Mesangial lesions and podocyte injury are essential manifestations of the progression of diabetic kidney disease (DKD). Although cross‐communication between mesangial cells (MCs) and podocytes has ...recently been suggested by the results of single‐nucleus RNA sequencing analyses, the molecular mechanisms and role in disease progression remain elusive. Our cDNA microarray data of diabetic mouse glomeruli suggested the involvement of endoplasmic reticulum (ER) stress in DKD pathophysiology. In vitro experiments revealed the suppression of the ER‐associated degradation (ERAD) pathway and induction of apoptosis in podocytes that were stimulated with the supernatant of MCs cultured in high glucose conditions. In diabetic mice, ERAD inhibition resulted in exacerbated albuminuria, increased apoptosis in podocytes, and reduced nephrin expression associated with the downregulation of ERAD‐related biomolecules. Flow cytometry analysis of podocytes isolated from MafB (a transcription factor known to be expressed in macrophages and podocytes)‐GFP knock‐in mice revealed that ERAD inhibition resulted in decreased nephrin phosphorylation. These findings suggest that an intraglomerular cross talk between MCs and podocytes can inhibit physiological ERAD processes and suppress the phosphorylation of nephrin in podocytes, which thereby lead to podocyte injury under diabetic conditions. Therapeutic intervention of the ERAD pathway through the cross talk between these cells is potentially a novel strategy for DKD.
Metabolic syndrome (MetS) is associated with chronic kidney disease and proteinuria. Previously, we reported that a synthetic serine protease inhibitor, camostat mesilate (CM), mitigated hypertension ...and proteinuria in rodent disease models. The present study evaluated the anti-hypertensive and anti-proteinuric effects of CM in MetS model rats (SHR/ND mcr-cp). Rats were divided into normal salt-fed (NS), high salt-fed (HS), HS and CM-treated (CM), and HS and hydralazine-treated (Hyd) groups. Rats were sacrificed after four weeks of treatment. Severe hypertension and proteinuria were observed in the HS group. Although CM and Hyd equally alleviated hypertension, CM suppressed proteinuria and glomerular sclerosis more efficiently than Hyd. The HS group revealed a decrease in podocyte number and podocyte-specific molecules, together with an increase in glomerular apoptotic cells and apoptosis-related proteins in the kidney. These changes were significantly attenuated by CM, but not by Hyd. Furthermore, CM ameliorated the apoptotic signals in murine cultured podocytes stimulated with the high glucose and aldosterone medium. In conclusion, CM could exert renoprotective effects in MetS model rats, together with the inhibition of podocyte apoptosis. Our study suggests that serine protease inhibition may become a new therapeutic strategy against MetS-related hypertension and renal injuries.
Cisplatin (CDDP) is a widely-used chemotherapeutic drug for solid tumors, but its nephrotoxicity is a major dose-limiting factor. Doxycycline (Dox) is a tetracycline antibiotic that has been commonly ...used in a variety of infections. Dox has been shown to possess several other properties, including antitumor, anti-inflammatory, antioxidative, and matrix metalloproteinase (MMP)-inhibiting actions. We, therefore, investigated whether Dox exerts renoprotective effects in CDDP-induced acute kidney injury (AKI). Twelve-week-old male C57BL/6J mice were divided into the following groups: 1) control, 2) Dox (2 mg/ml in drinking water), 3) CDDP (25 mg/kg body weight, intraperitoneally), and 4) CDDP+Dox. After seven days of pretreatment with Dox, CDDP was administered and the animals were killed at day 1 or day 3. We evaluated renal function along with renal histological damage, inflammation, oxidative stress, and apoptosis. MMP and serine protease activities in the kidney tissues were assessed using zymography. Administration of CDDP exhibited renal dysfunction and caused histological damage predominantly in the proximal tubules. Dox did not affect either expression of CDDP transporters or the accumulation of CDDP in renal tissues; however, it significantly ameliorated renal dysfunction and histological changes together with reduced detrimental responses, such as oxidative stress and inflammation in the kidneys. Furthermore, Dox inhibited the activity of MMP-2 and MMP-9, as well as serine proteases in the kidney tissues. Finally, Dox markedly mitigated apoptosis in renal tubules. Thus, Dox ameliorated CDDP-induced AKI through its pleiotropic effects. Our results suggest that Dox may become a novel strategy for the prevention of CDDP-induced AKI in humans.
