The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that ...anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the osteoanabolic and anti-resorptive activity is attenuated, but hypocalcemia is more prevalent in patients with advanced CKD (eGFR < 30 mL/min) treated with anti-sclerostin (romosozumab) therapy as compared to patients without kidney disease. Furthermore, sclerostin is prominently expressed in uremic arteries. Whether the inhibition of sclerostin has adverse effects on cardiovascular health in CKD is currently unknown. This review summarizes the current understanding of the physiology and pathophysiology of sclerostin in CKD, with a focus on the cardiovascular safety of anti-sclerostin therapy in patients with or without CKD.
ABSTRACT
Background
Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to ...vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro.
Methods
This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays.
Results
In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {−62% 95% confidence interval (CI) −76 to −44, P < .0001 and −38% −62 to −0.14, P < .001, respectively} compared with washout. Nine of 14 plasma cytokines/chemokines significantly decreased with high-dose SO, with consistent reductions in interleukin-6 (IL-6) and IL-8. Exposure of HASMC and HCAEC cultures to serum of SO-treated patients reduced calcification and markers of activation (IL-6, IL-8 and vascular cell adhesion protein 1) compared with washout. Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. Effects of CPP removal were confirmed in an independent cohort of chronic kidney disease patients.
Conclusions
High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.
Graphical Abstract
Graphical Abstract
Sclerostin and Dickkopf-1 in Renal Osteodystrophy Cejka, Daniel; Herberth, Johann; Branscum, Adam J ...
Clinical journal of the American Society of Nephrology,
04/2011, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The serum proteins sclerostin and Dickkopf-1 (Dkk-1) are soluble inhibitors of canonical wnt signaling and were recently identified as components of parathyroid hormone (PTH) signal transduction. ...This study investigated the associations between sclerostin and Dkk-1 with histomorphometric parameters of bone turnover, mineralization, and volume in stage 5 chronic kidney disease patients on dialysis (CKD-5D).
In a cross-sectional study, 60 CKD-5D patients underwent bone biopsies followed by histomorphometry. Levels of sclerostin, Dkk-1, and intact PTH (iPTH) were determined in blood.
Serum levels of sclerostin and iPTH correlated negatively. In unadjusted analyses, sclerostin correlated negatively with histomorphometric parameters of turnover, osteoblastic number, and function. In adjusted analyses, sclerostin remained a strong predictor of parameters of bone turnover and osteoblast number. An observed correlation between sclerostin and cancellous bone volume was lost in regression analyses. Sclerostin was superior to iPTH for the positive prediction of high bone turnover and number of osteoblasts. In contrast, iPTH was superior to sclerostin for the negative prediction for high bone turnover and had similar predictive values than sclerostin for the number of osteoblasts. Serum levels of Dkk-1 did not correlate with iPTH or with any histomorphometric parameter.
Our data describe a promising role for serum measurements of sclerostin in addition to iPTH in the diagnosis of high bone turnover in CKD-5D patients, whereas measurements of Dkk-1 do not seem to be useful for this purpose.
Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the ...non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression.
For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025.
The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.
EU CT-Number: 2022-500024-30-00.
Hemodialysis (HD) patients face increased fracture risk, which is further associated with elevated risk of hospitalization and mortality. High-resolution peripheral computed tomography (HR-pQCT) has ...advanced our understanding of bone disease in chronic kidney disease by characterizing distinct changes in both the cortical and trabecular compartments. Increased cortical porosity (Ct.Po) has been shown to be associated with fracture in patients with osteopenia or in postmenopausal diabetic women. We tested whether the degree of Ct.Po identifies hemodialysis patients with prevalent fragility fractures in comparison to bone mineral density (BMD) assessed by dual X-ray absorptiometry (DXA). We performed a post-hoc analysis of a cross-sectional study in 76 prevalent hemodialysis patients. Markers of mineral metabolism, coronary calcification score, DXA-, and HR-pQCT-data were analyzed, and Ct.Po determined at radius and tibia. Ct.Po was significantly higher in patients with fracture but association was lost after adjusting for age and gender (tibia p = 0.228, radius p = 0.5). Instead, femoral (F) BMD neck area (p = 0.03), F T-score neck area (p = 0.03), radius (R) BMD (p = 0.03), R T-score (p = 0.03), and cortical HR-pQCT indices such as cortical area (Ct.Ar) (tibia: p = 0.01; radius: p = 0.02) and cortical thickness (Ct.Th) (tibia: p = 0.03; radius: p = 0.02) correctly classified patients with fragility fractures. Area under receiver operating characteristic curves (AUC) for Ct.Po (tibia AUC: 0.711; p = 0.01; radius AUC: 0.666; p = 0.04), Ct.Ar (tibia AUC: 0.832; p<0.001; radius AUC: 0.796; p<0.001), and F neck BMD (AUC: 0.758; p = 0.002) did not differ significantly among each other. In conclusion, measuring Ct.Po is not superior to BMD determined by DXA for identification of HD patients with fragility fracture.
