ABSTRACT
Introduction: Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). Elucidating the metabolic characteristics of SHPT may provide a new theoretical basis for its prevention and treatment. This study aimed to perform a metabolomic analysis of SHPT in patients with CKD stages 3-5 not receiving dialysis. Methods: A total of 76 patients with CKD, 85 patients with CKD-SHPT, and 67 healthy controls were enrolled in this study. CKD was diagnosed according to the criteria specified in the Kidney Disease Improving Global Outcomes 2012 guidelines. SHPT was diagnosed by experienced clinicians according to the Renal Disease Outcomes Quality Initiative Clinical Practice Guidelines. Serum renal function markers and the lipid profile were analyzed. Untargeted ultra performance liquid chromatography-tandem mass spectrometry was used to analyze the serum metabolites of patients with CKD and SHPT. Multivariate analysis of the data was performed using principal component analysis and partial least square discriminant analysis. Serum differential metabolites were identified and further characterized using databases. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes database. Correlations between differential metabolites and clinical parameters were determined using the Spearman correlation. Results: The serum metabolomic profiles of patients with CKD with and without SHPT differed significantly. Differential metabolites were mainly enriched in the top four Kyoto Encyclopedia of Genes and Genomes pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; sphingolipid metabolism; glycerophospholipid metabolism; and phenylalanine metabolism. In total, 31 differential metabolites were identified; of these, L-tryptophan and (R)-(+)-1-phenylethylamine were decreased, while other amino acids and their derivatives, uremia toxins, carnitine, and lipids, were increased significantly in patients with SHPT compared to those without. The 14 lipid metabolites were positively correlated with levels of Urea, serum creatinine, cystatin C, and triglycerides and negatively correlated with the estimated glomerular filtration rate and levels of total and high- and low-density lipoprotein cholesterol. Discussion: Disturbed amino acid and lipid metabolism were more apparent in patients with SHPT than in those without. This metabolomic profile of SHPT may provide a therapeutic foundation for its future clinical management.
Subject(s)
Hyperparathyroidism, Secondary , Metabolomics , Renal Insufficiency, Chronic , Humans , Female , Male , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Middle Aged , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Renal Insufficiency, Chronic/complications , Metabolomics/methods , Aged , Adult , Renal Dialysis , Biomarkers/blood , Metabolome , Case-Control StudiesSubject(s)
Cinacalcet , Hyperparathyroidism, Secondary , Inflammation , Nutritional Status , Renal Insufficiency, Chronic , Humans , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/drug therapy , Hyperparathyroidism, Secondary/blood , Renal Insufficiency, Chronic/complications , Cinacalcet/therapeutic use , Male , Female , Middle Aged , Lipids/blood , AgedABSTRACT
Secondary hyperparathyroidism (SHPT) can progress to severe SHPT (sSHPT), which affects the survival rate and quality of life of patients. This retrospective cohort study investigated risk factors for sSHPT and the association between SHPT and mortality (all-cause and infection-related) among 771 clinically stable patients (421 male patients; mean age, 51.2 years; median dialysis vintage, 28.3 months) who underwent >3 months of regular peritoneal dialysis (PD) between January 2013 and March 2021. The sSHPT and non-sSHPT groups comprised 75 (9.7%) (median progression, 35 months) and 696 patients, respectively. sSHPT was defined as a serum intact parathyroid hormone (PTH) level >800 pg/mL observed three times after active vitamin D pulse therapy. The influence of sSHPT on the prognosis of and risk factors for sSHPT progression were evaluated using logistic and Cox regression analyses. After adjusting for confounding factors, higher (each 100-pg/mL increase) baseline PTH levels (95% confidence interval (CI) 1.206-1.649, p < .001), longer (each 1-year increase) dialysis vintages (95% CI 1.013-1.060, p = .002), higher concomitant diabetes rates (95% CI 1.375-10.374, p = .010), and lower (each 1-absolute unit decrease) Kt/V values (95% CI 0.859-0.984, p = .015) were independent risk factors for progression to sSHPT in patients on PD. During follow-up, 211 deaths occurred (sSHPT group, n = 35; non-sSHPT group, n = 176). The sSHPT group had significantly higher infection-related mortality rates than the non-sSHPT group (12.0% vs. 4.3%; p < .05), and sSHPT was associated with increased infection-related mortality. In conclusion, patients with sSHPT are at higher risk for death and infection-related mortality than patients without sSHPT.
Subject(s)
Hyperparathyroidism, Secondary , Kidney Failure, Chronic , Parathyroid Hormone , Peritoneal Dialysis , Humans , Male , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/blood , Middle Aged , Retrospective Studies , Female , Peritoneal Dialysis/adverse effects , Prognosis , Risk Factors , Parathyroid Hormone/blood , Adult , Kidney Failure, Chronic/therapy , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/blood , Disease Progression , Proportional Hazards ModelsABSTRACT
INTRODUCTION: Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD: Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS: Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In noncalcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION: The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.
