randomized to 100 mg of canagliflozin or placebo. The effects of canagliflozin treatment on pre-specified efficacy and safety outcomes were examined using Cox proportional-hazards regression between participants from EA countries (China, Japan, Malaysia, Philippines, South Korea, and Taiwan) and the remaining participants.

Results: Of 4401 participants, 604 (13.7%) were from EA countries; 301 and 303 were assigned to the canagliflozin and placebo groups, respectively. Canagliflozin lowered the risk of primary outcome (composite of end-stage kidney disease, doubling of serum creatinine level, or renal or cardiovascular death) in EA participants (hazard ratio, 0.54; 95% confidence interval, 0.35 to 0.84). The effects of canagliflozin on renal and cardiovascular outcomes in EA participants were generally similar to those of the remaining participants. Safety outcomes were similar between the EA and non-EA participants.

Conclusion: In the CREDENCE trial, the risk of renal and cardiovascular events was safely reduced in participants from EA countries at high risk of renal events.
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http://dx.doi.org/10.1111/jdi.13624DOI Listing
July 2021

Combined changes in albuminuria and kidney function and subsequent risk for kidney failure in type 2 diabetes.

BMJ Open Diabetes Res Care 2021 Jun;9(1)

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan

Introduction: Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.

Research Design And Methods: Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.

Results: Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of <2.5 mL/min/1.73 m/year): HR 4.19 (95% CI 1.87 to 9.38) and 2.89 (95% CI 1.32 to 6.33) for those with a decline of >5 and 2.5-5 mL/min/1.73 m/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m/year compared with those with a minor change in UACR and eGFR.

Conclusions: Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2021-002311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246293PMC
June 2021

Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice.

Stem Cell Res 2021 Jul 6;54:102425. Epub 2021 Jun 6.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan. Electronic address:

Adipose tissue-derived stem cells (ADSCs) have been suggested as a novel treatment for non-alcoholic steatohepatitis (NASH); however, the mechanisms underlying their therapeutic effect remain poorly understood. In this study, we aimed to investigate the association of Notch signaling, which is crucial for cellular proliferation and differentiation in ADSC-mediated treatment of NASH. Flow cytometry analysis of ADSCs showed that they expressed the Notch ligands JAG1, DLL1, and DLL4. The expression of genes associated with the Notch signaling pathway was attenuated in hepatocytes of NASH model mice. We further observed ADSC-mediated activation of Notch signaling in these hepatocytes in addition to an increase in proliferating cell nuclear antigen cells and a decrease in TdT-mediated dUTP-biotin nick end labeling apoptotic cells. Co-culture of palmitic acid-induced steatotic hepatocytes and ADSCs resulted in the activation of Notch signaling and reduction of apoptosis of steatotic hepatocytes. Moreover, inhibition of Notch signaling by a γ-secretase inhibitor and knockdown of Notch ligands using siRNA attenuated the anti-apoptotic effect of co-cultured ADSCs in vitro. Our findings show that the Notch signaling pathway is involved in the inhibition of apoptosis and restoration of cellular proliferation of hepatocytes from NASH mice following ADSC treatment.
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http://dx.doi.org/10.1016/j.scr.2021.102425DOI Listing
July 2021

Association between preoperative low muscle mass and psychological factors after surgery among patients with lumbar spinal stenosis: A longitudinal study.

J Clin Neurosci 2021 Jul 27;89:8-14. Epub 2021 Apr 27.

Rehabilitation Division, Tottori University Hospital, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan; School of Health Science, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.

