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World Journal of Diabetes Sep 2023Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial,...
BACKGROUND
Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial, and there is a lack of a relevant efficacy prediction model.
AIM
To determine the effects of paricalcitol combined with hemodiafiltration on bone-metabolism-related indexes in patients with DN and chronic renal failure (CRF), and to construct an efficacy prediction model.
METHODS
We retrospectively analyzed 422 patients with DN and CRF treated in Cangzhou Central Hospital between May 2020 and May 2022. We selected 94 patients who met the inclusion and exclusion criteria. Patients were assigned to a dialysis group ( = 45) and a joint group ( = 49) in relation to therapeutic regimen. The clinical efficacy of the two groups was compared after treatment. The changes in laboratory indexes after treatment were evaluated, and the two groups were compared for the incidence of adverse reactions. The predictive value of laboratory indexes on the clinical efficacy on patients was analyzed.
RESULTS
The dialysis group showed a notably worse improvement in clinical efficacy than the joint group ( = 0.017). After treatment, the joint group showed notably lower serum levels of serum creatinine, uric acid (UA) and blood urea nitrogen (BUN) than the dialysis group ( < 0.05). After treatment, the joint group had lower serum levels of phosphorus, procollagen type I amino-terminal propeptide (PINP) and intact parathyroid hormone than the dialysis group, but a higher calcium level ( < 0.001). Both groups had a similar incidence of adverse reactions ( > 0.05). According to least absolute shrinkage and selection operator regression analysis, UA, BUN, phosphorus and PINP were related to treatment efficacy. According to further comparison, the non-improvement group had higher risk scores than the improvement group ( < 0.0001), and the area under the curve of the risk score in efficacy prediction was 0.945.
CONCLUSION
For treatment of CRF and DN, combined paricalcitol and hemodiafiltration can deliver higher clinical efficacy and improve the bone metabolism of patients, with good safety.
PubMed: 37771325
DOI: 10.4239/wjd.v14.i9.1385 -
Biochemical and Biophysical Research... Nov 2023In the present study, the possible protective effects of paricalcitol (P) were investigated in testicular damage because of 1800 MHz radiofrequency radiation (RFR)...
In the present study, the possible protective effects of paricalcitol (P) were investigated in testicular damage because of 1800 MHz radiofrequency radiation (RFR) exposure. Male Sprague Dawley rats 8-10 weeks old (n = 28) were randomly divided into four groups as control (C) (n = 7), RFR (n = 7, 1800 MHz RFR 1 h/day for 30 days), P (n = 7, 0.2 μg/kg paricalcitol, 3 times a week for 30 days), and RFR + P (n = 7, 1800 MHz RFR 1 h/day for 30 days +0.2 μg/kg paricalcitol, 3 times a week for 30 days). Testicular tissue was evaluated with histological and biochemical methods. No statistically significant differences were detected between the groups in seminiferous tubule diameters and germinal epithelial thicknesses. While ultrastructural changes were observed in the seminiferous tubule and Leydig cells in the RFR group, these changes were decreased in the RFR + P group. It was found that the Johnsen Score, Ki67, and p63 immunoreactivity scores (IRS), superoxide dismutase (SOD), and catalase (CAT) activities in the RFR + P group were statistically increased as compared to the RFR group and the malondialdehyde (MDA) levels were decreased statistically and significantly. These results show that paricalcitol administration may have an ameliorative effect on testicular damage occurring because of 1800 MHz RFR exposure.
Topics: Rats; Animals; Male; Rats, Sprague-Dawley; Antioxidants; Testis; Seminiferous Tubules; Superoxide Dismutase; Oxidative Stress
PubMed: 37717340
DOI: 10.1016/j.bbrc.2023.09.024 -
American Journal of Kidney Diseases :... Jan 2024Optimal approaches to treat secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis (HD) have yet to be established in randomized controlled trials... (Observational Study)
Observational Study
Comparative Effectiveness of Alternative Treatment Approaches to Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis: An Observational Trial Emulation.
RATIONALE & OBJECTIVE
Optimal approaches to treat secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis (HD) have yet to be established in randomized controlled trials (RCTs).
STUDY DESIGN
Two observational clinical trial emulations.
SETTING & PARTICIPANTS
Both emulations included adults receiving in-center HD from a national dialysis organization. The patients who had SHPT in the period between 2009 and 2014, were insured for≥180 days by Medicare as primary payer, and did not have contraindications or poor health status limiting theoretical trial participation.
EXPOSURE
The parathyroid hormone (PTH) Target Trial emulation included patients with new-onset SHPT (first PTH 300-600pg/mL), with 2 arms defined as up-titration of either vitamin D sterols or cinacalcet within 30 days (lower target) or no up-titration (higher target). The Agent Trial emulation included patients with a PTH≥300 pg/mL while on≥6μg weekly of vitamin D sterol (paricalcitol equivalent dose) and no prior history of cinacalcet. The 2 arms were defined by the first dose or agent change within 30 days (vitamin D-favoring [vitamin-D was up-titrated] vs cinacalcet-favoring [cinacalcet was added] vs nondefined [neither applies]). Multiple trials per patient were allowed in trial 2.
