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Frontiers in Medicine 2022Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular... (Review)
Review
Alport syndrome (AS) is a hereditary kidney disease associated with proteinuria, hematuria and progressive kidney failure. It is characterized by a defective glomerular basement membrane caused by mutations in type IV collagen genes which result in defective type IV collagen α3, α4, or α5 chains, respectively. Alport syndrome has three different patterns of inheritance: X-linked, autosomal and digenic. In a study of CKD of unknown etiology type IV collagen gene mutations accounted for the majority of the cases of hereditary glomerulopathies which suggests that AS is often underrecognized. The natural history and prognosis in patients with AS is variable and is determined by genetics and environmental factors. At present, no preventive or curative therapies exist for AS. Current treatment includes the use of renin-angiotensin-aldosterone system inhibitors which slow progression of kidney disease and prolong life expectancy. Ramipril was found in retrospective studies to delay the onset of ESKD and was recently demonstrated to be safe and effective in children and adolescents, supporting that early initiation of Renin Angiotensin Aldosterone System (RAAS) blockade is very important. Mineralocorticoid receptor blockers might be favorable for patients who develop "aldosterone breakthrough." While the DAPA-CKD trial suggests a beneficial effect of SGLT2 inhibitors in CKD of non-metabolic origin, only a handful of patients had Alport in this cohort, and therefore conclusions can't be extrapolated for the treatment of AS with SGLT2 inhibitors. Advances in our understanding on the pathogenesis of Alport syndrome has culminated in the development of innovative therapeutic approaches that are currently under investigation. We will provide a brief overview of novel therapeutic targets to prevent progression of kidney disease in AS. Our review will include bardoxolone methyl, an oral NRf2 activator; lademirsen, an anti-miRNA-21 molecule; sparsentan, dual endothelin type A receptor (ETAR) and angiotensin 1 receptor inhibitor; atrasentan, oral selective ETAR inhibitor; lipid-modifying agents, including cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) inducers, discoidin domain receptor 1 (DDR1) inhibitors and osteopontin blocking agents; the antimalarial drug hydroxychloroquine; the antiglycemic drug metformin and the active vitamin D analog paricalcitol. Future genomic therapeutic strategies such as chaperone therapy, genome editing and stem cell therapy will also be discussed.
PubMed: 35547199
DOI: 10.3389/fmed.2022.848389 -
Nephron 2022The change of podocyte morphology is a pathologic feature of chronic kidney disease. Several studies have suggested that vitamin D plays a role in the protection of...
BACKGROUND
The change of podocyte morphology is a pathologic feature of chronic kidney disease. Several studies have suggested that vitamin D plays a role in the protection of podocytes, but the underlying mechanism remains unclear.
METHODS
The effects of paricalcitol on podocyte injury were tested in a puromycin aminonucleoside (PAN)-induced rat model and cultured mouse podocytes. Proteinuria, podocyte foot process (FP) effacement, and the expression of nestin and vitamin D receptor (VDR) were evaluated. VDR-siRNA or plasmids containing VDR-shRNA were transfected into podocytes to silence VDR expression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to verify the connection between VDR and nestin gene expression.
RESULTS
Paricalcitol significantly alleviated proteinuria and podocyte FP effacement in PAN-induced nephrosis, which was accompanied by increased VDR expression in the glomeruli. Paricalcitol also inhibited PAN-induced nestin overexpression in the glomeruli. In an in vivo study, PAN significantly inhibited VDR protein expression, stimulated nestin protein expression, and resulted in nestin filament derangement in mouse podocytes, while paricalcitol treatment abolished these effects. In contrast, downregulation of VDR resulted in derangement and overexpression of nestin. ChIP assays demonstrated the presence of a vitamin D response element (VDRE) in the nestin promoter, and paricalcitol enhanced the binding of VDR to VDRE. Furthermore, luciferase reporter assays of the nestin promoter fragment showed that paricalcitol effectively repressed nestin reporter gene expression after PAN treatment, and mutation of VDRE abolished this effect.
CONCLUSIONS
Paricalcitol directly regulates nestin transcription through the interaction of VDR/VDRE, thereby preventing morphological changes of podocytes in PAN nephropathy.