It remains controversial whether preoperative low muscle mass affects clinical outcomes after lumbar surgery. Previous studies evaluated outcomes such as pain, quality of life, and disability, but none investigated preoperative low muscle mass and psychological factors. The purpose of this study was to clarify the association between preoperative low muscle mass and postoperative psychological factors in lumbar spinal stenosis (LSS). A longitudinal analysis was performed in 85 consecutive preoperative patients with LSS. Demographic data, leg pain, low back pain, Japanese Orthopaedic Association score, Pain Catastrophizing Scale (PCS) score, Fear-Avoidance Beliefs Questionnaire on Physical Activity (FABQ-PA) score, Hospital Anxiety and Depression Scale (HADS) score, walking velocity, grip strength, and appendicular lean mass were assessed. Muscle mass was measured using bioelectrical impedance analysis. Patients were divided into two groups based on skeletal muscle mass index. These clinical outcomes were evaluated preoperatively and 1 year after surgery. In the 73 patients who were analyzed 1 year after surgery, the prevalence of preoperative low muscle mass was 21.9%. The normal muscle mass group showed significantly improved PCS, FABQ-PA, HADS-anxiety, and HADS-depression scores 1 year after surgery. The low muscle mass group did not demonstrate significantly improved PCS, FABQ-PA, or HADS-depression scores, and had a significantly smaller increase in the FABQ-PA score than the normal muscle mass group. Multivariate analysis showed that low muscle mass was significantly related to change in FABQ-PA score. Our results suggest that preoperative low muscle mass hinders improvement in fear-avoidance beliefs 1 year after surgery.
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http://dx.doi.org/10.1016/j.jocn.2021.04.008DOI Listing
July 2021

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study.

Clin Exp Nephrol 2021 Jun 10. Epub 2021 Jun 10.

Clinical Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Background: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine).

Methods: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K increase, and change in eGFR from baseline.

Results: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m at week 24.

Conclusions: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine.

Clinical Trial Registration: JapicCTI-173696.
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http://dx.doi.org/10.1007/s10157-021-02075-yDOI Listing
June 2021

Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy.

Regen Ther 2021 Dec 21;18:97-101. Epub 2021 May 21.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Introduction: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs.

Methods: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients.

Results: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered.

Conclusion: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
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http://dx.doi.org/10.1016/j.reth.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165289PMC
December 2021

Significance of the Gut Microbiota in Acute Kidney Injury.

Toxins (Basel) 2021 05 22;13(6). Epub 2021 May 22.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa 920-1192, Japan.

Recent studies have revealed that the gut microbiota plays a crucial role in maintaining a healthy, as well as diseased condition. Various organs and systems, including the kidney, are affected by the gut microbiota. While the impacts of the gut microbiota have been reported mainly on chronic kidney disease, acute kidney injury (AKI) is also affected by the intestinal environment. In this review, we discussed the pathogenesis of AKI, highlighting the relation to the gut microbiota. Since there is no established treatment for AKI, new treatments for AKI are highly desired. Some kinds of gut bacteria and their metabolites reportedly have protective effects against AKI. Current studies provide new insights into the role of the gut microbiota in the pathogenesis of AKI.
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http://dx.doi.org/10.3390/toxins13060369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224769PMC
May 2021

Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell.

BMC Nephrol 2021 May 31;22(1):203. Epub 2021 May 31.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Introduction: The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte.

Method: Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model.

Result: TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys.

Conclusion: EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.
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http://dx.doi.org/10.1186/s12882-021-02411-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167964PMC
May 2021

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Ther Apher Dial 2021 May 31. Epub 2021 May 31.

Department of Medicine, Diabetes Center, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m ), and severely impaired (S) (<30 ml/min/1.73 m ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m .
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http://dx.doi.org/10.1111/1744-9987.13694DOI Listing
May 2021

Prediabetes is associated with proteinuria development but not with glomerular filtration rate decline: A longitudinal observational study.

Diabet Med 2021 Aug 6;38(8):e14607. Epub 2021 Jun 6.

Comprehensive Health Science Center, Aichi Health Promotion Public Interest Foundation, Aichi, Japan.

Aims: Diabetes is recognized as the leading cause of chronic kidney disease (CKD); however, the association of prediabetes with CKD remains unclear, in particular, the independent effect of prediabetes on proteinuria or estimated glomerular filtration rate (eGFR) has not been evaluated. This study aimed to investigate the associations of prediabetes with the proteinuria development and with eGFR decline separately in the Japanese general population without CKD.

