Satoshi Umemura ● Hisatomi Arima ● Shuji Arima ● Kei Asayama ● Yasuaki Dohi ● Yoshitaka Hirooka ● Takeshi Horio ● Satoshi Hoshide ● Shunya Ikeda ● Toshihiko Ishimitsu ● Masaaki Ito ● Sadayoshi Ito ● Yoshio Iwashima ● Hisashi Kai ● Kei Kamide ● Yoshihiko Kanno ● Naoki Kashihara ● Yuhei Kawano ● Toru Kikuchi ● Kazuo Kitamura ● Takanari Kitazono ● Katsuhiko Kohara ● Masataka Kudo ● Hiroo Kumagai ● Kiyoshi Matsumura ● Hideo Matsuura ● Katsuyuki Miura ● Masashi Mukoyama ● Satoko Nakamura ● Takayoshi Ohkubo ● Yusuke Ohya ● Takafumi Okura ● Hiromi Rakugi ● Shigeyuki Saitoh ● Hirotaka Shibata ● Tatsuo Shimosawa ● Hiromichi Suzuki ● Shori Takahashi ● Kouichi Tamura ● Hirofumi Tomiyama ● Takuya Tsuchihashi ● Shinichiro Ueda ● Yoshinari Uehara ● Hidenori Urata ● Nobuhito Hirawa

The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019)

Objective Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic nephropathy (DN). However, the underlying mechanisms remain unclear. Studies suggest that T cell immunoglobulin domain and mucin domain-3 (Tim-3) has complicated roles in regulating macrophage activation, but its roles in the progression of DN are still completely unknown. Methods We downregulated Tim-3 expression in kidney (intrarenal injection of Tim-3 shRNA expressing lentivirus or global Tim-3 knockout mice) and induced DN by streptozotocin (STZ). We analyzed the degree of renal injury, especially the podocyte injury induced by activated macrophages in vitro and in vivo. Then, we transferred different bone marrow derived macrophages (BMs) into STZ-induced Tim-3 knockdown mice to examine the effects of Tim-3 on macrophages in DN. Results First, we found that Tim-3 expression on renal macrophages was increased in patients with DN and in two diabetic mouse models, i.e. STZ-induced diabetic mice and db/db mice, and positively correlated with renal dysfunction of DN patients. Tim-3 deficiency ameliorated renal damage in STZ-induced diabetes with concurrent increase in protein levels of Nephrin and WT-1. Similar effects were observed in mice with Tim-3 knockdown diabetic mice. Second, adoptive transfer of Tim-3-expressing macrophages, but not Tim-3 knockout macrophages, accelerated diabetic renal injury in DN mice, suggesting a key role for Tim-3 on macrophages in the development of DN. Furthermore, we found NF-κB activation and TNF-α excretion were upregulated by Tim-3 in diabetic kidneys, and podocyte injury was associated with the Tim-3-mediated activation of the NF-κB/TNF-α signaling pathway in DN macrophages both in vivo and in vitro. Conclusions These results suggest that Tim-3 functions as a key regulator in renal inflammatory processes and serves as a potential therapeutic target for renal injury in DN.

Tim-3 aggravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α pathway

Background and objectives Up to 50% of patients undergoing hemodialysis suffer from symptoms of depression and/or anxiety. Access to traditional pharmacotherapies and psychotherapies for depression or anxiety in this patient population has been inadequate. The objective of this study was to investigate the feasibility and effectiveness of brief mindfulness meditation intervention for patients on hemodialysis with depression and anxiety symptoms. Design, setting, participants, & measurements This study was a randomized, controlled, assessor-blinded trial conducted in an urban hemodialysis unit. Forty-one patients were randomly assigned to intervention (n=21) and treatment-as-usual (n=20) groups. The intervention group received an 8-week individual chairside meditation intervention lasting 10–15 minutes, three times a week during hemodialysis. Feasibility outcomes were primarily assessed: enrollment rates, intervention completion rates, and intervention tolerability. Symptoms of depression and anxiety were measured using the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder-7 (GAD-7). Results Of those deemed eligible for the study, 67% enrolled (41 of 61). Of the participants randomized to the intervention group, 71% completed the study, with meditation being well tolerated (median rating of 8 of 10 in a Likert scale; interquartile range=10–5 of 10). Barriers to intervention delivery included frequent hemodialysis shift changes, interruptions by staff or alarms, space constraints, fluctuating participant medical status, and participant fatigue. Meditation was associated with subjective benefits but no statistically significant effect on depression scores (change in PHQ-9, −3.0±3.9 in the intervention group versus −2.0±4.7 in controls; P=0.45) or anxiety scores (change in GAD-7, −0.9±4.6 versus −0.8±4.8; P=0.91). Conclusions On the basis of the results of this study, mindfulness meditation appears to be feasible and well tolerated in patients on hemodialysis with anxiety and depression symptoms. The study did not reveal significant effects of the interventions on depression and anxiety scores. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_10_12_CJASNPodcast_17_12_.mp3

