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The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease. The polyol pathway, which converts glucose into sorbitol and fructose, is active in chronic conditions like hepatic steatosis and chronic kidney disease. Here, Andres-Hernando et al . show that fructose production promotes renal injury and fructokinase inhibition protects against kidney damage during ischaemic acute kidney disease.

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome. Consumption of high amounts of glucose leads to the development of insulin resistance and metabolic syndrome. Here, Lanaspa et al. show that the hepatic conversion of glucose into fructose is a key step in the development of glucose-induced metabolic syndrome and fatty liver in mice.

Background Lipoprotein(a) (Lp(a)) is an independent risk factor for fatal cardiovascular disease (CVD) in dialysis patients; however, evidence regarding its association with CVD, particularly nonfatal events, remains inconsistent. This study aimed to evaluate the relationship between Lp(a) levels at dialysis initiation and subsequent CVD events in Japanese patients. Methods We conducted a single-center, retrospective, observational cohort study of patients who initiated dialysis in Japan between January 2015 and December 2019. Patients were classified into low (< 30 mg/dL) and high (≥ 30 mg/dL) Lp(a) groups on the basis of Lp(a) levels measured at dialysis initiation. The primary outcome was the occurrence of CVD events (death from CVD, hospitalization due to coronary artery disease, arteriosclerosis obliterans, stroke, and congestive heart failure). The patients were monitored for up to 5 years. The associations were evaluated using a Cox proportional hazards model. Results Among 181 eligible patients, 69 (38.1%) had high Lp(a) levels and 64 patients (35.4%) experienced CVD events during the follow-up. The 5-year CVD-free survival rate was significantly lower in the high Lp(a) level group than in the low Lp(a) level group (44.1% versus 63.1%; log-rank test, p  = 0.008). Elevated Lp(a) was independently associated with increased CVD risk using Cox proportional hazard models adjusted for traditional CVD risk factors (hazard ratio: 1.99; 95% confidence interval: 1.19–3.34; p  = 0.012). Conclusions Lp(a) levels ≥ 30 mg/dL at dialysis initiation were an independent predictor of cardiovascular events, including nonfatal outcomes.

Background Systemic capillary leak syndrome (SCLS) is a rare disorder characterized by hypotension, hemoconcentration, and hypoalbuminemia associated with increased capillary endothelium permeability. Patients with a chronic form of SCLS present with persistent and progressive generalized edema. However, there have been no reports of chronic SCLS in patients undergoing hemodialysis. Herein, we report a case of chronic SCLS associated with an intravascular large B-cell lymphoma (IVLBCL) in a patient undergoing hemodialysis. Case presentation A 71-year-old male had been on hemodialysis for five years due to diabetic nephropathy. Difficulty in body fluid removal was observed during hemodialysis, and the patient was admitted to our hospital due to exacerbated weight gain and lower limb edema. He had elevated serum lactate dehydrogenase (LDH) levels and thrombocytopenia. His blood pressure was low, and his serum brain natriuretic peptide level was relatively low, despite the increase in body fluid volume. His clinical characteristics suggested a chronic form of SCLS. Random skin biopsy revealed IVLBCL; however, the association between IVLBCL and chronic SCLS remained unclear. He underwent chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, followed by rituximab. After the treatment, his serum LDH level decreased, and the difficulty in body fluid removal during hemodialysis improved. The patient’s chronic SCLS seemed to be complicated by IVLBCL. Conclusions Patients with chronic SCLS who are undergoing hemodialysis seem to present with difficulties in fluid removal. The frequency of SCLS complications in cases with malignant lymphomas, including IVLBCL, is considered to be extremely low. However, clinicians should be aware of SCLS as a complication of malignant lymphomas.

Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the “radar” of innate immunity.

