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Key Points In patients with diabetes undergoing haemodialysis, both extremely high and low glycaemic levels are associated with increased morbidity and shortened survival owing to vascular and diabetic complications and malnutrition Factors that are associated with an increased risk of hypoglycaemia in patients on haemodialysis include decreased renal gluconeogenesis, deranged metabolic pathways (including altered metabolism of medications) and decreased insulin clearance Glucose loss to the dialysate and diffusion of glucose into erythrocytes during haemodialysis are also associated with haemodialysis-induced hypoglycaemia Inclusion of glucose in the dialysate is important to prevent haemodialysis-induced hypoglycaemia; use of glucose-free or low-glucose dialysates should be avoided in patients with diabetes After the completion of a haemodialysis session, a paradoxical hyperglycaemia may ensue via a mechanism similar to the Somogyi effect, together with insulin resistance and insulin removal by the dialyzer Appropriate glycaemic control tailored for diabetic patients is required to avoid haemodialysis-induced hypoglycaemia and other glycaemic disarrays In diabetic patients undergoing maintenance haemodialysis, extremely high and low glycaemic levels are associated with increased morbidity and mortality owing to vascular and diabetic complications. The prevention of glycaemic disarrays in this population is challenging owing to factors including changes in the metabolism of glucose and drugs, malnutrition and insulin resistance. Here, the authors review the pathophysiology and management of haemodialysis-induced hypoglycaemia and hyperglycaemia in patients with diabetes. In patients with diabetes receiving chronic haemodialysis, both very high and low glucose levels are associated with poor outcomes, including mortality. Conditions that are associated with an increased risk of hypoglycaemia in these patients include decreased gluconeogenesis in the remnant kidneys, deranged metabolic pathways, inadequate nutrition, decreased insulin clearance, glucose loss to the dialysate and diffusion of glucose into erythrocytes during haemodialysis. Haemodialysis-induced hypoglycaemia is common during treatments with glucose-free dialysate, which engenders a catabolic status similar to fasting; this state can also occur with 5.55 mmol/l glucose-containing dialysate. Haemodialysis-induced hypoglycaemia occurs more frequently in patients with diabetes than in those without. Insulin therapy and oral hypoglycaemic agents should, therefore, be used with caution in patients on dialysis. Several hours after completion of haemodialysis treatment a paradoxical rebound hyperglycaemia may occur via a similar mechanism as the Somogyi effect, together with insulin resistance. Appropriate glycaemic control tailored for patients on haemodialysis is needed to avoid haemodialysis-induced hypoglycaemia and other glycaemic disarrays. In this Review we summarize the pathophysiology and current management of glycaemic disarrays in patients on haemodialysis.

The freshwater snail Lymnaea stagnalis has a long research history, but only relatively recently has it emerged as an attractive model organism to study molecular mechanisms in the areas of developmental biology and translational medicine such as learning/memory and neurodegenerative diseases. The species has the advantage of being a hermaphrodite and can both cross- and self-mate, which greatly facilitates genetic approaches. The establishment of body-handedness, or chiromorphogenesis, is a major topic of study, since chirality is evident in the shell coiling. Chirality is maternally inherited, and only recently a gene-editing approach identified the actin-related gene Lsdia1 as the key handedness determinant. This short article reviews the natural habitat, life cycle, major research questions and interests, and experimental approaches.

Carnitine is a naturally occurring amino acid derivative that is involved in the transport of long-chain fatty acids to the mitochondrial matrix. There, these substrates undergo β-oxidation, producing energy. The major sources of carnitine are dietary intake, although carnitine is also endogenously synthesized in the liver and kidney. However, in patients on dialysis, serum carnitine levels progressively fall due to restricted dietary intake and deprivation of endogenous synthesis in the kidney. Furthermore, serum-free carnitine is removed by hemodialysis treatment because the molecular weight of carnitine is small (161 Da) and its protein binding rates are very low. Therefore, the dialysis procedure is a major cause of carnitine deficiency in patients undergoing hemodialysis. This deficiency may contribute to several clinical disorders in such patients. Symptoms of dialysis-related carnitine deficiency include erythropoiesis-stimulating agent-resistant anemia, myopathy, muscle weakness, and intradialytic muscle cramps and hypotension. However, levocarnitine administration might replenish the free carnitine and help to increase carnitine levels in muscle. This article reviews the previous research into levocarnitine therapy in patients on maintenance dialysis for the treatment of renal anemia, cardiac dysfunction, dyslipidemia, and muscle and dialytic symptoms, and it examines the efficacy of the therapeutic approach and related issues.

