Background: Klotho is a single transmembrane protein originally identified as an ‘aging suppressor'. Emerging evidence reveals that soluble Klotho (sKl) in the circulation plays important roles in anti-aging, anti-oxidation, anti-apoptosis and Wnt signaling. However, the role of serum sKl in the vascular calcification in hemodialysis patients is not clear. The aim of this study was to determine the associations of sKl with abdominal aortic calcification in patients on maintenance hemodialysis (MHD). Methods: 129 MHD patients were enrolled prospectively. Serum sKl level was detected by ELISA. Abdominal aortic calcification was measured by abdomen lateral plain radiograph, and the abdominal aorta calcification (AAC) score was calculated. The sKl levels were observed in patients with different degrees of calcification. Logistic regression analysis was used to determine the risk factor of abdominal aortic calcification in MHD patients. The diagnostic value of sKl for abdominal aortic calcification was assessed using receiver operator characteristic (ROC). Results: Abdominal aortic calcification was seen in 87 of 129 patients. The median AAC score was 4.0 (0.00, 11.00) and the median sKl level was 616.29 (378.19, 821.61) pg/ml. Serum sKl levels were inversely associated with AAC. When evaluated as AAC categories (15) with ordinal logistic regression, each SD higher sKl was associated with 37.1% lower odds of AAC severity (proportional odds ratio: 0.629; 95% confidence interval: 0.413-0.959, p = 0.031) in models adjusted for demographic data, lifestyle factors, traditional CVD risk factors and uremic risk factors. Multivariate logistic regression analysis showed that serum sKl levels and smoking were independent risk factors for severe AAC. The area under the receiver-operating characteristic curve (AUC) of serum sKl for severe abdominal aortic calcification was 0.746 (0.612-0.880, p = 0.001), sensitivity was 0.885, and specificity was 0.562 for a cutoff value of 265.39 pg/ml. Conclusions: Lower serum sKl levels are independently associated with severe AAC. Serum sKl might have a diagnostic value for the severe AAC in MHD patients.

To determine the relationship between the variability of serum phosphorus and mortality among maintenance hemodialysis (MHD) patients. A total of 502 MHD cases were studied from the Shanghai Renal Registry Network. Serum phosphorus variability was indicated by a coefficient of variation (CV). According to the CV median of serum phosphorus, patients were divided into two groups: a high-variability group (CV ≥ 0.226 mmol/L) and a low-variability group (CV < 0.226 mmol/L). Average phosphorus ≤ 1.78 mmol/L was defined as the standard phosphorus group and serum phosphorus > 1.78 mmol/L was defined as the non-standard phosphorus group. The relationship between serum phosphorus variability and all-cause and cardiovascular disease (CVD) mortality was assessed. In the 502 MHD cases, the average age of patients was 63.9 ± 14.60 years, and dialysis vintage was 82.0 (43.0 - 139.0) months. 118 patients (23.5%) died, succumbing to all-cause mortality, while 64 patients (14.3%) died from CVD. The high-variability group had increased all-cause mortality (27.7% vs. 19.3%, p = 0.028). Death from CVD was increased in the high-variability group, but had no statistical significance (15.4% vs. 10.0%, p = 0.082). Cox regression analysis showed that older age, low hemoglobin levels, a higher phosphorus CV, and low serum albumin were independent risk factors for all-cause and CVD mortality. The standard group with low-phosphorus variability had a decreased mortality compared with the non-standard group with high variability (15.3 vs. 29.2%, p = 0.047 and 6.0 vs. 15.0%, p = 0.033, respectively). The Kaplan-Meier method revealed that patients with low phosphorus variability had a decreased all-cause and CVD mortality (p = 0.023 and p = 0.047, respectively) compared with high phosphorus variability patients. Higher phosphorus CV was independently correlated with all-cause and CVD mortality. Low phosphorus variability with on-target levels resulted in decreased patient mortality. Thus, stable serum phosphorus levels may improve survival in MHD patients. .

