Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine.

BACKGROUND: Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis. METHODS: The physiological role of ARG2 and spermidine was investigated using Arg2-deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients. RESULTS: In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2-deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2-deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2-deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients. CONCLUSIONS: ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.

Magnesium inhibits peritoneal calcification as a late-stage characteristic of encapsulating peritoneal sclerosis.

Peritoneal calcification is a prominent feature of the later stage of encapsulating peritoneal sclerosis (EPS) in patients undergoing long-term peritoneal dialysis (PD). However, the pathogenesis and preventive strategy for peritoneal calcification remain unclear. Peritoneum samples from EPS patients were examined histologically. Peritoneal calcification was induced in mice by feeding with an adenine-containing diet combined with intraperitoneal administration of lipopolysaccharide and a calcifying solution containing high calcium and phosphate. Excised mouse peritoneum, human mesothelial cells (MeT5A), and mouse embryonic fibroblasts (MEFs) were cultured in calcifying medium. Immunohistochemistry confirmed the appearance of osteoblastic differentiation-marker-positive cells in the visceral peritoneum from EPS patients. Intraperitoneal administration of magnesium suppressed peritoneal fibrosis and calcification in mice. Calcifying medium increased the calcification of cultured mouse peritoneum, which was prevented by magnesium. Calcification of the extracellular matrix was accelerated in Met5A cells and MEFs treated with calcification medium. Calcifying medium also upregulated osteoblastic differentiation markers in MeT5A cells and induced apoptosis in MEFs. Conversely, magnesium supplementation mitigated extracellular matrix calcification and phenotypic transdifferentiation and apoptosis caused by calcifying conditions in cultured MeT5A cells and MEFs. Phosphate loading contributes to the progression of EPS through peritoneal calcification and fibrosis, which can be prevented by magnesium supplementation.

Arginase 2 Promotes Cisplatin-Induced Acute Kidney Injury by the Inflammatory Response of Macrophages.

Acute kidney injury (AKI) is a complex clinical syndrome with a rapid decrease in renal function caused by several different etiologies, including sepsis, ischemia, and the administration of nephrotoxic drugs. Tubular arginase 2 (ARG2), an arginine-metabolic enzyme, is a potential therapeutic target for AKI, but it has not been confirmed under various AKI conditions. The aim of this study was to investigate ARG2 as a therapeutic target for cisplatin-induced AKI. Cisplatin-treated mice with a genetic deficiency in Arg2 had significant amelioration of renal dysfunction, characterized by decreased acute tubular damage and apoptosis. In contrast, cisplatin-induced tubular toxicity was not ameliorated in proximal tubule cells derived from Arg2-deficient mice. Immunohistochemical analysis demonstrated the increased infiltration of ARG2-positive macrophages in kidneys damaged by cisplatin. Importantly, cisplatin-treated Arg2 knockout mice exhibited a significant reduction in kidney inflammation, characterized by the decreased infiltration of inflammatory macrophages and reduced gene expression of interleukin (IL)-6 and IL-1ß. The secretion of IL-6 and IL-1ß induced by lipopolysaccharides was decreased in bone marrow-derived macrophages isolated from Arg2-deficient mice. Furthermore, the lipopolysaccharide-induced elevation of mitochondrial membrane potential and production of reactive oxygen species were reduced in bone marrow-derived macrophages lacking Arg2. These findings indicate that ARG2 promotes the inflammatory responses of macrophages through mitochondrial reactive oxygen species, resulting in the exacerbation of AKI. Therefore, targeting ARG2 in macrophages may constitute a promising therapeutic approach for AKI.

Spermidine from arginine metabolism activates Nrf2 and inhibits kidney fibrosis.

Kidney metabolism may be greatly altered in chronic kidney disease. Here we report that arginine metabolism is the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine is the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine shown by immunostaining is associated with the amount of fibrosis. In human proximal tubule cells, spermidine induces nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, fibrotic signals, such as transforming growth factor ß1 secretion, collagen 1 mRNA, and oxidative stress, represented by a decrease in the mitochondrial membrane potential is suppressed by spermidine. UUO kidneys of Arg2 knockout mice show less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation is reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevents significant fibrotic progression in Arg2 knockout mice. Spermidine is increased in kidney fibrosis, but further increases in spermidine may reduce fibrosis.

Acrolein produced during acute kidney injury promotes tubular cell death.

