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Background: Intradialytic hypotension (IDH) has been reported to be an important prognostic factor in hemodialysis patients. However, a standard definition of IDH has not yet been determined., Methods: We retrospectively analyzed blood pressure (BP) metrics obtained during serial dialysis sessions over a 90-day period from a single dialysis center from 2016 to 2017. The mean values and the frequency of specific values of BP were analyzed as predictors of 3-year mortality., Results: A total of 430 patients who underwent maintenance dialysis were included. The mean age was 63.3 ± 12.4 years and 58.6% were male. A low minimum systolic blood pressure (SBP) <110 mmHg during dialysis was significantly associated with increased all-cause mortality. The frequency of a minimum SBP <100 mmHg was the most significant predictor of 3-year mortality, with an area under the curve (AUC) of 0.722. Furthermore, the frequency of a minimum SBP <100 mmHg significantly increased the predictability of mortality when combined with the presence of other clinical factors including age, body mass index and vascular access type (AUC 0.786 vs. 0.835; p = 0.005)., Conclusion: Among the various intradialytic BP metrics, the frequency of a minimum SBP <100 mmHg is the most significant factor related to all-cause mortality. The guidelines for the management of blood pressure in dialysis patients should consider including a minimum SBP <100 mmHg as a definition for IDH., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Arteriovenous fistulas (AVFs) are the preferred vascular access type in most hemodialysis patients. However, the optimal vascular access type in octogenarians and older (≥80 years) hemodialysis patients remains widely debated given their limited life expectancy and lower AVF maturation rates., Methods: Among incident hemodialysis patients receiving care in a large national dialysis organization during 2007-2011, we examined patterns of vascular access type conversion in 1 year following dialysis initiation in patients <80 versus ≥80 years of age. Among a subcohort of patients ≥80 years of age, we examined the association between vascular access type conversion and mortality using multivariable survival models., Results: In the overall cohort of 100 804 patients, the prevalence of AVF/arteriovenous graft (AVG) as the primary vascular access type increased during the first year of hemodialysis, but plateaued thereafter. Among 8356 patients ≥80 years of age and treated for >1 year, those with initial AVF/AVG use and placement of AVF from a central venous catheter (CVC) had lower mortality compared with patients with persistent CVC use. When the reference group was changed to patients who had AVF placement from a CVC in the first year of dialysis, those with initial AVF use had similar mortality. A longer duration of CVC use was associated with incrementally worse survival., Conclusions: Among incident hemodialysis patients ≥80 years of age, placement of an AVF from a CVC within the first year of dialysis had similar mortality compared with initial AVF use. Our data suggest that initial CVC use with later placement of an AVF may be an acceptable option among elderly hemodialysis patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs)., Results: Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism., Conclusions: Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Background: Recent data suggest that aldosterone antagonists have beneficial effects on diabetic nephropathy. In this study, we investigated the dose-dependent effect of eplerenone and a combined treatment with eplerenone and enalapril compared with each drug alone on renal function in type II diabetic rats. To further explore the molecular mechanism of action of combination therapy, we also performed in vitro study., Methods: The animals were divided into six groups as follows: normal control Long-Evans Tokushima Otsuka (LETO) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, OLETF rats treated with low dose of eplerenone (50 mg/kg/day), OLETF rats treated with high dose of eplerenone (200 mg/kg/day), OLETF rats treated with enalapril (10 mg/kg/day) and OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and enalapril 10 mg/kg/day) for 6 months., Results: Treatment of OLETF rats had no significant effect on body weight, kidney weight and blood glucose levels. However, urinary albumin excretion, glomerular filtration rate and glomerulosclerosis were significantly improved in the enalapril group and improvement was observed in a dose-dependent manner in the eplerenone groups; the most dramatic decreases were observed in the combination group. In accordance with these findings, renal expressions of TGF-beta1, type IV collagen and PAI-1 were also markedly decreased in the treatment groups, with the combined treatment providing the most significant level of improvement. In cultured mesangial cells, combined treatment resulted in an additive decrease in TGF-beta1, PAI-1 and collagen gene expressions and protein production induced by high glucose and aldosterone stimulation., Conclusions: Aldosterone receptor antagonism provided additional benefits beyond blockade of the renin-angiotensin system in type II diabetic nephropathy.