Post-extubation airway obstruction is an important complication of tracheal intubation. The cuff leak test is traditionally used to estimate the risk of this complication. However, the cuff leak test ...parameters are not constant and may depend on the respiratory system and ventilator settings. Furthermore, deflating the cuff also be a risk factor for patient-ventilator asynchrony and ventilator-associated pneumonia. Instead of using the cuff leak test, we measured the pressure of the leak to the upper airway through the gap between the tube and glottis with a constant low flow from the lumen above the cuff without deflating the cuff and called it "pressure above the cuff." The purpose of this study was to investigate whether pressure above the cuff can be used as an alternative to the cuff leak volume.
This prospective observational study was conducted at Kumamoto University Hospital after obtaining approval from the institutional review board. The pressure above the cuff was measured using an endotracheal tube with an evacuation lumen above the cuff and an automated cuff pressure modulation device. We pumped 0.16 L per minute of air and measured the steady-state pressure using an automated cuff pressure modulation device. Then, the cuff leak test was performed, and the cuff leak volume was recorded. The cuff leak volume was defined as the difference between the expiratory tidal volume with the cuff inflated and deflated. The relationship between the pressure above the cuff and cuff leak volume was evaluated. The patient-ventilator asynchrony during each measurement was also examined.
The pressure above the cuff was measured, and the cuff leak volume was assessed 27 times. The pressure above the cuff was significantly correlated with the cuff leak volume (r = -0.76, p < 0.001). Patient-ventilator asynchrony was detected in 37% of measurements during the cuff leak test, but not during the pressure above the cuff test.
This study suggests that pressure above the cuff measurement may be a less complicated alternative to the conventional cuff leak test for evaluation of the risk of post-extubation airway obstruction.
University Hospital Medical Information Network Clinical Trials Registry (UMIN000039987; March 30, 2020). https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044604.
Abstract
Background
Patients undergoing hemodialysis treatment have a poor prognosis, as many develop premature aging. Systemic inflammatory conditions often underlie premature aging phenotypes in ...uremic patients. We investigated whether angiopoietin-like protein 2 (ANGPTL 2), a factor that accelerates the progression of aging-related and noninfectious inflammatory diseases, was associated with increased mortality risk in hemodialysis patients.
Methods
We conducted a multicenter prospective cohort study of 412 patients receiving maintenance hemodialysis and evaluated the relationship between circulating ANGPTL2 levels and the risk for all-cause mortality. Circulating ANGPTL2 levels were log-transformed to correct for skewed distribution and analyzed as a continuous variable.
Results
Of 412 patients, 395 were included for statistical analysis. Time-to-event data analysis showed high circulating ANGPTL2 levels were associated with an increased risk for all-cause mortality after adjustment for age, sex, hemodialysis vintage, nutritional status, metabolic parameters and circulating high-sensitivity C-reactive protein levels {hazard ratio HR 2.04 95% confidence interval (CI) 1.10–3.77}. High circulating ANGPTL2 levels were also strongly associated with an increased mortality risk, particularly in patients with a relatively benign prognostic profile HR 3.06 (95% CI 1.86–5.03). Furthermore, the relationship between circulating ANGPTL2 levels and mortality risk was particularly strong in patients showing few aging-related phenotypes, such as younger patients HR 7.99 (95% CI 3.55–18.01), patients with a short hemodialysis vintage HR 3.99 (95% CI 2.85–5.58) and nondiabetic patients HR 5.15 (95% CI 3.19–8.32).
Conclusion
We conclude that circulating ANGPTL2 levels are positively associated with mortality risk in patients receiving maintenance hemodialysis and that ANGPTL2 could be a unique marker for the progression of premature aging and subsequent mortality risk in uremic patients, except those with significant aging-related phenotypes.
Abstract
Background
Pembrolizumab, a highly selective humanized monoclonal IgG4κ isotype antibody against PD-1, is one of the immune checkpoint inhibitors approved for treatment of various cancers. ...The most frequent immune-related adverse events include skin, gastrointestinal, and endocrine abnormalities. In rare cases, however, adverse events on the kidney do occur.