Background Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study were (1) to measure serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + -M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis. Methods Serum WFA + -M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists. Results For stages 0 ( n  = 35), 1 ( n  = 113), 2 ( n  = 49), 3 ( n  = 41), and 4 ( n  = 51) of liver fibrosis, the serum WFA + -M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA + -M2BP values were associated with the stage of fibrosis (≥stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA + -M2BP were 0.876, 85.9, and 74.6 %, respectively, for severe fibrosis (≥stage 3) and were 0.879, 74.6, and 87.0 %, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA + -M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis. Conclusions Serum WFA + -M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.

We have demonstrated that complement 3 (C3) is upregulated and induces epithelial-mesenchymal transition (EMT) phenomenon and renal fibrosis in unilateral ureteral obstruction (UUO) kidney. We investigated roles of twist-related protein 1 (TWIST1) in EMT phenomenon and renal fibrosis through C3 upregulation in a mouse UUO model with gene silencer pyrrole-imidazole (PI) polyamides targeting TWIST1. We designed and synthesized PI polyamides targeting TWIST1 binding site on mouse pre-pro C3 promoter. Increased expression C3 mRNA with interferon-γ was significantly inhibited with PI polyamide in nephrotubular epithelial cells. Immunofluorescence showed suppression of E-cadherin and enhancement of α-smooth muscle actin (α-SMA) stainings as EMT phenomena in UUO kidney. TWIST1 and C3 expression was significantly increased in UUO kidney versus contralateral unobstructed kidney (CUK). Expression of transforming growth factor-β1 (TGF-β1), α-SMA and renin mRNAs was increased in UUO kidney versus CUK. Systemic administration of TWIST1 PI polyamide significantly suppressed increased C3 expression in UUO kidney versus CUK. PI polyamide administration also suppressed the increased expression of TGF-β1, α-SMA and renin mRNAs and histologically improved renal fibrosis in UUO kidney. These findings indicate that TWIST1 induces EMT phenomenon and renal fibrosis by TGF-β1 upregulation of C3 in mouse UUO model and that TWIST1 PI polyamide may be a novel medicine for renal fibrosis.

The complement system has recently been reported to contribute to the development and pathogenesis of hypertension, several cardiovascular and renal diseases, and cardiometabolic disorders accompanied by inflammation and tissue remodeling. We have demonstrated that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHRs) and induces the synthetic phenotype and exaggerated growth of mesenchymal cells by maintenance effect on dedifferentiated cells. To verify the role of C3 in the pathogenesis of hypertension, we targeted the C3 gene from SHRs by zinc-finger nuclease gene-editing technology and demonstrated that the increased expression of C3 induces salt-sensitive hypertension with activation of the renal renin-angiotensin system in SHRs. We recently found that increased expression of C3 is associated with the suppression of miR145 and induces Krüppel-like factor 5 and the synthetic phenotype of mesenchymal cells in SHRs. We also demonstrated that C3 is involved in the epithelial-to-mesenchymal transition and dedifferentiation of epithelial cells in kidneys subjected to unilateral ureteral obstruction with elevation of blood pressure. Thus, C3 is an essential factor in the pathogenesis of hypertension due to its maintenance effect on undifferentiated mesenchymal cells.

BackgroundThe effects of direct-acting antivirals (DAAs) on survival and recurrence rates after curative hepatocellular carcinoma (HCC) treatment in patients with hepatitis C virus (HCV) infection remain controversial.MethodsThis retrospective, multicenter study involved Child–Pugh class A patients within the Milan criteria who had a first diagnosis of HCC and survived 6 months or longer after undergoing hepatectomy or radiofrequency ablation (RFA). The DAA-treated group (DAA group) included 56 patients, and the DAA-untreated group (untreated group) included 261 patients. The study was conducted using the propensity score-matched (1:2) DAA group and untreated group, 56 and 112 patients, respectively.ResultsThe survival rate at 48 months in the DAA group and the untreated group was 91.0% and 68.7%, respectively, showing significantly better survival in the DAA group (HR: 0.33; 95% CI 0.13–0.84; p = 0.021). The recurrence rate at 48 months was 36.7% and 66.7%, respectively, showing a significantly lower recurrence rate in the DAA group (HR, 0.46; 95% CI 0.27–0.77; p = 0.003). The median albumin–bilirubin (ALBI) score at 3 years post-HCC treatment was − 2.84 in the DAA group and − 2.34 in the untreated group. The ALBI score showed a significant improvement from baseline to 3 years post-HCC treatment (p = 0.001), whereas that in the untreated group showed a significant decline (p = 0.040).ConclusionsDAAs after HCC treatment prevents deterioration of hepatic functional reserve and significantly improves both recurrence and survival rates.