Methods: Participants who underwent health check-ups in 2014 and had adequate data after 2 years were retrospectively analysed. A total of 405,487 participants without CKD (eGFR, ≥60 ml min  1.73 m , with negative or trace urinary protein) at baseline were categorized according to fasting plasma glucose as having diabetes (≥126 mg/dl [7.0 mmol/l]), prediabetes (100-125 mg/dl [5.6-6.9 mmol/l]) or normal glucose level (˂100 mg/dl [5.6 mmol/l]). Logistic regression analysis was used to analyse the effects of prediabetes (vs. normal glucose level) on the proteinuria development (urinary protein of ≥1+) and eGFR decline (˂60 ml min  1.73 m ) after 2 years.

Results: After 2 years, 7037 participants (1.7%) developed proteinuria alone, 19,015 (4.7%) presented eGFR decline alone and 636 (0.2%) showed both proteinuria and eGFR decline. Compared to normal glucose level and adjusting for prognostic factors, prediabetes was independently associated with the proteinuria development (odds ratio [OR] 1.233; 95% confidence interval [CI] 1.170-1.301], whereas prediabetes was not associated with eGFR decline (OR 0.981; 95% CI 0.947-1.017).

Conclusions: Prediabetes is associated with the proteinuria development but not with eGFR decline in the general population.
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http://dx.doi.org/10.1111/dme.14607DOI Listing
August 2021

Serum hemoglobin concentration, as a reflection of renal fibrosis, and risk of renal decline in early-stages of diabetic kidney disease: a nationwide, biopsy-based cohort study.

Nephrol Dial Transplant 2021 May 24. Epub 2021 May 24.

Okayama University, Okayama, Japan.

Background: Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression.

Methods: Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: aged 56 (45, 63); 62.6% men; Hb 13.3 (12.0, 14.5) g/dL; eGFR 76.2 (66.6, 88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio [UACR] 534 (100, 1480) mg/g Crea. Serum hemoglobin concentration were divided into quartiles: ≤12, 12.1-13.3, 13.4-14.5, and ≥14.6 g/dL. The association between serum hemoglobin concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR, or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum hemoglobin concentration to the known risk factors of DKD was assessed.

Results: Serum hemoglobin levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ =-0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second, and third quartile (the fourth quartile as a reference) were 2.74 (95% CI 1.26-5.97), 2.33 (95% CI 1.07-5.75), and 1.46 (95% CI 0.71-3.64), respectively. Addition of the serum hemoglobin concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global chi-statistics increased from 55.1 to 60.8; P < 0.001).

Conclusions: Serum hemoglobin concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.
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http://dx.doi.org/10.1093/ndt/gfab185DOI Listing
May 2021

Identification of candidate PAX2-regulated genes implicated in human kidney development.

Sci Rep 2021 Apr 27;11(1):9123. Epub 2021 Apr 27.

Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

PAX2 is a transcription factor essential for kidney development and the main causative gene for renal coloboma syndrome (RCS). The mechanisms of PAX2 action during kidney development have been evaluated in mice but not in humans. This is a critical gap in knowledge since important differences have been reported in kidney development in the two species. In the present study, we hypothesized that key human PAX2-dependent kidney development genes are differentially expressed in nephron progenitor cells from induced pluripotent stem cells (iPSCs) in patients with RCS relative to healthy individuals. Cap analysis of gene expression revealed 189 candidate promoters and 71 candidate enhancers that were differentially activated by PAX2 in this system in three patients with RCS with PAX2 mutations. By comparing this list with the list of candidate Pax2-regulated mouse kidney development genes obtained from the Functional Annotation of the Mouse/Mammalian (FANTOM) database, we prioritized 17 genes. Furthermore, we ranked three genes-PBX1, POSTN, and ITGA9-as the top candidates based on closely aligned expression kinetics with PAX2 in the iPSC culture system and susceptibility to suppression by a Pax2 inhibitor in cultured mouse embryonic kidney explants. Identification of these genes may provide important information to clarify the pathogenesis of RCS, human kidney development, and kidney regeneration.
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http://dx.doi.org/10.1038/s41598-021-88743-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079710PMC
April 2021

Carnitine/organic cation transporter 1 precipitates the progression of interstitial fibrosis through oxidative stress in diabetic nephropathy in mice.

