Phosphate and Coronary Artery Disease in Patients with Chronic Kidney Disease.

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Both traditional and CKD-related factors are associated with CVD in CKD patients. Traditional factors that play an important role in the atherosclerotic process directly contribute to a higher risk of coronary artery disease in patients with early-stage CKD. Among CKD-related factors, CKD-mineral and bone disorder plays a critical role in the pathomechanism of nonatherosclerotic diseases, which increases the risk of cardiovascular morbidity and mortality in patients with advanced CKD. Higher serum phosphate levels were significantly associated with cardiovascular events and all-cause mortality in patients with or without CKD. An increased phosphate load, directly and indirectly, promotes arterial medial calcification and left ventricular hypertrophy, both of which predispose patients to coronary artery disease. Calciprotein particles that form in a hyperphosphatemic state promote the transformation of vascular smooth muscle cells (VSMCs) into osteoblastic cells, thereby providing a scaffold for medial calcification in the artery. Increases in fibroblast growth factor-23 and disturbed vitamin D metabolism induced by an excessive phosphate load play a significant role in the development of cardiomyocyte hypertrophy and cardiac fibrosis. Recently, hyperphosphatemia was reported to promote de novo cholesterol synthesis in VSMCs and macrophages, which is likely to contribute to statin resistance in patients with end-stage kidney disease. This review outlines the association between increased phosphate load and coronary artery disease in patients with CKD.

IgG4-Related Pericarditis Diagnosed by Accumulated Pericardial Effusion.

IgG4-related pericarditis has rarely been reported. Here, we report a case of IgG4-related disease that presented with pericardial effusion. A 67-year-old female who presented with palpitations and chest pain was admitted because of a large amount of pericardial effusion that required drainage. The patient underwent pericardial drainage, and the symptoms were gradually alleviated. IgG4 levels were elevated in the serum and pericardial effusions. A biopsy specimen of 18F-FDG accumulated in the submandibular gland showed lymphocyte infiltration with IgG4-positive cells. The patient was diagnosed with IgG4-related pericarditis. Glucocorticoids resolved serological and imaging abnormalities. Prompt treatment improves the disease status.

Seasonal variation of serum 25-hydroxyvitamin D level in hemodialysis patients in the northernmost island of Japan.

BACKGROUND: Serum vitamin D level shows a seasonal variation, being lower in winter than in summer in healthy subjects. The aim of this study was to determine whether there is presence of such a seasonal variation in hemodialysis patients. METHODS: A total of 102 patients on hemodialysis were enrolled in February 2017 (winter) for analyses of serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and treatments for chronic kidney disease-mineral and bone disorder (CKD-MBD). The examinations were repeated in August 2017 (summer). After exclusion of patients with malignancy, loss of follow-up and missing data, 78 patients contributed to the analyses. RESULTS: Serum level of 25(OH)D, but not that of 1,25(OH)2D, was significantly lower in winter (14.0 ng/mL) than in summer (15.5 ng/mL), though there was no significant difference in regimen for CKD-MBD treatment including vitamin D receptor activators (VDRAs) between the two seasons. Serum intact parathyroid hormone level tended to be higher and alkaline phosphatase was significantly higher in winter than in summer. Linear mixed-effects model analysis showed that level of 25(OH)D, but not that of 1,25(OH)2D, was significantly associated with season (winter and summer) after adjustment of age, sex, dialysis vintage, albumin level and use of drugs for CKD-MBD. CONCLUSION: Serum 25(OH)D has a seasonal variation, being lower in winter than in summer, independent of CKD-MBD treatment including treatment with VDRAs in Japanese hemodialysis patients. The impact of the seasonal variation on risk of vitamin D deficiency and its effect on prognosis remain to be investigated.

Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model.

BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.

Activation of the angiotensin II receptor promotes autophagy in renal proximal tubular cells and affords protection from ischemia/reperfusion injury.

Roles of the renin-angiotensin system in autophagy and ischemia/reperfusion (I/R) injury in the kidney have not been fully characterized. Here we examined the hypothesis that modest activation of the angiotensin II (Ang II) receptor upregulates autophagy and increases renal tolerance to I/R injury. Sprague-Dawley rats were assigned to treatment with a vehicle or a non-pressor dose of Ang II (200 ng/kg/min) for 72 h before 30-min renal I/R. LC3-immunohistochemistry showed that Ang II treatment increased autophagosomes in proximal tubular cells by 2.7 fold. In Ang II-pretreated rats, autophagosomes were increased by 2.5 fold compared to those in vehicle-treated rats at 4 h after I/R, when phosphorylation of Akt and S6 was suppressed and ULK1-Ser555 phosphorylation was increased. Serum creatinine and urea nitrogen levels, incidence of oliguria, and histological score of tubular necrosis at 24 h after I/R were attenuated by Ang II-pretreatment. In NRK-52E cells, Ang II induced LC3-II upregulation, which was inhibited by losartan but not by A779. The results indicate that a non-pressor dose of Ang-II promotes autophagy via ULK1-mediated signaling in renal tubular cells and attenuates renal I/R injury. The AT1 receptor, but not the Mas receptor, contributes to Ang-II-induced autophagy and presumably also to the renoprotection.

Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1.