OUTCOME
The primary outcome was all-cause death over 24 months; secondary outcomes included cardiovascular (CV) hospitalization or the composite of CV hospitalization or death.
ANALYTICAL APPROACH
Pooled logistic regression.
RESULTS
There were 1,152 patients in the PTH Target Trial (635 lower target and 517 higher target). There were 2,726 unique patients with 6,727 patient trials in the Agent Trial (6,268 vitamin D-favoring trials and 459 cinacalcet-favoring trials). The lower PTH target approach was associated with reduced adjusted hazard of death (HR, 0.71 [95% CI, 0.52-0.93]), CV hospitalization (HR, 0.78 [95% CI, 0.63-0.98]), and their composite (HR, 0.74 [95% CI, 0.61-0.89]). The cinacalcet-favoring approach demonstrated lower adjusted hazard of death compared to the vitamin D-favoring approach (HR, 0.79 [95% CI, 0.62-0.99]), but not of CV hospitalization or the composite outcome.
LIMITATIONS
Potential for residual confounding; low use of cinacalcet with low power.
CONCLUSIONS
SHPT management that is focused on lower PTH targets may lower mortality and CV disease in patients receiving HD. These findings should be confirmed in a pragmatic randomized trial.
PLAIN-LANGUAGE SUMMARY
Optimal approaches to treat secondary hyperparathyroidism (SHPT) have not been established in randomized controlled trials. Data from a national dialysis organization was used to identify patients with SHPT in whom escalated treatment may be indicated. The approach to treatment was defined based on observed upward titration of SHPT-controlling medications: earlier titration (lower target) versus delayed titration (higher target); and the choice of medication (cinacalcet vs vitamin D sterols). In the first trial emulation, we estimated a 29% lower rate of death and 26% lower rate of cardiovascular disease or death for patients managed with a lower versus higher target approach. Cinacalcet versus vitamin D-favoring approaches were not consistently associated with outcomes in the second trial emulation. This observational study suggests the need for additional clinical trials of SHPT treatment intensity.
Topics: Adult; Humans; Cinacalcet; Naphthalenes; Treatment Outcome; Hyperparathyroidism, Secondary; Vitamin D; Renal Dialysis; Vitamins; Parathyroid Hormone; Sterols; Cardiovascular Diseases
PubMed: 37690631
DOI: 10.1053/j.ajkd.2023.05.016 -
Antioxidants (Basel, Switzerland) Aug 2023Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of...
Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of pulmonary fibrosis remains largely unknown. Analysis of bulk and single-cell RNA profiling datasets revealed VDR upregulation in lung fibroblasts from patients with pulmonary fibrosis or fibrotic mice, which was validated in lung fibroblasts from bleomycin-exposed mice and bleomycin-treated fibroblasts. Stable VDR knockdown promoted, whereas the VDR agonist paricalcitol suppressed lung fibroblast proliferation and activation. Gene set enrichment analysis (GSEA) showed that the JAK/STAT pathway and unfolded protein response (UPR), a process related to endoplasmic reticulum (ER) stress, were enriched in lung fibroblasts of fibrotic lungs. Stable VDR knockdown stimulated, but paricalcitol suppressed ER stress and JAK1/STAT3 activation in lung fibroblasts. The STAT3 inhibitor blocked bleomycin- or stable VDR knockdown-induced ER stress. Paricalcitol inhibited the bleomycin-induced enrichment of STAT3 to the ATF6 promoter, thereby suppressing ATF6 expression in fibroblasts. Paricalcitol or intrapulmonary VDR overexpression inactivated JAK1/STAT3 and suppressed ER stress in bleomycin-treated mice, thus resulting in the inhibition of fibroblast proliferation and activation. Collectively, this study suggests that fibroblast VDR upregulation may be a self-protective response to limit fibroblast proliferation and activation during pulmonary fibrosis by suppressing the JAK1/STAT3/ER stress pathway.
PubMed: 37627629
DOI: 10.3390/antiox12081634 -
Kidney Diseases (Basel, Switzerland) May 2023Parathyroid hormone-lowering responses after administration of three different therapies capable of raising serum total 25-hydroxyvitamin D (25OHD) were evaluated in...
INTRODUCTION
Parathyroid hormone-lowering responses after administration of three different therapies capable of raising serum total 25-hydroxyvitamin D (25OHD) were evaluated in patients with secondary hyperparathyroidism (SHPT), vitamin D insufficiency (VDI), and stage 3 or 4 chronic kidney disease (CKD).
METHODS
Sixty-nine adult subjects with intact parathyroid hormone (iPTH) ≥85 and <500 pg/mL and VDI (25OHD <30 ng/mL) were randomized after ≥4-week washout to 2 months of open-label treatment with: (1) extended-release calcifediol (ERC) 60 μg/day; (2) immediate-release calcifediol (IRC) 266 μg/month; (3) high-dose cholecalciferol (HDC) 300,000 IU/month; or (4) paricalcitol plus low-dose cholecalciferol (PLDC) 1 or 2 μg and 800 IU/day, used as reference hormone replacement therapy. Serum 25OHD, calcium (Ca), phosphorus (P), plasma iPTH, and adverse events were monitored weekly. No clinically significant differences were observed at baseline between treatment groups.