Acute kidney injury is an important global health concern as it is associated with high morbidity and mortality. Polyamines, essential for cell growth and proliferation, are known to inhibit cardiovascular disease. However, under conditions of cellular damage, toxic acrolein is produced from polyamines by the enzyme spermine oxidase (SMOX). We used a mouse renal ischemia-reperfusion model and human proximal tubule cells (HK-2) to investigate whether acrolein exacerbates acute kidney injury by renal tubular cell death. Acrolein visualized by acroleinRED was increased in ischemia-reperfusion kidneys, particularly in tubular cells. When HK-2 cells were cultured under 1% oxygen for 24 h, then switched to 21% oxygen for 24 h (hypoxia-reoxygenation), acrolein accumulated and SMOX mRNA and protein levels were increased. Acrolein induced cell death and fibrosis-related TGFB1 mRNA in HK-2 cells. Administration of the acrolein scavenger cysteamine suppressed the acrolein-induced upregulation of TGFB1 mRNA. Cysteamine also inhibited a decrease in the mitochondrial membrane potential observed by MitoTrackerCMXRos, and cell death induced by hypoxia-reoxygenation. The siRNA-mediated knockdown of SMOX also suppressed hypoxia-reoxygenation-induced acrolein accumulation and cell death. Our study suggests that acrolein exacerbates acute kidney injury by promoting tubular cell death during ischemia-reperfusion injury. Treatment to control the accumulation of acrolein might be an effective therapeutic option for renal ischemia-reperfusion injury.

Glucose degradation products in peritoneal dialysis solution impair angiogenesis by dysregulating angiogenetic factors in endothelial and vascular smooth muscle cells.

BACKGROUND: The accumulation of glucose degradation products (GDPs) during peritoneal dialysis (PD) can lead to immature angiogenesis in the peritoneum. However, the effect of GDPs on angiogenesis, at concentrations observed in dialysate effluent, has not been widely investigated. We do not know how the inflammation observed in PD-related peritonitis affects angiogenesis of the peritoneum. METHODS: Human umbilical vessel endothelial cells (HUVEC) and human umbilical aortic smooth muscle cells (HUASMC) were used to examine the response to the three main GDPs found in peritoneal dialysate (methylglyoxal (MGO), 3-deoxyglucosone (3-DG), and 5-hydroxymethylfurfural (5-HMF). Supernatant from lipopolysaccharide (LPS)-activated murine macrophage cell lines (RAW 264.7 cells) were used to stimulate angiogenesis in the peritoneum. Changes in the expression of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor B (PDGFB) in HUVEC, and PDGF-receptor beta (PDGF-Rß) in HUASMC, were examined by real-time PCR, Western blot, and ELISA. RESULTS: In HUVECs, the expression of PDGFB mRNA and protein were decreased by exposure to MGO, 3-DG, and 5-HMF at concentrations observed in dialysate effluent. A subsequent decrease in secreted PDGF-BB was observed. In HUASMCs, MGO and 5-HMF increased the expression of VEGF-A mRNA and protein, while 5-HMF decreased the expression of PDGF-Rß. VEGF-A is upregulated, and PDGF-Rß is downregulated, by conditioned medium of LPS-stimulated macrophages in HUASMCs. CONCLUSIONS: The GDPs of PD effluent cause an imbalance of angiogenic factors in endothelial cells and vascular smooth muscle cells that may lead to immature angiogenesis in the peritoneum.

Axillary arterial angiosarcoma in a nonfunctioning arteriovenous fistula limb of a patient undergoing hemodialysis: case report with literature review.

A 54-year-old man was admitted to our hospital with a painful left axillary mass. He had a 27-year history of hemodialysis for end-stage kidney disease because of chronic glomerulonephritis. He had a right radial artery-cephalic vein arteriovenous fistula and left nonfunctioning arteriovenous fistula. Computed tomography imaging showed a left axillary arterial mass with peripheral hematoma and multiple lung tumors. On hospital day 3, he showed disturbances in consciousness as well as enlargement of the axillary mass and hematoma. We performed emergency surgery to resect the left axillary tumor. The patient was diagnosed with angiosarcoma upon histopathological examination of the resected specimen on hospital day 15. Because his condition was extremely poor, we provided supportive care to him, not chemotherapy. He expired on hospital day 25. Angiosarcoma remains a rare disease; however, this case highlights the importance of including angiosarcoma in the differential diagnosis for upper extremity pain in patients undergoing hemodialysis.

Lidocaine-Propitocain Cream, a Eutectic Mixture of Local Anesthetics, Effectively Relieves Pain Associated With Vascular Access Intervention Therapy in Patients Undergoing Hemodialysis: A Placebo-Controlled, Double-Blind, Crossover Study.