Background: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T 50 calcification ...inhibition test (T 50 -test) is a global functional test analyzing the overall propensity of calcification in serum, and low T 50 -time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T 50 -time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T 50 -time in CKD patients. Material and Methods: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO 3 – ≤21 mmol/L), in which patients are randomized to either achieve serum HCO 3 – levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T 50 -time was assessed. Results: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T 50 -time was 275 (± 64) min. After 4 weeks, the mean change of T 50 -time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (β = –25; 95% CI: –71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T 50 -time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T 50 -time (β = –145; 95% CI: –237 to –52). Conclusion: Oral sodium bicarbonate supplementation showed no effect on T 50 -time in acidotic CKD patients.
Background:
The propensity of serum to calcify, as assessed by the T
50
-test, associates with mortality in patients with chronic kidney disease. In chronic heart failure, phosphate and fibroblast ...growth factor-23 (FGF-23), which are important components of the vascular calcification pathway, have been linked to patient survival. Here, we investigated whether T
50
associates with overall and cardiovascular survival in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Methods:
We measured T
50
, intact and c-terminal FGF-23 levels in a cohort of 306 HFrEF patients. Associations with overall and cardiovascular mortality were analyzed in survival analysis and Cox-regression models.
Results:
After a median follow-up time of 3.2 years (25th−75th percentile: 2.0–4.9 years), 114 patients (37.3%) died due to any cause and 76 patients (24.8%) died due to cardiovascular causes. 139 patients (45.4%) had ischemic and 167 patients (54.6%) had non-ischemic HFrEF. Patients with ischemic HFrEF in the lowest T
50
-tertile had significantly greater 2-year cardiovascular mortality compared to patients in higher tertiles (
p
= 0.011). In ischemic but not in non-ischemic HFrEF, T
50
was significantly associated with cardiovascular mortality in univariate (
p
= 0.041) and fully adjusted (
p
= 0.046) Cox regression analysis. Significant associations of intact and c-terminal FGF-23 with all-cause and cardiovascular mortality in univariate Cox regression analysis did not remain significant after adjustment for confounding factors.
Conclusion:
T
50
is associated with 2-year cardiovascular mortality in patients with ischemic HFrEF but not in non-ischemic HFrEF. More research on the role of T
50
measurements in coronary artery disease is warranted.
Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) ...tissues and its potential role as a molecular drug target for HCC therapy.
HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis.
Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect.
Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy.
Dialysis patients are at high risk for low-trauma bone fracture. Bone density measurements using dual-energy x-ray absorptiometry (DXA) do not reliably differentiate between patients with and without ...fractures. The aim of this study was to identify differences in bone microarchitecture between patients with and without a history of fracture using high-resolution peripheral quantitative computed tomography (HR-pQCT).
Seventy-four prevalent hemodialysis patients were recruited for measurements of areal bone mineral density (aBMD) by DXA and bone microarchitecture by HR-pQCT. Patients with a history of trauma-related fracture were excluded. Forty healthy volunteers served as controls. Blood levels of parathyroid hormone, vitamin D, and markers of bone turnover were determined.
Dialysis patients, particularly women, had markedly impaired bone microarchitecture. Patients with fractures had significantly reduced cortical and trabecular microarchitecture compared with patients without fractures. aBMD tended to be lower in patients with fractures, but differences were statistically not significant. The strongest determinant of fracture was the HR-pQCT-measured trabecular density of the tibia, which also had the highest discriminatory power to differentiate patients according to fracture status. Radial DXA had a lower discriminatory power than trabecular density.
Bone microarchitecture is severely impaired in dialysis patients and even more so in patients with a history of fracture. HR-pQCT can identify dialysis patients with a history of low-trauma fracture.
To characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX).
We conducted a multicenter retrospective ...cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between "nephrotic" and "nephritic" indications. The primary outcome was the incidence of SI within 12 months after the first RTX application.
A total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m
26.9 kg/m
, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI.
After RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.
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