Sci Rep 2021 Apr 27;11(1):9093. Epub 2021 Apr 27.

Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

Carnitine/organic cation transporter 1 (OCTN1) is the only known uptake transporter for ergothioneine which is a food-derived strong antioxidant amino acid that is absorbed by OCTN1. We previously reported the roles of OCTN1/ergothioneine in the progression of kidney fibrosis in ischemic kidney disease. In this study, we evaluated the roles of OCTN1 in the progression of diabetic kidney disease. A diabetic kidney disease model was induced in octn1 knockout and wild-type mice by streptozotocin (STZ). Oxidative stress, represented by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), were higher in the octn1 knockout mice. Azan- and Sirius red-positive areas increased significantly in the octn1 knockout mice. Gene expression was evaluated by cluster analysis, and shown to be different in the octn1 knockout mice compared with the wild-type mice. In a pathway analysis, the pathway associated with the cytoskeleton and cell adhesion increased. In accordance with interstitial fibrosis in octn1 knockout mice, gene expression of moesin in the injured kidney, known as an associated protein of cytoskeleton and cell membranes, was doubled 28 weeks after STZ injection. In addition, the moesin protein was expressed in a part of α-SMA-positive renal tubular epithelial cells. These findings were confirmed by cultured murine proximal tubular epithelial cells: The expression of moesin was induced under oxidative stress with hydrogen peroxide. These data indicate that OCTN1 would play some roles in progression of interstitial fibrosis under oxidative stress via moesin expression in diabetic kidney disease.
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http://dx.doi.org/10.1038/s41598-021-88724-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079701PMC
April 2021

Gender difference in the association of dietary intake of antioxidant vitamins with kidney function in middle-aged and elderly Japanese.

J Nutr Sci 2021 22;10:e2. Epub 2021 Jan 22.

Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

Dietary intake modification is important for the treatment of chronic kidney disease (CKD); however, little is known about the association between dietary intake of antioxidant vitamins and kidney function based on gender difference. We examined the relationship of dietary intake of antioxidant vitamins with decreased kidney function according to gender in Japanese subjects. This population-based, cross-sectional study included 936 Japanese participants with the age of 40 years or older. A validated brief self-administered diet history questionnaire was used to measure dietary intakes of vitamin E and its four isoforms, vitamin A and vitamin C. Decreased kidney function was defined as estimated glomerular filtration rate <60 ml/min/1·73 m. A total of 498 (53·2 %) of the study participants were women. Mean age was 62·4 ± 11·3 years. Overall, 157 subjects met the criteria of decreased kidney function. In the fully adjusted model, a high vitamin E intake is inversely associated with decreased kidney function in women (odds ratio, 0·886; 95 % confidence interval, 0·786-0·998), whereas vitamin E intake was not associated with decreased kidney function (odds ratio, 0·931; 95 % confidence interval, 0·811-1·069) in men. No significant association between dietary intake of vitamins A and C and decreased kidney function was observed in women and men. Higher dietary intake of vitamin E was inversely associated with decreased kidney function in middle-aged and older women, and the result may provide insight into the more tailored dietary approaches to prevent CKD.
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http://dx.doi.org/10.1017/jns.2020.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057365PMC
January 2021

Comparison of annual eGFR decline among primary kidney diseases in patients with CKD G3b-5: results from a REACH-J CKD cohort study.

Clin Exp Nephrol 2021 Aug 21;25(8):902-910. Epub 2021 Apr 21.

Department of Nephrology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.

Background: Disease-specific trajectories of renal function in advanced chronic kidney disease (CKD) are not well defined. Here, we compared these trajectories in the estimated glomerular filtration rate (eGFR) by CKD stages.

Methods: Patients with multiple eGFR measurements during the 5-year preregistration period of the REACH-J study were enrolled. Mean annual eGFR declines were calculated from linear mixed effect models with the adjustment variables of baseline CKD stage, age, sex and the current CKD stage and the level of proteinuria (CKDA1-3).