Subject(s)
Biomarkers , Bone Density , Bone Remodeling , Hyperparathyroidism, Secondary , Vitamin D , Humans , Female , Male , Aged , Vitamin D/blood , Vitamin D/analogs & derivatives , Bone Density/physiology , Hyperparathyroidism, Secondary/blood , Biomarkers/blood , Bone Remodeling/physiology , Middle Aged , Prevalence , Vitamin D Deficiency/blood , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Aged, 80 and overSubject(s)
Choline , Hyperparathyroidism, Secondary , Radiopharmaceuticals , Humans , Choline/analogs & derivatives , Hyperparathyroidism, Secondary/diagnostic imaging , Hyperparathyroidism, Secondary/blood , Fluorine Radioisotopes , Positron Emission Tomography Computed Tomography/methods , Hyperparathyroidism/diagnostic imaging , Hyperparathyroidism/bloodABSTRACT
In primary hyperparathyroidism, postoperative hypocalcemia can be exacerbated by magnesium deficiency. However, the significance of magnesium homeostasis in surgery for secondary hyperparathyroidism is unknown. In this study, 268 consecutive adult patients on renal replacement therapy who underwent parathyroidectomy for secondary hyperparathyroidism were included for analysis. We found that about one fifth presented with hypomagnesemia (5.6%) or hypermagnesemia (14.6%). Hypomagnesemia was associated with lower calcium levels and longer postoperative hospital stays. Hypermagnesemia was associated with higher calcium-phosphorus products and lower parathyroid hormone levels. In multivariate analysis, patient age, alkaline phosphatase, and osteocalcin were independent predictors of prolonged stay after parathyroidectomy. There was a positive correlation between serum magnesium levels and severity of itching in these patients. Calcium-phosphorus products and serum magnesium levels were independently associated with pruritus. In conclusion, magnesium abnormalities play a minor role in hungry bone syndrome after parathyroidectomy for secondary hyperparathyroidism. Patients with higher serum magnesium levels had greater severity of pruritus.
Subject(s)
Hyperparathyroidism, Secondary , Magnesium , Parathyroidectomy , Renal Dialysis , Humans , Magnesium/blood , Female , Male , Middle Aged , Hyperparathyroidism, Secondary/surgery , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Aged , Adult , Pruritus/etiology , Pruritus/blood , Calcium/blood , Hypocalcemia/etiology , Hypocalcemia/blood , Postoperative Complications/blood , Postoperative Complications/etiology , Length of Stay , Retrospective StudiesABSTRACT
OBJECTIVES: To analyze conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) features in patients with secondary hyperparathyroidism (SHPT) and to evaluate the clinical-ultrasonographic feature based model for predicting the severity of SHPT. METHODS: From February 2016 to March 2021, a total of 59 patients (age 51.3 ± 11.7 years, seCr 797.8 ± 431.7 µmol/L, iPTH 1535.1 ± 1063.9 ng/L) with SHPT (including 181 parathyroid glands (PTGs)) without the history of intact parathyroid hormone (iPTH)-reducing drugs using were enrolled. The patients were divided into the mild SHPT group (mSHPT, iPTH <800 ng/L) and the severe SHPT group (sSHPT, iPTH ≥ 800 ng/L) according to the serum iPTH level. The clinical test data of patients were collected and CUS and CEUS examinations were performed for every patient. Multivariable logistic regression model according to clinical-ultrasonographic features was adopted to establish a nomogram. We performed K-fold cross-validation on this nomogram model and nomogram performance was determined by its discrimination, calibration, and clinical usefulness. RESULTS: There were 19 patients in the mSHPT group and 40 patients in the sSHPT group. Multivariable logistic regression indicated serum calcium, serum phosphorus and total volume of PTGs were independent predictors related with serum iPTH level. Even though CEUS score of wash-in and wash-out were showed related to severity of SHPT in univariate logistic regression analysis, they were not predictors of SHPT severity (p = 0.539, 0.474 respectively). The nomogram developed by clinical and ultrasonographic features showed good calibration and discrimination. The accuracy and the area under the curve (AUC), positive predictive value (PPV), negative predictive value (NPV) and accuracy of this model were 0.888, 92.5%, 63.2% and 83.1%, respectively. When applied to internal validation, the score revealed good discrimination with stratified fivefold cross-validation in the cohort (mean AUC = 0.833). CONCLUSIONS: The clinical-ultrasonographic features model has good performance for predicting the severity of SHPT.
Subject(s)
Hyperparathyroidism, Secondary/diagnostic imaging , Kidney Failure, Chronic/complications , Parathyroid Glands/diagnostic imaging , Renal Dialysis/adverse effects , Ultrasonography, Doppler, Color/methods , Adult , Aged , Calcium/blood , Female , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/surgery , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/therapy , Logistic Models , Male , Middle Aged , Multivariate Analysis , Nomograms , Parathyroid Glands/blood supply , Parathyroid Glands/pathology , Parathyroid Hormone/blood , Parathyroidectomy , Phosphorus/blood , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.