ERK and Akt have been shown to regulate cell sensitivity to death-inducing stress by phosphorylating GSK-3ß, a major modulator of the threshold for mitochondrial permeability transition. Here we examined intra-mitochondrial localization of the pro-survival kinases and their regulation by phosphatases. Stepwise trypsin digestion of mitochondria isolated from HEK293 or H9c2 cells was performed, and immunoblotting revealed that GSK-3ß and ERK localized dominantly in the outer membrane (OM), while Akt resided at comparable levels in OM, the inner membrane (IM) and the matrix. Treatment with IGF-1 increased the protein level of Akt in the matrix, while ERK and GSK-3ß protein levels were increased in OM. Simultaneously, IGF-1 treatment elevated the level of Thr202/Tyr204-phospho-ERK in IM and matrix and levels of Ser473-phospho-Akt and Ser9-phospho-GSK-3ß in OM, IM and matrix. Exposing cells to reactive oxygen species (ROS) by using antimycin A increased the levels of DUSP5 and PHLPP-1 mainly in OM and induced dephosphorylation of Akt, ERK and GSK-3ß. The mitochondrial localization of DUSP5 was confirmed by experiments with mitochondria purified by Percoll gradient centrifugation and by transfection of cells with GFP-tagged DUSP5. Knockdown of either DUSP5 or PHLPP-1 increased the levels of both Thr202/Tyr204-phospho-ERK and Ser473-phospho-Akt in mitochondria. Cell death induced by antimycin A was suppressed by siRNA-mediated knockdown of DUSP5. The results suggest that Akt and ERK in mitochondria show distinct intra-mitochondrial localization and crosstalk in GSK-3ß regulation and that recruitment of DUSP5 as well as PHLPP-1 to mitochondria contributes to ROS-induced termination of the protective signaling.

mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation.

Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4 ±â€¯1.3% to 46.1 ±â€¯2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/ß, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.

Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium-glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. MATERIALS AND METHODS: Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. RESULTS: Canagliflozin reduced blood glucose levels in OLETF, and blood ß-hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels in the kidney by 3.2- and 1.6-fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll-like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre-MI fasting suppressed MI-induced renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood ß-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with ß-hydroxybutyrate attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. CONCLUSIONS: The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI-induced cardiorenal syndrome, possibly by ß-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study.

BACKGROUND/AIMS: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. METHODS: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. RESULTS: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95%CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). CONCLUSION: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen.

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes.

Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

Anti-glomerular basement membrane disease accompanied by systemic lupus erythematosus presenting central nervous system involvement.

We report a case of rapidly progressive glomerulonephritis caused by anti-glomerular basement membrane (GBM) disease accompanied by systemic lupus erythematosus (SLE) presenting central nervous system involvement in a 32-year-old Japanese male. He was admitted to our hospital because of a 3-week history of fever and rapidly failing renal function requiring hemodialysis (HD). Laboratory tests showed anti-GBM antibody elevation with a value of 16,385 units/ml. On day 85, he had generalized tonic-clonic seizure. Brain magnetic resonance T2 Flair imaging showed multiple high intensity lesions in a broad area. We made a diagnosis of central nervous system involvement in SLE based on positivity for antinuclear and anti-DNA antibodies, hypocomplementemia, and discoid skin rash. After combined therapy consisting of plasma exchange, HD, and steroid pulse, the patient made a good recovery without any residual neurological sequelae, though kidney dysfunction requiring maintenance HD remained. Anti-GBM antibody finally became undetectable on the 144th hospital day.

Acute interstitial nephritis with membranous nephropathy in bucillamine-treated rheumatoid arthritis.

In bucillamine-treated patients, persistent proteinuria caused by membranous nephropathy (MN) is a major adverse effect affecting the kidneys. We experienced a case of acute interstitial nephritis (AIN) with MN caused by bucillamine. An 81-year-old Japanese woman with a past medical history of rheumatoid arthritis and hypertension presented with a fever, epigastric pain, and nausea of 1 week's duration. She had commenced bucillamine 4 months earlier. At the time of admission, her baseline creatinine (0.8 mg/dl) had risen to 6.8 mg/dl. A renal biopsy revealed AIN with concomitant MN. Renal function gradually improved after bucillamine administration was stopped. In addition to MN, bucillamine can cause AIN, which requires a renal biopsy for definitive diagnosis. Given the host of pathological findings that tend to develop in patients using bucillamine, patients receiving the drug who present with symptoms of acute kidney injury should undergo a renal biopsy to determine the presence of AIN.

Aortic valve aneurysm responsible for acute congestive heart failure and histological findings: A case report.

We experienced a case of acute congestive heart failure in a 73-year-old man who had been followed up due to mild-to-moderate aortic stenosis and moderate-to-severe aortic regurgitation. A huge aortic valve aneurysm was found to extend from his right coronary cusp to a left ventricular outflow tract, resulting in moderate subaortic obstruction and severe aortic regurgitation. Surgical repair was performed and a perforated aneurysm of right aortic cusp was identified. Histological examinations suggested that healed infective endocarditis was responsible for the formation of an aneurysm in the aortic valve. .

Cardiac metaiodobenzylguanidine imaging and heart failure.

The autonomic nervous system has pivotal roles in pathophysiology and prognosis in patients with heart failure. Cardiac (123)I-labeled metaiodobenzylguanidine (MIBG) imaging enables noninvasive and quantitative assessment of cardiac sympathetic innervation in cardiology practice. Several investigations have demonstrated independent and incremental prognostic values of this imaging technique in combination with clinical information in patients with heart failure. Cardiac MIBG imaging may help cardiologists evaluate cardiac sympathetic nerve function and predict lethal event risk in heart failure. It can contribute not only to the identification of low-risk or high-risk probability for lethal events but also to the selection of the appropriate therapeutic strategy, such as medical and device therapy in patients at greater risk for lethal outcomes due to pump failure or sudden arrhythmic events. Thus, precise risk stratification through cardiac MIBG imaging may contribute to more effective use of medical resources and more appropriate selection of therapeutic strategy in heart failure patients.