Results: Among 1,969 eligible patients with CKDG3b-5, the adjusted eGFR decline (ml/min/1.73 m/year) was significantly faster in diabetic kidney disease (DKD) patients and polycystic kidney disease (PKD) patients than in patients with other kidney diseases (DKD, - 2.96 ± 0.13; PKD, - 2.82 ± 0.17; and others, - 1.95 ± 0.05, p < 0.01). The declines were faster with higher CKD stages. In DKD patients, the eGFR decline was significantly faster in CKDG5 than CKDG4 (- 4.10 ± 0.18 vs - 2.76 ± 0.20, p < 0.01), while these declines in PKD patients were similar. The eGFR declines in PKD patients were significantly faster than DKD patients in CKDG4 (- 2.92 ± 0.23 vs - 2.76 ± 0.20, p < 0.01) and in CKDA2 (- 3.36 ± 0.35 vs - 1.40 ± 0.26, p < 0.01).

Conclusion: Our study revealed the disease-specific annual eGFR declines by CKD stages and the level of proteinuria. Comparing to the other kidney diseases, the declines in PKD patients were getting faster from early stages of CKD. These results suggest the importance of CKD managements in PKD patients from the early stages.
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http://dx.doi.org/10.1007/s10157-021-02059-yDOI Listing
August 2021

Impact of high-load resistance training on bone mineral density in osteoporosis and osteopenia: a meta-analysis.

J Bone Miner Metab 2021 Apr 13. Epub 2021 Apr 13.

Rehabilitation Division, Tottori University Hospital, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Introduction: This study aimed to examine the effect of high-load resistance training (HLRT) on bone mineral density (BMD) in patients with osteoporosis and osteopenia using a meta-analysis.

Materials And Methods: We searched for randomized controlled trials (RCTs) on HLRT in patients with osteoporosis and osteopenia from medical databases. Our meta-analysis was performed with the primary endpoints being the standardized mean difference (SMD) of the change in BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH). The robustness of the results was assessed by subgroup analysis. Heterogeneity factors were examined by meta-regression. Publication bias was evaluated using a funnel plot.

Results: We selected nine RCTs, with 259 patients in the HLRT group (women, 55.2%) and 236 patients in the control group (women, 62.7%). The HLRT group showed a significant increase in BMD in the LS [SMD = 1.40, 95% confidence interval (CI) = 0.68-2.12, p < 0.001, I = 90%], the FN (SMD = 0.86, 95% CI = 0.05-1.67, p = 0.04, I = 92%), and the TH (SMD = 1.26, 95% CI = 0.45-2.08, p = 0.002, I = 91%). Subgroup analysis confirmed the robustness of the results only in LS. Total sessions and a high risk of bias were identified as the factors of heterogeneity in FN and TH (p < 0.05). The funnel plot showed asymmetry in all measurement sites.

Conclusion: This study suggested that HLRT can be effective in increasing BMD, mainly of LS, in patients with osteoporosis and osteopenia. However, due to high heterogeneity and publication bias, additional studies with a low risk of bias should be conducted to generalize our findings.
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http://dx.doi.org/10.1007/s00774-021-01218-1DOI Listing
April 2021

Comparison of Circulating Biomarkers in Predicting Diabetic Kidney Disease Progression With Autoantibodies to Erythropoietin Receptor.

Kidney Int Rep 2021 Feb 10;6(2):284-295. Epub 2020 Nov 10.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts.

Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes.

Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit,  < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers.

Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus.
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http://dx.doi.org/10.1016/j.ekir.2020.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879109PMC
February 2021

Anti-proliferative and anti-migratory properties of coffee diterpenes kahweol acetate and cafestol in human renal cancer cells.