In hemodialysis patients, it remains unclear whether patient characteristics influence the clinical impacts of changes in serum mineral metabolism parameters on mortality. In this 9-year cohort study, we investigated the associations between the changes in calcium/phosphate levels and all-cause mortality using a time-dependent approach after adjustment for potential confounders in groups stratified by performance status (PS), a history of atherosclerotic cardiovascular disease (ACVD), or diabetic nephropathy (DN). In patients with baseline serum calcium levels of 9.5–<10.0 mg/dL, increases in serum calcium levels were associated with higher mortality exclusively in patients with PS Grade 0. In the same baseline calcium range, a significant association was observed between reduced serum calcium levels and lower mortality only in patients with a history of ACVD or DN. Similarly, in patients with baseline serum phosphate levels of 5.0–<5.5 mg/dL, reduced serum phosphate levels were associated with lower mortality only in those with PS Grade 0, a history of ACVD or DN. These findings indicate that PS should be considered in treating mild hypercalcemia or hyperphosphatemia in hemodialysis patients. Moreover, stringent management of hypercalcemia and hyperphosphatemia in patients with a history of ACVD or DN might be associated with a better prognosis.

In patients undergoing hemodialysis, the impact of atrial fibrillation (AF) through cardiac thromboembolism on the development of ischemic stroke may be influenced by the severity of atherosclerosis present. However, there are no large-scale reports confirming whether the severity of atherosclerosis influences the relationship between AF and stroke development in patients requiring hemodialysis. We aimed to investigate the effects of atherosclerotic disease on the relationship between AF and new-onset ischemic stroke. This nationwide longitudinal study based on dialysis facilities across Japan used data collected from the Japanese Renal Data Registry at the end of 2019 and 2020. The exposure was AF at the end of 2019, identified using a resting 12-lead electrocardiography. The primary outcome was the incidence of cerebral infarction (CI) after 1 year. To examine whether the number of atherosclerotic diseases modified the association between AF and the outcome, we estimated the odds ratios (ORs) using a logistic regression model and then assessed the presence of global interaction using Wald test. Following the study criteria, data from 151,350 patients (mean age, 69 years; men, 65.2%; diabetic patients, 48.7%) were included in the final analysis. A total of 9841 patients had AF (prevalence, 6.5%). Between 2019 and 2020, 4967 patients (3.2%) developed ischemic stroke. The adjusted OR of AF for new-onset CI was 1.5, which showed a decreasing trend with an increasing number of atherosclerotic diseases; the interaction was not significant (P = 0.34). While age, diabetes mellitus, smoking, systolic blood pressure, and serum C-reactive protein concentration were positively associated with CI, intradialytic weight gain, body mass index, and serum albumin level were negatively associated. While we demonstrated the association between AF and new-onset CI among Japanese patients on hemodialysis, we failed to demonstrate the evidence that the association was attenuated with an increasing numbers of atherosclerotic complications.

Dialyzers are classified into five types based on their β 2 -microglobulin clearance rate and albumin sieving coefficient: Ia, Ib, IIa, and IIb. In addition, a new classification system introduced a type S dialyzer. However, limited information is available regarding the impact of dialyzer type on patient outcomes. A cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry database. Total 181,804 patients on hemodialysis (HD) were included in the study, categorized into four groups (type Ia, IIa, IIb, and S). The associations between each group and two-year all-cause mortality were assessed using Cox proportional hazard models. Furthermore, propensity score-matching analysis was performed. By the end of 2019, 34,185 patients on dialysis had died. After adjusting for all confounders, the risk for all-cause mortality was significantly lower in the type IIa, and S groups than in the type Ia group. These significant findings were consistent after propensity score matching. In conclusion, our findings suggest that super high-flux dialyzers, with a β 2 -microglobulin clearance of ≥ 70 mL/min, may be beneficial for patients on HD, regardless of their albumin sieving coefficient. In addition, type S dialyzers may be beneficial for elderly and malnourished patients on dialysis. Trial registration number: UMIN000018641