RESULTS
Sixty-two subjects completed the study per protocol (PP; 14-17 per group). Mean (SD) 25OHD and iPTH at baseline were 20.6 (6.6) ng/mL and 144.8 (90) pg/mL, respectively. Mean 25OHD increased at end of treatment (EOT) to 82.9 (17.0) ng/mL with ERC ( < 0.001) and 30.8 (11.6) ng/mL with HDC ( < 0.05), but remained unchanged with IRC and PLDC. EOT 25OHD levels reached ≥30 ng/mL in all subjects treated with ERC and in 44% with HDC. All subjects attained EOT 25OHD levels ≥50 ng/mL with ERC versus none with other therapies. iPTH response rates at EOT (≥10, 20 or 30% below baseline) were similar for ERC and PLDC; rates for IRC and HDC were much lower. No significant changes from baseline were observed in ionized or corrected total Ca or P in any group. One episode of hypercalcemia (>10.3 mg/dL) occurred with PLDC. Hyperphosphatemia (>5.5 mg/dL) occurred once with ERC, eight times with HDC, 3 times with IRC, and twice with PLDC.
CONCLUSION
ERC was highly effective in both raising serum 25OHD and decreasing iPTH in patients with SHPT, VDI, and stage 3 or 4 CKD. iPTH-lowering response rates with ERC were similar to daily PLDC, the reference therapy; rates with IRC or HDC were significantly lower. ERC is an attractive alternative to vitamin D hormone therapy in CKD patients.
PubMed: 37497207
DOI: 10.1159/000529523 -
Scientific Reports Jul 2023To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis...
To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-β, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-β condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-β induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.
Topics: Humans; Reactive Oxygen Species; Src Homology 2 Domain-Containing, Transforming Protein 1; Constriction, Pathologic; Human Umbilical Vein Endothelial Cells; Arteriovenous Fistula; Receptors, Calcitriol
PubMed: 37422508
DOI: 10.1038/s41598-023-37510-5 -
Seminars in Dialysis 2024Vascular calcification is an intervenable factor in the pathophysiology of cardiovascular disease. Treatment-related factors might worsen the arterial stiffness in... (Comparative Study)
Comparative Study
INTRODUCTION
Vascular calcification is an intervenable factor in the pathophysiology of cardiovascular disease. Treatment-related factors might worsen the arterial stiffness in chronic hemodialysis patients. The aim of the study is to compare the effects of 1-year treatment with paricalcitol or calcitriol on pulse wave velocity (PWV), which is an indicator of arterial stiffness and osteocalcin and fetuin-A levels.
METHODS
Seventy-six hemodialysis patients who had similar PWV1 at the beginning were evaluated after a 1-year treatment of paricalcitol or calcitriol. PWV2, serum osteocalcin, and fetuin-A levels were measured at the end of the study.
RESULTS
At the end of the study, PWV2 of paricalcitol group was statistically lower than the calcitriol group. Osteocalcin levels were statistically lower and fetuin-A levels were statistically higher in the paricalcitol group than the calcitriol group at the end of the study. The number of patients with PWV2 > 7 m/s and using paricalcitol was 16 (39%) but 25 (41%) patients were using calcitriol; the differences were statistically significant.
CONCLUSIONS
The long-term benefits of paricalcitol were superior to the benefits of calcitriol. Paricalcitol has protective effects from vascular calcification in chronic hemodialysis patients.
Topics: Humans; alpha-2-HS-Glycoprotein; Calcitriol; Ergocalciferols; Osteocalcin; Parathyroid Hormone; Pulse Wave Analysis; Renal Dialysis; Vascular Calcification
PubMed: 37392044
DOI: 10.1111/sdi.13167 -
Theranostics 2023Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating...
Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Renal tubule specific ELA knockout ( KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
Topics: Mice; Animals; Microcirculation; Dinoprostone; Kidney; Acute Kidney Injury; Renal Insufficiency, Chronic; Reperfusion Injury; Ischemia; Peptide Hormones; Reperfusion
PubMed: 37351176
DOI: 10.7150/thno.84308 -
Children (Basel, Switzerland) May 2023Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000...
Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.
PubMed: 37238410
DOI: 10.3390/children10050862 -
The Journal of Clinical Endocrinology... Oct 2023Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid... (Meta-Analysis)
Meta-Analysis
CONTEXT
Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia.
OBJECTIVE
The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD).
METHODS
A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting.
RESULTS
Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed.
CONCLUSION
This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.
Topics: Humans; Calcifediol; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Network Meta-Analysis; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Randomized Controlled Trials as Topic
PubMed: 37235771
DOI: 10.1210/clinem/dgad289