Sci Rep 2021 01 12;11(1):675. Epub 2021 Jan 12.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

Despite improvements in systemic therapy options for renal cancer, it remains one of the most drug-resistant malignancies. Interestingly, reports have shown that kahweol and cafestol, natural diterpenes extracted from coffee beans, exhibit anti-cancer activity. However, the multiple potential pharmacological actions of both have yet to be fully understood. This study therefore investigated the effects of kahweol acetate and cafestol on human renal cancer ACHN and Caki-1 cells. Accordingly, the combination of kahweol acetate and cafestol administration synergistically inhibited cell proliferation and migration by inducing apoptosis and inhibiting epithelial-mesenchymal transition. Mechanistic dissection revealed that kahweol acetate and cafestol inhibited Akt and ERK phosphorylation. Moreover, kahweol acetate and cafestol downregulated the expression of not only C-C chemokine receptors 2, 5, and 6 but also programmed death-ligand 1, indicating their effects on the tumor microenvironment. Thus, kahweol acetate and cafestol may be novel therapeutic candidates for renal cancer considering that they exert multiple pharmacological effects.
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http://dx.doi.org/10.1038/s41598-020-80302-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804192PMC
January 2021

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

Clin Exp Nephrol 2021 May 7;25(5):456-466. Epub 2021 Jan 7.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.

Methods: This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety.

Results: Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.

Conclusions: In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.
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http://dx.doi.org/10.1007/s10157-020-02005-4DOI Listing
May 2021

Relationships between kidney dysfunction and left ventricular diastolic dysfunction: a hospital-based retrospective study.

J Nephrol 2021 06 5;34(3):773-780. Epub 2021 Jan 5.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Background: Preclinical left ventricular diastolic dysfunction (LVDD) is a high-risk state for heart failure. Kidney dysfunction is a known risk factor for heart failure, but its association with asymptomatic LVDD is not well-known.

Methods: A hospital-based retrospective cohort study was conducted on patients who underwent echocardiogram between 2006 and 2016 to assess the association between baseline kidney function and LVDD on echocardiogram. E/e' ratio was defined as the ratio of peak velocity of early diastolic left ventricular inflow (E) to mitral annular velocity (e'). The primary outcome was time to development of LVDD, which was defined as E/e' ratio > 14. The changes in the E/e' ratio and other echocardiographic parameters were assessed using a mixed effects model.

Results: Among 1167 patients, the mean age was 61 years, and the mean baseline E/e' ratio and ejection fraction were 9.6 and 69%, respectively. During a median follow-up of 3.2 years, 231 (19.8%) people developed LVDD. According to eGFR (mL/min/1.73 m), the risk for LVDD based on hazard ratio [95% confidence interval (95% CI)] was 1.20 (0.82, 1.75) for 60 to < 90, 1.42 (0.87, 2.31) for 45 to < 60, and 2.57 (1.61, 4.09) for < 45 (P trend < 0.001). The adjusted risks (95% CI) for annual change in E/e' ratio was 0.09 (0.03, 0.14) overall and 0.28 (0.11, 0.45) in the lowest eGFR group; the trend in changes in annual E/e' ratio by baseline eGFR was significant (P trend = 0.01).

Conclusions: Relatively low kidney function was related with the risks for LVDD. Long-term cohort studies are warranted to confirm the association between LVDD and symptomatic heart failure in patients with kidney dysfunction.
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http://dx.doi.org/10.1007/s40620-020-00940-9DOI Listing
June 2021

D-Serine inhibits the attachment and biofilm formation of methicillin-resistant Staphylococcus aureus.

Biochem Biophys Res Commun 2021 01 29;537:50-56. Epub 2020 Dec 29.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Japan.

Introduction: Although therapeutic agents for methicillin-resistant Staphylococcus aureus (MRSA) are clinically available, MRSA infection is still a life-threatening disease. Bacterial attachment and biofilm formation contribute significantly to the initiation of MRSA infection. Controlling MRSA's attachment and biofilm formation might reduce the frequency of MRSA infection. According to recent data, some amino acids can reduce MRSA's attachment on plates; however, their precise inhibitory mechanisms remain unclear. Therefore, we explored the effect of the amino acids on bacterial adhesion and biofilm formation in vitro and in vivo MRSA infection models.

Methods: We tested the inhibitory effect of amino acids on MRSA and Escherichia coli (E. coli) in the attachment assay. Moreover, we evaluated the therapeutic potential of amino acids on the in vivo catheter infection model.