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT-associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine-propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT-associated pain in patients undergoing hemodialysis. This placebo-controlled, double-blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA-placebo arm or placebo-EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 ± 21.1 vs. 68.6 ± 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT-associated pain in patients undergoing hemodialysis.

Severe Hypocalcemia and Resulting Seizure Caused by Vitamin D Deficiency in an Older Patient Receiving Phenytoin: Eldecalcitol and Maxacalcitol Ointment as Potential Therapeutic Options for Hypocalcemia.

An 82-year-old man treated with phenytoin for the prevention of symptomatic epilepsy was hospitalized to treat consciousness disturbance, seizure, and hypocalcemia (serum calcium: 4.6 mg/dL). Serum 25-hydroxyvitamin D level was very low (5.4 ng/mL), whereas serum calcitriol level was normal (27 pg/mL) and serum intact parathyroid hormone level was increased (369 pg/mL). He was finally diagnosed with vitamin D deficiency associated with low sunlight exposure and long-term phenytoin use for symptomatic epilepsy: phenytoin is shown to accelerate catabolism of 25-hydroxyvitamin D. Combination treatment with eldecalcitol and maxacalcitol ointments successfully normalized corrected serum calcium level: both eldecalcitol and maxacalcitol are vitamin D receptor activators used for osteoporosis and psoriasis, respectively. Our case illustrates the importance of periodic serum calcium level monitoring in patients receiving anti-epileptic drugs and the usefulness of eldecalcitol and maxacalcitol ointment as a therapeutic option for hypocalcemia, especially in countries where native vitamin D and 25-hydroxyvitamin D are not available.

Hypercalcemia and acute kidney injury induced by eldecalcitol in patients with osteoporosis: a case series of 32 patients at a single facility.

BACKGROUND: Eldecalcitol (ELD) is an active vitamin D3 analog that is widely used in Japan for the treatment of osteoporosis. The most common adverse drug reaction of ELD is hypercalcemia. However, few reports have focused on acute kidney injury (AKI) associated with ELD-induced hypercalcemia. MATERIALS AND METHODS: We retrospectively reviewed the medical records at our hospital for cases of hypercalcemia-induced AKI between April 2013 and February 2018. Among them, we focused on patients who developed AKI secondary to ELD-induced hypercalcemia. RESULTS: Among 69 patients who developed hypercalcemia-induced AKI, 32 patients (46.4%) developed AKI associated with ELD-induced hypercalcemia. Their mean age was 82 ± 5 years, 97% of them were female, mean corrected serum calcium level was 12.2 ± 1.5 mg/dL, serum creatinine level was 2.5 ± 2.2 mg/dL, and estimated glomerular filtration rate was 23.9 ± 14.4 ml/min/1.73 m2 on admission. ELD administration was discontinued in all patients and some of them were treated with hydration with or without calcitonin, which was followed by a normalization of serum calcium level. Corrected serum calcium level on admission was significantly higher (p < .05) in patients treated with magnesium oxide. Although there were no significant differences, serum calcium and creatine levels on admission tended to be higher in patients who were treated with other drugs that affect renal hemodynamics and renal calcium metabolism than those not taking these drugs. CONCLUSIONS: Prescribers of ELD should regularly monitor serum calcium levels and kidney function to prevent hypercalcemia and AKI associated with ELD and pay more attention to concomitant drugs especially magnesium oxide.

Better Oral Hygiene Habits Are Associated With a Lower Incidence of Peritoneal Dialysis-Related Peritonitis.

Some peritoneal dialysis (PD)-related peritonitis cases are thought to be caused by the pathogens in the oral cavity; however, the relationship between peritonitis and oral hygiene habits is unclear. In this study, we retrospectively examined the relationship between oral hygiene habits and peritonitis in patients who agreed to a questionnaire survey. Of the 75 patients, 37 patients developed PD-related peritonitis during the observation period. Peritonitis-free survival was significantly higher in patients who spent more time on oral hygiene daily and in patients who replaced their toothbrush more frequently (P < 0.05). According to multivariable analysis, increased daily oral hygiene duration and more frequent toothbrush replacement were associated with a significantly (P < 0.01) lower risk for peritonitis (hazard ratio [HR] 0.37 [95% CI, 0.18-0.77] and HR 0.35 [95% CI, 0.17-0.70], respectively). In conclusion, PD patients with superior oral hygiene habits showed a lower risk for PD-related peritonitis.

A case of congenital left ventricular diverticulum in a patient with autosomal dominant polycystic kidney disease: possible mechanistic link between polycystin and ventricular diverticulum.