Topics: Mice; Rats; Animals; Vitamin D Response Element; Nestin; Receptors, Calcitriol; Mutation
PubMed: 35526529
DOI: 10.1159/000524200 -
International Immunopharmacology Jul 2022Particulate matter (PM) could induce renal injury other than lung and heart damage. The renal injury always displays in the way of renal inflammation. Vitamin D (VitD)...
BACKGROUND
Particulate matter (PM) could induce renal injury other than lung and heart damage. The renal injury always displays in the way of renal inflammation. Vitamin D (VitD) has been identified as renal-protective factor with its anti-inflammatory effect.
AIM OF THE STUDY
This study explored the therapeutic effect of VitD receptor (VDR) agonist (paricalcitol) on PM-induced toxicity and inflammation in mouse renal tubular epithelial cells (mRTECs) and its molecular mechanisms.
METHODS
The variation between PM and paricalcitol solution was investigated in different concentration solutions with transmission electron microscopy (TEM), laser-induced fluorescence (LIF) and liquid chromatography-mass spectrometry (LC-MS). The detoxication and anti-inflammation effects of paricalcitol on PM in vitro were analyzed by LIF, MTT, western blot (WB), ELISA and flow cytometry (FCM).
RESULTS AND CONCLUSION
PM became more compact after paricalcitol treatment on account of stripped polycyclic aromatic hydrocarbons (PAHs). In the cellular experiments, PM (160 μg/ml) evoked mRTECs inflammation and apoptosis through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) /IL-1β axis, while paricalcitol (120 μg/ml) reversed these processes. The fluorescence intensity of cell supernatant detected by PAH-LIF was weakened after adding paricalcitol, compared with.PM treatment alone. Interestingly, paricalcitol can significantly reduce the concentration of highly toxic PAHs and increase the proportion of nontoxic small PAHs. Furthermore, VDR expression was negatively correlated with the inflammation and cell apoptosis. In summary, VitD and VDR promote biological detoxication on PM though PAH degradation from a molecular effect, and exert anti-inflammatory effects against NLRP3/IL-1β axis caused by PM.
Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Epithelial Cells; Inflammation; Interleukin-1beta; Kidney Tubules; Mice; Mice, Inbred NOD; NLR Family, Pyrin Domain-Containing 3 Protein; Particulate Matter; Vitamin D; Vitamins
PubMed: 35429817
DOI: 10.1016/j.intimp.2022.108747 -
Annals of Palliative Medicine Jan 2022The aim of this retrospective observational study based on real-world data was to evaluate the efficacy and safety profile of paricalcitol in Chinese hemodialysis (HD)... (Observational Study)
Observational Study
BACKGROUND
The aim of this retrospective observational study based on real-world data was to evaluate the efficacy and safety profile of paricalcitol in Chinese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT) in routine clinical practice.
METHODS
From the Better Life for Future database, a total of 668 Chinese hemodialysis patients from 104 dialysis centers between January 2015 and May 2019 were included in the analysis set. Intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphate (P), dosage of intravenous (IV) paricalcitol (Zemplar®) were analyzed and discussed via retrospective analysis of the database during the treatment.
RESULTS
Patients were divided into five groups according to the duration of follow-up. Median iPTH levels decreased from 1,183 pg/mL at baseline to 676 pg/mL at the final visit, or 30.88% (P<0.0001). A total of 56.14% of patients had a ≥30% decrease and 29.34% of patients had a ≥50% decrease in iPTH level. Serum Ca levels shown significantly increased in the group of Month 12-24 (P=0.0479). Serum phosphate levels remained stable in all follow-up groups. The average dose of paricalcitol was 20±9 µg/week. The total dose of paricalcitol and baseline iPTH were negatively correlated with the decrease in iPTH levels.
CONCLUSIONS
This is the first national retrospective real-world observational study since intravenous paricalcitol is available in China since 2014. This study demonstrates the use of paricalcitol as an effective and well-tolerated treatment for the control of PTH during its use in routine practice.
Topics: Ergocalciferols; Humans; Kidney Failure, Chronic; Renal Dialysis; Retrospective Studies
PubMed: 35144414
DOI: 10.21037/apm-21-3966 -
Journal of Hematology Dec 2021The monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how...
Monthly Continuous Erythropoietin Receptor Activator Versus Weekly Epoetin-Beta, Similar Hemoglobinization but Different Anisocytosis Degree in Hemodialysis Patients: A Randomized Controlled Trial.