Background: Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a role in insulin sensitivity, lipid metabolism and inflammation. However, the effects of PPARgamma agonist on renal inflammation have not been fully examined in type 2 diabetic nephropathy., Methods: In the present study, we investigated the effect and molecular mechanism of the PPARgamma agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-kappaB, MCP-1 and pro-fibrotic cytokines were determined by RT-PCR, western blot, immunohistochemical staining and EMSA. In addition, to evaluate the direct anti-inflammatory effect of PPARgamma agonist, we performed an in vitro study using mesangial cells., Results: Treatment of OLETF rats with pioglitazone improved insulin sensitivity and kidney/body weight, but had a little effect on blood pressure. Pioglitazone treatment markedly reduced urinary albumin and MCP-1 excretion, and ameliorated glomerulosclerosis. In cDNA microarray analysis using renal cortical tissues, several inflammatory and profibrotic genes were significantly down-regulated by pioglitazone including NF-kappaB, CCL2, TGFbeta1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-kappaB activation in association with a decrease in type IV collagen, PAI-1, and TGFbeta1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARgamma transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-kappaB activation., Conclusions: These data suggest that pioglitazone not only improves insulin resistance, glycaemic control and lipid profile, but also ameliorates renal injury through an anti-inflammatory mechanism in type 2 diabetic rats.

Background: Ischaemia/reperfusion is a major cause of acute kidney injury and can result in poor long-term graft function. Although most of the patients with acute kidney injury recover their renal function, significant portion of patients suffer from progressive deterioration of renal function. A persistent inflammatory response might be associated with long-term changes following acute ischaemia/reperfusion. Macrophages are known to infiltrate into tubulointersitium in animal models of chronic kidney disease. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. We aimed to investigate the role of macrophages on the development of tubulointerstitial fibrosis and functional impairment following acute ischaemia/reperfusion injury by depleting macrophages with liposome clodronate., Methods: Male Sprague-Dawley rats underwent right nephrectomy and clamping of left renal vascular pedicle or sham operation. Liposome clodronate or phosphate buffered saline was administered for 8 weeks. Biochemical and histological renal damage and gene expression of various cytokines were assessed at 4 and 8 weeks after ischaemia/reperfusion., Results: Ischaemic/reperfusion injury resulted in persistent inflammation and tubulointerstital fibrosis with decreased creatinine clearance and increased urinary albumin excretion at 4 and 8 weeks. Macrophage depletion attenuated those changes. This beneficial effect was accompanied with a decrease in gene expression of inflammatory and profibrotic cytokines., Conclusions: These results suggest that macrophages play an important role in mediating persistent inflammation and fibrosis after ischaemia/reperfusion leading to a development of chronic kidney disease. Strategies targeting macrophage infiltration or activation can be useful in the prevention of development of chronic kidney disease following ischaemic injury.

The frequency of neutropenia in patients receiving long-term cefepime therapy for osteomyelitis compared with that in patients receiving other antimicrobials was studied. A comparative case review was conducted of home infusion patients receiving cefepime and patients receiving other antimicrobials for osteomyelitis. All courses of antimicrobial therapy for osteomyelitis between January 2001 and December 2002 were evaluated. The duration of prescribed therapy was approximately six weeks. Weekly laboratory tests included complete blood counts with differential. A total of 134 courses of antimicrobial therapy were reviewed (13 courses of cefepime therapy in 12 patients and 121 courses of therapy with other i.v. antimicrobials in 120 patients). Eight (62%) of the cefepime courses resulted in neutropenia, compared with none in the courses of other antimicrobials. Neutropenia was detected after 17-30 days of cefepime therapy. Blood counts returned to normal within one week of cefepime discontinuation. Eight of 13 courses of extended therapy with i.v. cefepime for osteomyelitis resulted in neutropenia, compared with none of 121 courses of other antimicrobials. Clinicians should exercise extreme caution when prescribing cefepime for longer than 14 days.