Brief Mindfulness Meditation for Depression and Anxiety Symptoms in Patients Undergoing Hemodialysis: A Pilot Feasibility Study

The efficacy and safety of renin-angiotensin system inhibitors (RAS-I) in hypertensive adults with non-diabetic chronic kidney disease (CKD) differ depending on the presence or the absence of proteinuria. To estimate the effects of RAS-I in this population, we performed a systematic review and meta-analysis of randomized controlled trials where treatment with angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers were compared with placebo or active controls in adults with non-diabetic CKD. The treatment effects were separately reviewed in patients with and without proteinuria. Based on a search of Medline and the Cochrane Library up to September 2017, we identified 42 eligible trials (28, proteinuria-positive group; 6, proteinuria-negative group; 2, mixed-proteinuria group; and 6, proteinuria data-unavailable group). RAS-I reduced renal failure events in comparison to placebo or active agents in the proteinuria-positive group (relative risk [RR] 0.63, 95% confidence interval [CI] 0.52-0.75), but showed no significant effects on renal failure risk in the proteinuria-negative group (RR 0.64, 95% CI 0.18-2.30) although it reduced microalbuminuria. For cardiovascular events, RAS-I was not associated with a significantly reduced risk in both the proteinuria-positive and proteinuria-negative group (RR 0.77 and 1.06, 95% CI 0.51-1.16 and 0.85-1.32, respectively). In the mixed-proteinuria group and proteinuria data-unavailable group, RAS-I showed no significant effects on renal and cardiovascular events. Among adverse events, hyperkalemia increased with RAS-I administration in the proteinuria-positive group (RR 2.01, 95% CI 1.07-3.77). Our analysis showed the renoprotective effects of RAS-I treatment in patients with non-diabetic CKD having proteinuria, supporting its use as the first-line antihypertensive therapy in this population.

Renin-angiotensin system inhibitors in hypertensive adults with non-diabetic CKD with or without proteinuria: a systematic review and meta-analysis of randomized trials.

Malnutrition and inflammation are associated with severity of depressive and cognitive symptoms of old patients affected by chronic kidney disease.

The aim of this study was to evaluate the expression of TIM-3 in renal tissue from patients with systemic lupus erythematosus (SLE) and patients without SLE, and to evaluate the difference of TIM-3 expression between them A total of 272 patients with SLE as SLE group and 62 patients without SLE as control group were enrolled in the present study Patients with SLE accepted percutaneous renal biopsy We examined the expression of TIM-3 in renal tissue and the serological parameters in serum from all enrolled cases The expression of TIM-3 and serological parameters were compared between the different groups Positive staining of TIM-3 protein was seen in 971 % patients with SLE (264 out of 272), but 952 % negative staining in the cases without SLE (59 out of 62), only 3 out of 62 patients in control group were positive staining of TIM-3 There were significant differences between two groups in almost all serological markers which reflect SLE activity There was a nearly positive correlation between pathological manifestations and expression degree of TIM-3 High immuno-reactivity of TIM-3 was found to be significantly correlated with serological grade (p < 0001), but there was the phenomenon in control group The results showed that there was the expression of TIM-3 in renal tissue from the patients with SLE, but rarely expression in cases without SLE Expression of TIM-3 was associated with the diseases’ activity

Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) on kidney tissue from systemic lupus erythematosus (SLE) patients

Background To investigate the clinical significance of serum CA125 in the patients with nephrotic syndrome (NS). Methods Three hundred and twenty-two patients with NS and 120 healthy volunteers were enrolled in our study. We measured serum CA125 and analyzed the probable relationship between elevated CA-125 levels in patients with NS, with and without ascites. Ascites were determined by B-mode ultrasonography in patients with NS. Results Serum CA-125 in NS patients with ascites was significantly increased compared to NS patients without ascites (p 0.05). Conclusions Serum CA125 is a useful index in the diagnosis of ultrasonographically detected ascites in patients with NS.