Results: Among the amino acids, D-Serine (D-Ser) was found to reduce MRSA's ability to attach on plate assay. The proliferation of MRSA was not affected by the addition of D-Ser; thus, D-Ser likely only played a role in preventing attachment and biofilm formation. Then, we analyzed the expression of genes related to attachment and biofilm formation. D-Ser was found to reduce the expressions of AgrA, SarS, IcaA, DltD, and SdrD. Moreover, the polyvinyl chloride catheters treated with D-Ser had fewer MRSA colonies. D-Ser treatment also reduced the severity of infection in the catheter-induced peritonitis model. Moreover, D-Ser reduced the attachment ability of E. coli.

Conclusion: D-Ser inhibits the attachment and biofilm formation of MRSA by reducing the expression of the related genes. Also, the administration of D-Ser reduces the severity of catheter infection in the mouse model. Therefore, D-Ser may be a promising therapeutic option for MRSA as well as E. coli infection.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.078DOI Listing
January 2021

Renal complications in coronavirus disease 2019: a systematic review.

Inflamm Regen 2020 Dec 15;40(1):31. Epub 2020 Dec 15.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.

The world today is facing a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which mainly causes a respiratory disease known as coronavirus disease 2019 (COVID-19). Therefore, its pathogenesis and complications should be identified and understood. SARS-CoV-2 infects the host using the angiotensin-converting enzyme 2 (ACE2) as its receptor, which is expressed in several organs including the lungs, heart, kidneys, and intestines. Kidney complications are relatively common, and acute kidney injury (AKI) is a life-threatening complication in patients with COVID-19. In this review, the renal histological patterns of COVID-19 are described in detail, and its potential mechanisms associated with AKI are discussed.
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http://dx.doi.org/10.1186/s41232-020-00140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735801PMC
December 2020

Higher serum levels of autotaxin and phosphatidylserine-specific phospholipase A in patients with lupus nephritis.

Int J Rheum Dis 2021 Feb 11;24(2):231-239. Epub 2020 Dec 11.

Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.

Background: Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine-specific phospholipase A (PS-PLA ), are candidates for novel biomarkers in melanoma, glaucoma and diabetic nephropathy. However, it is not clear whether serum levels of ATX/ PS-PLA would be associated with pathological and clinical findings of lupus nephritis (LN).

Methods: In this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS-PLA were evaluated for an association with renal pathology and clinical phenotypes of LN.

Results: The serum levels of ATX and PS-PLA were higher in the patients with LN as compared to those with other glomerular diseases. Among the classes of LN, the patients with class IV showed the trend of lower serum levels of ATX. Moreover, the patients with lower levels of ATX exhibited higher scores of activity index (AI) and chronicity index (CI). The level of ATX tended to be negatively correlated with AI and CI. These results might be explained by the effect of treatment, because the serum levels of ATX and PS-PLA were inversely correlated with the daily amount of oral prednisolone. Moreover, they did not reflect the level of proteinuria or kidney survival in LN patients.

Conclusion: Although the serum levels of ATX and PS-PLA were affected by the treatment, these levels were higher in the patients with LN. The potential clinical benefits of these markers need to be clarified in further studies.
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http://dx.doi.org/10.1111/1756-185X.14031DOI Listing
February 2021

Preoperative low muscle mass is a predictor of falls within 12 months of surgery in patients with lumbar spinal stenosis.

BMC Geriatr 2020 11 30;20(1):516. Epub 2020 Nov 30.

Rehabilitation Division, Tottori University Hospital, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Background: Patients with lumbar spinal stenosis (LSS) may be at high risk of falls due to various factors. No effective fall risk assessments or fall prevention measures have been performed for patients with LSS because only a few studies have evaluated falls in these patients. This study aimed to evaluate the incidence and preoperative predictors of falls within 12 months of surgery in patients with LSS.