BACKGROUND
The monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor.
METHODS
Thirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16).
RESULTS
The mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P < 0.01, partial η = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group.
CONCLUSIONS
Monthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.
PubMed: 35059087
DOI: 10.14740/jh862 -
European Review For Medical and... Jan 2022The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our...
OBJECTIVE
The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of SHPT treatment in (chronic kidney disease) CKD.
MATERIALS AND METHODS
The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness and side effects of calcifediol, ergocaliferol, calcitriol, paricalcitol, and cinacalcet were compared and analyzed.
RESULTS
Extended-release (ER) calcifediol raised the total serum 25-hydroxyvitamin D level over the threshold of 30 ng/mL in 80% of the patients analyzed in the study. It is the level required for intact PTH (iPTH) suppression. ER calcifediol reduced the iPTH level by 30% in about 30% of the patients, whereas only 2.1% of them had hypercalcemia. Calcitriol significantly decreased the iPTH values. It was the cause of hypercalcemia in 1.7% of the patients. The reduction of the iPTH level by more than 30% was observed in 85.7% of the patients in the paracalcitol group after 48-week supplementation. Paricalcitol was the cause of hypercalcemia in 1.9% of the patients. The cinacalcet therapy resulted in the highest percentage of patients with the iPTH level within the limits recommended by the KDOQI (70-110 ng/L for stage 4 CKD and 150-300 ng/L for stage 5 CKD). 92% of the patients met the KDOQI guidelines and the mean decrease in the serum iPTH level was 68%.
CONCLUSIONS
Calcifediol ER, paricalcitol, and cinacalcet significantly decreased the iPTH level in the patients under study. Paricalcitol increased the serum calcium concentration the most of all the drugs under analysis. It is noteworthy that only cinacalcet does not carry the risk of hypercalcemia.
Topics: Calcitriol; Calcium; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 35049000
DOI: 10.26355/eurrev_202201_27773 -
Neurochemistry International Feb 2022Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of...
Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes β-amyloid (Aβ) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aβ production via promoting the lysosomal degradation of β-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3β phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3β activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Aspartic Acid Endopeptidases; Humans; Iron; Mice; Mice, Transgenic; Phosphorylation; Presenilin-1; Receptors, Calcitriol; tau Proteins
PubMed: 34953963
DOI: 10.1016/j.neuint.2021.105260 -
Paricalcitol in hemodialysis patients with secondary hyperparathyroidism and its potential benefits.World Journal of Clinical Cases Nov 2021Secondary hyperparathyroidism (SHPT) is a common complication in patients with end-stage renal disease and it is also common in hemodialysis patients. SHPT can increase... (Clinical Trial)
Clinical Trial
BACKGROUND
Secondary hyperparathyroidism (SHPT) is a common complication in patients with end-stage renal disease and it is also common in hemodialysis patients. SHPT can increase bone fragility and calcification of blood vessels and soft tissues, which greatly increases the risk of death.
AIM
To discuss the outcome, safety and other potential benefits of paricalcitol injection in hemodialysis patients with SHPT.
METHODS
We recruited 40 patients who received hemodialysis at our hospital for chronic renal failure with SHPT between March and December 2019. They received paricalcitol injection for 24 wk (starting dose, 0.06-0.08 μg/kg), three times per week. They were followed up at the baseline (week 0), week 4, week 12 and week 24. The primary outcome indicator was the percentage of patients with a > 30% decrease in intact parathyroid hormone (iPTH) levels at week 24 compared with the baseline. The secondary outcome indicators included percentage decrease in iPTH levels at week 24, standard-reaching rate of iPTH (percentage of patients with iPTH down to 130-585 pg/mL), changes in serum levels of calcium (Ca), phosphate (P), Ca × P product, alkaline phosphatase (ALP), creatinine (Cre), hemoglobin (Hb), and C-reactive protein (CRP), and incidence of adverse events (AEs).