Clinical significance of serum CA125 in nephrotic syndrome.

Objective: To compare the renoprotective effects of the calcium channel blocker (CCB) benidipine (CAS 105979-17-7) and the angiotensin II receptor blocker (ARB) valsartan (CAS 137862-53-4) in primary hypertensive patients with proteinuria. Methods: 236 patients with primary hypertension were randomly divided into different groups and were administered either benidipine or valsartan. The alterations of the glomerular filtration rate (GFR) and proteinuria were compared between the different groups. Results: Valsartan could decrease the level of proteinuria significantly as compared with that in benidipine-treated hypertensive patients with proteinuria at levels < 1 g/24 h (P < 0.01). There was no significant difference of the effects of benidipine and valsartan on proteinuria reduction in hypertensive patients with proteinuria at levels 1-3 g/24 h. There was no significant difference of the effects of benidipine and valsartan on GFR in benidipine- and valsartan-treated patients. Conclusion: The results showed that valsartan was more effective in decreasing the levels of proteinuria in hypertensive patients with proteinuria at an early stage of nephropathy. The renoprotective effects of benidipine and valsartan in primary hypertensive patients with proteinuria were similar.

A Comparative Study of the Renoprotective Effects of Benidipine and Valsartan in Primary Hypertensive Patients with Proteinuria

OBJECTIVE To compare the renal protective effects between calcium channel blocker benidipine and angiotensin II receptor blocker valsartan in primary hypertension patients with proteinuria METHODS A total of 236 patients were divided to low (< 1 g/24 h) and high (1 - 3 g/24 h) proteinuria groups and treated with benidipine (8 mg/d) or valsartan (80 mg/d) for 48 weeks Blood pressure, glomerular filtration rate (GFR) and 24 h protein were measured at baseline, 12, 24 and 48 weeks RESULTS Blood pressure was significantly and equally reduced in all treated groups (all P < 005 vs baseline) GFR was also significantly and equally improved in all treated groups after 24 weeks treatments (all P < 005 at 24 weeks and 48 weeks) Proteinuria reduction at 24 and 48 weeks was more significant in patients treated with valsartan compared to patients treated with benidipine in low proteinuria group [24 weeks: (027 +/- 007) g/24 h vs (039 +/- 006) g/24 h, P < 001; 48 weeks: (018 +/- 001) g/24 h vs (030 +/- 005) g/24 h, P < 001] CONCLUSION The renal protection efficacy of valsartan and benidipine was similar in primary hypertensive patients with proteinuria

Renal protective effects of benidipine and valsartan in primary hypertension patients with proteinuria

Diabetic nephropathy (DN) is the most important cause of chronic renal and end-stage kidney disease in China. Hypertension (HTN) is highly prevalent in individuals with diabetic nephropathy. Arterial HTN affects two-thirds of people with type 2 diabetes (T2D). In these patients, HTN increased the potential of both micro- and macrovascular complications, and the co-occurrence of 2 such principal causes results in a 4-fold increased risk for cardiovascular disease (CVD) when contrasted with normotensive controls without diabetes. Therefore, the results of valsartan and amlodipine tablets combined with alpha-lipoic acid on total antioxidant capacity (T-AOC) need to be investigated. The aim of this study was to analyze the effects of valsartan (VA) and amlodipine tablets combined with alpha-lipoic acid (α-LA) on T-AOC, IL-6 and β2-MG levels in patients with DN. We performed statistical analysis including the chi-square test, independent t-test, paired t-test and Analysis of Variance (ANOVA). Our findings indicate that VA, amlodipine and α-LA has a significant effect in patients with DN.

Effects of Valsartan and Amlodipine Tablets Combined with α-Lipoic Acid on T-AOC, IL-6 and β2-MG Levels in Patients with Diabetic Nephropathy.

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