Introduction: As glomerular filtration rate (GFR) decreases, serum phosphate level increases. Previous reports indicated that serum phosphate level was associated with mortality in patients on dialysis. However, few reports have examined the association using dialysis initiation as the baseline period. Methods: This was a multicenter prospective cohort analysis including 1492 patients. Patients were classified into four quartiles based on the serum phosphate level at dialysis initiation, with Q1 being the lowest and Q4 the highest. All-cause mortality after dialysis initiation was compared using the log-rank test. The propensity score represented the probability of being assigned to group Q1 or Q2-4. All-cause mortality was compared in propensity score-matched patients by using the log-rank test for Kaplan-Meier curves. All-cause mortality of Q1 was compared with that for Q2-4 using multivariate Cox proportional hazard regression analysis. All-cause mortality was also determined among stratified groups with or without use of phosphate binders. Results: Significant differences in cumulative survival rates were observed between the four groups (p < .001). After propensity score-matching, mortality was significantly higher in the Q1 group than the Q2-4 group (p = .046). All-cause mortality was significantly higher in the Q1 group after adjustment for history of CAD (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.58 − 1.00, p = .048). However, there was no significant difference between the two groups after adjustment for estimated GFR. Conclusion: The serum phosphate level at the time of dialysis initiation was associated with all-cause mortality. However, the serum phosphate level was dependent on the renal function.

As hypertension and diabetes mellitus increase, the number of patients developing complications of cardiovascular disease (CVD) associated with conventional risk factors is increasing. In addition to these risk factors for CVD, chronic kidney disease (CKD) has also been reported to play an important role. We investigated the association of representative ischemic heart disease and CKD. Between July 1, 2000, and June 30, 2005, a total of 790 patients who underwent percutaneous coronary intervention (PCI) for angina pectoris or myocardial infarction in our division of cardiovascular disease were reviewed. Serum markers at the implementation of PCI were compared in patients classified according to renal function. For prognosis, in-hospital mortality, 1-year survival rate, overall mortality, and CVD death were investigated. Changes in renal function were also monitored during the follow-up period. The glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease Study Group (MDRD) formula. The mean estimated GFR (eGFR) at PCI implementation was 66.2 +/- 21.0 ml/min/1.73 m(2). Stage 2 CKD was shown in 51.5% of all the patients. During the overall follow-up period, 126 patients died. With the progression of CKD stage, all-cause, CVD, and in-hospital mortality increased, and the 1-year survival rate decreased. It was proved that a medical history of hypertension, hyperlipidemia, and diabetes, multiple vessel lesions, hypoalbuminemia, C-reactive protein (CRP), and estimated GFR were independent risk factors for all-cause death. In CVD death, in addition to the above risk factors, anemia and total cholesterol were also an independent risk factor. Renal function deteriorated significantly during the follow-up period. Patients with ischemic heart disease requiring PCI often develop renal dysfunction, which may considerably affect prognosis.

The purpose of the treatment and management of chronic renal failure during the predialysis period is mainly to retard the progression of the deterioration of renal function. Optimal dialysis initiation is important to improve the patient's outcome after therapy. We investigated whether providing information through an original educational program could facilitate dialysis initiation, with the patient in a better condition, and therefore greater cost-effectiveness. One hundred and seventy-six patients who underwent dialysis initiation for chronic renal failure in our hospital between April 2002 and March 2005 were divided into two groups according to their participation or nonparticipation in an educational program. Participation in the education program was of their own free will. The instructors consisted of nephrologists, nursing staff, clinical engineering technologists, national registered dietitians, and medical social workers. We investigated whether the education program facilitated trouble-free dialysis initiation by comparing findings of blood tests at the start, the existence of heart-failure symptoms, type of blood access, percentage of scheduled initiation, and the number of days and cost of hospitalization as indices between participating and nonparticipating groups. The number of patients using a double-lumen dialysis catheter, and the duration and cost of hospitalization in training the participating group, were significantly less than those in the nonparticipating group. Although there was no significant difference in renal function at the initiation of renal replacement therapy (RRT) between the two groups, serum albumin, hemoglobin, and hematocrit in the participating group were significantly higher than those of the nonparticipating group. This study suggests that providing sufficient information before dialysis initiation may be effective in both physical condition at dialysis initiation, and medical economic benefits through the understanding of the dialysis.