Methods: In this prospective study of 82 consecutive preoperative patients with LSS, preoperative demographic data, previous fall history, leg pain, low back pain, Japanese Orthopaedic Association (JOA) score, Hospital Anxiety and Depression Scale (HADS) scores, lower extremity muscle strength, walking speed, grip strength, and muscle mass were assessed at baseline. Falls were assessed at 3, 6, 9, and 12 months after surgery. Participants were categorized as fallers and non-fallers and baseline variables were compared. Binomial logistic regression was used to identify predictors of falls within 12 months of surgery.

Results: Seventy-four patients (90.2%) completed the 12-month follow-up after surgery, of whom 24 patients (32.4%) experienced falls. A higher proportion of fallers were female and had a history of falls compared to non-fallers. Fallers had a significantly lower JOA score and a higher HADS-depression score compared to non-fallers. Fallers had significantly lower tibialis anterior muscle strength, gait speed, grip strength, and skeletal muscle mass index. Fallers had a higher prevalence of low muscle mass compared with non-fallers. The presence of low muscle mass was significantly predictive of falls within 12 months of surgery (odds ratio, 4.46; 95% confidence interval, 1.02-19.63).

Conclusions: Patients with LSS have a high incidence of falls after surgery and preoperative low muscle mass may be a predictor of postoperative falls.
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http://dx.doi.org/10.1186/s12877-020-01915-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708230PMC
November 2020

Healthy lifestyle reduces incidence of trace/positive proteinuria and rapid kidney function decline after 2 years: from the Japan Ningen Dock study.

Nephrol Dial Transplant 2021 May;36(6):1039-1048

Department of Neurology, KKR Tachikawa Hospital, Tokyo, Japan.

Background: Lifestyle modification is recommended for subjects with trace proteinuria during health checkups. However, whether overall healthy lifestyle reduces the incidence of trace/positive proteinuria or rapid decline in estimated glomerular filtration rate (eGFR) is not clarified.

Methods: A total of 451 534 people (277 494 men and 174 040 women) ages 20-79 years with negative proteinuria were included. The number of three healthy lifestyle factors (LFs) was assessed: noncurrent smoking, healthy eating habits (late dinner, snacking and skipping breakfast <3 times/week) and body mass index <25. The incidence of trace (±) and positive (≥1+) proteinuria by the dipstick method and eGFR decline ≥20% over 2 years were compared with the number of healthy LFs.

Results: The incidence of trace/positive proteinuria and rapid eGFR decline decreased with an increasing number of healthy LFs as follows: odds ratios (ORs) for trace proteinuria, 0.91 [95% confidence interval (CI) 0.86-0.96], 0.82 (0.78-0.87) and 0.72 (0.68-0.77); ORs for positive proteinuria, 0.76 (95% CI 0.67-0.86), 0.56 (0.50-0.63) and 0.46 (0.40-0.53); and ORs for an eGFR decline ≥20%, 0.93 (95% CI 0.82-1.05), 0.90 (0.79-1.02) and 0.81 (0.70-0.93) for those with one, two and three healthy LFs compared with those with none of the three healthy LFs, respectively. Overall, subjects with a healthy lifestyle showed 28, 54 and 19% reduced risk of developing trace proteinuria, positive proteinuria and eGFR decline ≥20%, respectively, compared with those with an unhealthy lifestyle after 2 years. This association was similarly observed even among subjects without hypertension (HT) or diabetes mellitus (DM).

Conclusions: Subjects with an overall healthy lifestyle showed a lower incidence of trace/positive proteinuria by dipstick test and rapid eGFR decline over 2 years in a nationwide general population. Thus lifestyle modification should be recommended for subjects with trace proteinuria during health checkups, even for subjects without HT or DM.
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http://dx.doi.org/10.1093/ndt/gfaa224DOI Listing
May 2021

Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial.

Clin J Am Soc Nephrol 2020 12 25;15(12):1715-1727. Epub 2020 Nov 25.

Clinical Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Background And Objectives: Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.

Design, Setting, Participants, & Measurements: In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).

Results: Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; 0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.

Conclusions: Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.
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http://dx.doi.org/10.2215/CJN.06870520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769030PMC
December 2020
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