RESULTS
After 24 wk of treatment, iPTH levels decreased significantly (598.88 ± 381.29 pg/mL 888.84 ± 376.88 pg/mL, < 0.05). More than 30% decrease of iPTH was found in 21 of 36 (58.33%) patients. The average decrease in iPTH levels was 32.16 ± 4.33%; the standard-reaching rate of iPTH levels was 66.67% (24/36); and ALP levels decreased significantly compared with the baseline (113.72 ± 41.73 IU/L 133.45 ± 56.86 IU/L) ( = 2.798, < 0.05). There were no significant differences in the serum levels of calcium, Hb, Cre and CRP compared with the baseline ( > 0.05). After 24 wk of treatment, serum P levels decreased compared with the baseline (1.91 ± 0.40 mmol/L 2.16 ± 0.66 mmol/L) ( = 2.830, < 0.05). Ca × P product decreased significantly compared with the baseline (56.38 ± 13.22 mg/dL 63.97 ± 20.30 mg/dL) ( = 2.717, < 0.05). No serious adverse events occurred.
CONCLUSION
Paricalcitol was a safe and effective treatment for hemodialysis patients with SHPT. It decreased serum levels of iPTH, ALP and P and maintained stability of serum Ca levels.
PubMed: 34904087
DOI: 10.12998/wjcc.v9.i33.10172 -
World Journal of Clinical Pediatrics Nov 2021Alopecia areata (AA) is an inflammatory disease with autoimmune, environmental, and inherited components directed at the hair follicle, either limited to patchy hair...
BACKGROUND
Alopecia areata (AA) is an inflammatory disease with autoimmune, environmental, and inherited components directed at the hair follicle, either limited to patchy hair loss over the scalp (Focalis, AF), total loss of scalp hair (Totalis, AT), or total loss of both scalp and body hair (Universalis, AU). Despite multiple treatment modalities, no therapy exists. Vitamin D deficiency in patients with AA/AT/AF influences disease severity and duration, inversely correlating with inflammation histologically.
CASE SUMMARY
Three girls presented with AT (P1), AU (P2), and AF (P3) at the ages of 1, 5, and 5 years, respectively. For P1-P2, all available treatments implemented for 2 years had failed. We started an initial 6-mo repletion with oral cholecalciferol 2000/4000 IU/d, with no apparent effect. Then we attempted immunomodulation using oral calcitriol and its analog paricalcitol. On calcitriol, 0.5 mcg/d P1 regrew hair within 6 mo. After 4 years, a relapse with loss of eyebrow hair was resolved after doubling the calcitriol dose to 0.5 mcg × 2/d; the results have been maintained for 6 years to date. On calcitriol, 0.25 mcg × 3/d P2 led to the development of asymptomatic hypercalcemia-hypercalciuria, which was immediately resolved by switching to paricalcitol 2 mcg × 3/d; mild tolerable hypercalciuria was maintained. Hair regrowth was observed at 6 mo, stabilizing only as fur at 12 mo. AF in P3 was resolved completely within 3 mo on a daily high dose (8000 IU) of cholecalciferol.
CONCLUSION
Vitamin D may have immunomodulating therapeutic impact on AT/AU/AF, which needs to be explored with further pilot clinical trials.
PubMed: 34868895
DOI: 10.5409/wjcp.v10.i6.192 -
Iranian Journal of Medical Sciences Nov 2021Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related...
BACKGROUND
Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related to a range of clinical complaints. We aimed to investigate the effects of paricalcitol on body composition in VDD rats.
METHODS
Thirty adult male rats aged 10 weeks were randomly divided into three groups of 10, comprising control, VDD, and VDD plus paricalcitol (32 ng/rat intraperitoneal injection) (VDD+P), at the Animal Lab of the Endocrinology and Metabolism Research Center, Shiraz, Iran, in 2020. Body composition was assessed after three weeks via serum biochemical tests and dual-energy X-ray absorptiometry. Finally, the data were analyzed by using the paired-sample test, the one-way ANOVA, and the Tukey test.
RESULTS
Global lean mass and fat mass were lower in the VDD and VDD+P groups than in the controls (P<0.001). Global fat percentage was reduced significantly in the VDD+P group (P=0.029).
CONCLUSION
Paricalcitol reduced global fat mass and fat percentage in a rat model with VDD. Evaluation of insulin and adiponectin levels is suggested to clarify the physiology of paricalcitol in VDD states.
Topics: Animals; Body Composition; Ergocalciferols; Male; Rats; Vitamin D; Vitamin D Deficiency
PubMed: 34840387
DOI: 10.30476/ijms.2020.85368.1503