Case presentation
We here report a case of acute kidney injury presenting thrombocytopenia and hemolytic anemia with the presence of schistocytes, which developed in a 68-year-old man with urothelial cancer, 7 months after initiation of pembrolizumab treatment (10 cycles) and 3 weeks after treatment cessation. The patient had previously undergone unilateral nephrectomy and prior treatment with combined gemcitabine and carboplatin regimen. Although corticosteroid, hemodialysis, and plasma exchange were initiated, the patient died within a few days of respiratory failure. Pathological examination at autopsy revealed multiple carcinomas including the lung, liver, and spine, together with the diagnosis of thrombotic microangiopathy by electron microscopy findings of the renal tissue. To our knowledge, this is the first report describing severe thrombotic microangiopathy in a patient possibly associated with pembrolizumab, leading to death.
Conclusion
Physicians should be aware of this potential side effect in patients presenting acute kidney injury and thrombocytopenia.
Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain ...to be elucidated. We have previously reported that camostat mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
Abstract
Background
Malnutrition is associated with discontinuing peritoneal dialysis (PD). The prognostic nutritional index (PNI), composed of serum albumin level and total lymphocyte count, has ...been suggested as a prognostic marker for mortality in patients undergoing PD. However, the relationship between PNI and PD discontinuation has not yet been well addressed. We evaluated the relationship between PNI and PD discontinuation in patients with end-stage kidney disease who initiated PD treatment.
Methods
This retrospective cohort study included patients who underwent PD at a single academic hospital between 2007 and 2022. We examined the association between PNI (< 40 vs. ≥ 40) and PD discontinuation using Cox proportional hazards regression models. We used restricted cubic spline analysis to examine the continuous associations between the PNI and outcomes.
Results
The mean age (and standard deviation) of the 91 patients was 57.1 ± 13.4 years; 72 (79.1%) discontinued PD during the median follow-up period of 25.0 months. Lower PNI was associated with an increased risk of PD discontinuation. The hazard ratios (95% confidence intervals) with three levels of adjustments were 1.74 (1.08, 2.79), 2.21 (1.32, 3.66), and 1.81 (1.01, 3.24) (reference: PNI ≥ 40). Restricted cubic spline analysis showed that a PNI < 40 was continuously associated with a higher risk of PD discontinuation.
Conclusion
A lower PNI (< 40) was associated with a higher risk of PD discontinuation. Our findings suggest that evaluating the PNI may help identify patients at high risk of PD discontinuation and lead to appropriate nutritional management for dialysis maintenance.
We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from ...telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.
The inflammatory mediator calprotectin (CPT, myeloid-related protein 8/14) is known as an endogenous ligand contributing to pathophysiology in inflammatory diseases. Serum CPT reportedly became a ...potential biomarker in these conditions, though there is no report predicting the prognosis in hemodialysis patients. The aim of this study is to investigate the predictive role of serum CPT on mortality in hemodialysis patients.
We conducted a multicenter, observational cohort study of 388 Japanese subjects undergoing hemodialysis. Serum CPT were measured using an ELISA. The potential associations between serum CPT and clinical variables were cross-sectionally examined. Multivariate Cox regression was used to estimate the association between serum CPT, high-sensitivity C reactive protein (hs-CRP), white blood cell (WBC) count and mortality. Median follow-up was 6.6 years.
The median CPT level was 6108 ng/ml (median in healthy subjects, 2800) at baseline. Serum CPT positively correlated with WBC count (ρ = 0.54, P < 0.001) and hs-CRP values (ρ = 0.35, P < 0.001). In multivariate analysis, hs-CRP was an independent predictor of all-cause mortality after adjusting confounding factors (middle vs. low: hazard ratio HR 2.09, 95% confidence interval CI 1.23-3.66; high vs. low: 2.47, 1.40-4.47). In the analysis by stratum of phosphate levels, elevated CPT levels were significantly associated with all-cause mortality in the highest tertile (18.1; 3.15-345.9) among the high-phosphate group, but not among the low-phosphate group.
Serum CPT would become a potential predictive marker on mortality in hemodialysis patients with high-phosphate levels.
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