Objective: The objective of this study is to investigate the relationship between blood pressure changes and all-cause mortality, and between blood pressure changes and cardiovascular mortality, for maintenance hemodialysis (MHD) patients during dialysis. Methods: Data regarding general condition, biochemical indices, and survival prognosis of MHD patients who were treated at the Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital from July 2007 to December 2012 were collected, in order to evaluate the relationship between patients’ blood pressure changes during hemodialysis and mortality. Results: Among 364 patients, with an average age of 63.07 ± 13.93 years, an average dialysis vintage of 76.00 (range, 42.25–134.00) months, and a follow-up time of 54.86 ± 19.84 months, there were 85 cases (23.4%) of all-cause death and 46 cases (14.2%) of cardiovascular death. All-cause mortality and cardiovascular mortality were lowest (OR, 0.324 and 0.335; 95% CI, 0.152–0.692 and 0.123–0.911; p value, .004 and .032, respectively) in patients whose systolic blood pressure difference (ΔSBP) before and after dialysis was between 7.09 and 14.25 mmHg. Kaplan–Meier analysis indicated that both all-cause mortality and cardiovascular mortality were markedly increased for patients with ΔSBPless than −0.25 mmHg (p value, .001 and .044, respectively). Cox regression analysis showed that ΔSBP< −0.25 mmHg, hemoglobin concentration, Kt/v and albumin were independent risk factors for all-cause mortality in MHD patients. Conclusions: MHD patients whose blood pressure increased significantly after hemodialysis had a higher risk of dying; ΔSBP, hemoglobin concentration, Kt/v and albumin were independent risk factors for all-cause mortality in MHD patients.

Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts antiapoptotic and antiinflammatory effects to confer protection against podocyte loss. Among the 3 TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. Therefore, we posited that the agonistic PS/TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonists as an optimal therapeutic approach to glomerular disease. Among the small-molecule TYRO3 agonistic compounds screened, compound 10 (C-10) showed a selective activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 were lost in Tyro3 -knockout mice, indicating that C-10 is a selective agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.

Key Points: Protein L-isoaspartyl/D-aspartyl methyltransferase (PCMT1) expression was lower in fibrotic kidney tubule, and tubule-specific deficiency worsened the pathogenesis and progression of CKD. Decreased PCMT1 levels inversely correlated with kidney function, highlighting its potential as a diagnostic and therapeutic target. PCMT1 enzymatically regulated the deamidation and protein stability of TGF- β receptor 2, inhibited TGF- β 1/Smad signaling, and impeded the profibrotic process. Background: Kidney fibrosis, the excessive accumulation and dysregulated remodeling of the extracellular matrix, is the principal pathophysiologic process in CKD. Protein L-isoaspartyl/D-aspartyl methyltransferase (PCMT1) is crucial in repairing post-translational modifications of L-isoaspartyl residues, which are important for extracellular matrix proteins because of their low turnover rate and susceptibility to accelerating factors. This study aimed to reveal a novel role of PCMT1 in kidney fibrosis. Methods: Kidney tissues from mice and humans were evaluated for PCMT1 expression and its association with fibrosis and kidney function. PCMT1's effects on the TGF- β 1/Smad signaling were analyzed, and its functional role was assessed in tubule-specific Pcmt1 knockout murine models of kidney fibrosis. The ability of secreted PCMT1 to repair L-isoaspartyl residues on the ectodomain of TGF- β receptor 2 (TGFBR2) was investigated using immunoprecipitation, gene lentivirus overexpression or knockout, and post-translational modification mass spectrometry. Results: PCMT1 expression was decreased in the tubules of human kidney biopsies from patients with CKD and murine fibrosis models. Renal tubule-specific PCMT1 deficiency in murine kidney fibrosis models worsened tubular injury, extracellular matrix protein deposition, myofibroblast activation, and TGF- β 1/Smad signaling overactivation. Mechanistically, PCMT1 was unconventionally secreted and enzymatically inhibited TGF- β 1–induced extracellular matrix protein deposition in vitro . PCMT1 interacted with TGFBR2, reversing N63 deamidation on its ectodomain, which triggered TGFBR2 ubiquitination and degradation. PCMT1 supplementation in kidneys decreased TGFBR2 levels, attenuated TGF- β 1/Smad overactivation, and impeded the profibrotic process. Conclusions: Our study highlights the importance of PCMT1 in maintaining extracellular matrix homeostasis and mitigating kidney fibrosis by regulating TGFBR2 deamidation and its protein stability, suppressing the TGF- β 1/Smad signaling.