A 40-year-old woman had been followed as an outpatient to manage chronic kidney disease secondary to autosomal dominant polycystic kidney disease (ADPKD). Atrial premature contraction was found incidentally on an electrocardiogram during her regular follow-up examination. Subsequent transthoracic echocardiography detected an abnormal structure located very close to the left ventricular outflow tract (23 mm long × 15 mm wide in diastole). The structure was finally diagnosed as congenital left ventricular diverticulum (CLVD) using transesophageal echocardiography, contrast-enhanced computed tomography, and magnetic resonance imaging. Although CLVD occasionally causes intraventricular coagulation, lethal arrhythmia, and congestive heart failure, the size and location of her diverticulum remained unchanged over time and a 24-h Holter electrocardiogram showed no lethal arrhythmias. Accordingly, neither anticoagulation therapy nor surgical resection of the diverticulum was performed. To the best of our knowledge, ours is the first case of CLVD in a patient with ADPKD. Because gene abnormalities in polycystin coding are mechanistically related to the development of colonic diverticulum and abnormal cyst formation in ADPKD patients, we suspected that CLVD and abnormal cyst formation were related to the same gene abnormality in ADPKD. More case reports, case series studies, and basic research are required to determine whether CLVD in ADPKD is mechanistically associated with abnormal polycystin or just a coincidence.

Cholesterol Crystal Embolism Induced by Direct Factor Xa Inhibitor: A First Case Report.

An 80-year-old man presented at our hospital with renal failure. He had been treated with edoxaban, an oral direct factor Xa inhibitor, for deep vein thrombosis for 10 months prior to admission. Although the pulses in his bilateral pedal arteries were palpable, cyanosis was present in the bilateral toes. Laboratory data indicated azotemia and eosinophilia. A skin biopsy confirmed a diagnosis of cholesterol crystal embolism (CCE). Because no invasive vascular procedure was performed, we assumed that CCE was related to edoxaban. To the best of our knowledge, this is the first case report suggesting CCE induced by an Xa inhibitor.

Modified Simple Peritoneal Wall Anchor Technique (PWAT) in Peritoneal Dialysis.

♦ BACKGROUND: Outflow obstruction, a common complication in patients with peritoneal dialysis (PD), usually results in unnecessary catheter removal or replacement. This study describes a modified simple method of anchoring a PD catheter on the anterior peritoneal wall without using a laparoscopic system (peritoneal wall anchor technique, PWAT). ♦ METHODS: We performed a retrospective cohort study of consecutive PD catheter insertions, and compared the catheter survival rate between the traditional method and the modified simple PWAT. The traditional method was used in 54 cases and the modified simple PWAT was used in 17 cases. The primary endpoint was the occurrence of surgical catheter repair because of outflow obstruction by day 365. The secondary endpoint was the occurrence of catheter migration with obstruction requiring any interventions, including the alpha-replacement method by day 365. Catheter survival was analyzed by Kaplan-Meier survival curves. ♦ RESULTS: Migration-free catheter survival was significantly (p = 0.02) higher in the PWAT group (100%, 17/17) than in the traditional group (72.2%, 39/54). Catheter survival without surgical repair or cessation of PD was also significantly (p = 0.04) higher in the PWAT group (100%, 17/17) than in the traditional group (77.8%, 42/54). Similarly, migration-free and surgery-free catheter survival rates in cases with a straight-type catheter in the PWAT group were significantly higher than those in cases with a straight-type catheter in the traditional group. ♦ CONCLUSIONS: Our results suggest that the modified simple PWAT provides a better catheter survival rate than the traditional method by preventing catheter migration with obstruction in PD.

The Successful Treatment of Calciphylaxis with Sodium Thiosulfate and Hyperbaric Oxygen in a Non-dialyzed Patient with Chronic Kidney Disease.

We present the case of a non-dialyzed patient with chronic kidney disease and biopsy-proven calciphylaxis who presented with painful cutaneous ulcers on both legs. The skin ulcers drastically improved within 6 months after the initiation of hemodialysis, aggressive wound care, the control of a mineral and bone disorder, and the administration of sodium thiosulfate and hyperbaric oxygen therapy. Notably, the patient's serum levels of C-reactive protein and calciprotein particles decreased and her serum albumin and fetuin-A levels increased in parallel with the alleviation of her calciphylaxis. This case highlights the importance of applying combined medical treatment to calciphylaxis and suggests the possible involvement of calciprotein particles in the pathogenesis of calciphylaxis.