Subject(s)
Calcimimetic Agents/therapeutic use , Hyperparathyroidism, Secondary/drug therapy , Hyperphosphatemia/complications , Renal Dialysis , Renal Insufficiency, Chronic/complications , Aged , Cinacalcet/therapeutic use , Female , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/complications , Hyperphosphatemia/blood , Male , Middle Aged , Parathyroid Hormone/blood , Peptides/therapeutic use , Phosphorus/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Retrospective StudiesABSTRACT
BACKGROUND Intraoperative intact parathyroid hormone (IO-iPTH) monitoring has not reached a consensus in predicting surgical outcomes of secondary hyperparathyroidism. Here, we explore the predictive effect of IO-iPTH monitoring on surgical outcomes of secondary hyperparathyroidism as a potentially effective standard. MATERIAL AND METHODS We enrolled 119 patients who underwent total parathyroidectomy with autotransplantation from January 2016 to August 2019. Intact parathyroid hormone (iPTH) levels were tested 1 day before surgery (iPTHpre), 10 min after glands resection (iPTH10min), and 1 and 7 days after the operation (iPTHd1, iPTHd7). According to iPTHpre levels, patients were divided into a <2000 pg/ml group and a ≥2000 pg/ml group, and the cutoff values were compared. In patients with successful parathyroidectomy, the value of iPTHpre minus iPTH10min (iPTHdec) and relative-iPTH10min were compared between groups. RESULTS Using cutoff values, the predictive criterion was defined as iPTH10min ≤314.5 pg/ml or relative-iPTH10min ≤12.4%. In the iPTHpre ≥2000 pg/ml group, iPTH10min had a higher predictive value (318 pg/ml vs 218 pg/ml) whereas relative-iPTH10min had a lower predictive value (12.1% vs 20.3%). In patients with successful PTX, the iPTHdec value of the iPTHpre ≥2000 pg/ml group was significantly higher than that of the <2000 pg/ml group. Additionally, the relative-iPTH10min was significantly lower in the ≥2000 pg/ml group than in the <2000 pg/ml group. CONCLUSIONS An intraoperative predictive criterion of iPTH10min ≤314.5 pg/ml or relative-iPTH10min ≤12.4% is associated with effectively predicting surgical success of secondary hyperparathyroidism. The predictive value is affected by iPTHpre level; therefore, a variable prediction standard based on iPTHpre levels shall be established.
Subject(s)
Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/surgery , Monitoring, Intraoperative/methods , Parathyroid Hormone/blood , Female , Humans , Male , Middle Aged , Reproducibility of Results , Retrospective Studies , Treatment OutcomeABSTRACT
The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT.
Subject(s)
Calcium-Regulating Hormones and Agents/therapeutic use , Cinacalcet/therapeutic use , Hyperparathyroidism, Secondary/therapy , Polymorphism, Single Nucleotide , Receptors, Calcium-Sensing/genetics , Renal Insufficiency, Chronic/therapy , Age Factors , Aged , Alleles , Calcitriol/blood , Calcium/blood , Ergocalciferols/blood , Female , Gene Expression , Genotype , Heterozygote , Homozygote , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/genetics , Hyperparathyroidism, Secondary/pathology , Logistic Models , Male , Middle Aged , Parathyroid Hormone/blood , Parathyroid Hormone/genetics , Phosphates/blood , Receptors, Calcium-Sensing/blood , Renal Dialysis/methods , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Retrospective StudiesABSTRACT
BACKGROUND: In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. METHODS: A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. RESULTS: The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. CONCLUSIONS: Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.
Subject(s)
COVID-19/mortality , Calcitriol/administration & dosage , Ergocalciferols/administration & dosage , Renal Dialysis/mortality , Aged , Aged, 80 and over , COVID-19/blood , Calcifediol/blood , Calcium/blood , Cross-Sectional Studies , Female , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/drug therapy , Male , Retrospective Studies , SARS-CoV-2/isolation & purification , Survival Analysis , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/mortality , Vitamin D Deficiency/virologyABSTRACT
BACKGROUND: Chronic renal failure (CRF) referred to chronic progressive renal parenchymal damage caused by various causes, with metabolite retention and imbalance of water, electrolyte, and acid-base balance as the main clinical manifestations. Secondary hyperparathyroidism (sHPT) was a common complication in maintenance hemodialysis patients with CRF. Nuclear factor IB (NFIB) was a newly found tumor suppressor gene in various cancers. The present study aimed to illustrate the role of NFIB in sHPT clinical diagnosis and treatment response. METHODS: A retrospective, case-control study, including 189 patients with sHPT and 106 CRF patients without sHPT, compared with 95 controls. Serum NFIB and 1,25(OH)2 D3 levels were measured by RT-qPCR and ELISAs, respectively. ROC analysis was conducted to verify the diagnostic value of NFIB in sHPT. Spearman's correlation analysis was conducted to verify the association between NFIB and bone mineral density (BMD) scores. After 6 months of treatment, the variance of NFIB and 1,25(OH)2 D3 in different groups was recorded. RESULTS: The expression of NFIB was significantly lower in serum samples from sHPT and non-sHPT CRF patients, compared to controls. Clinicopathological information verified sHPT was associated with NFIB, parathyroid hormone (PTH), serum calcium, serum phosphorus, time of dialysis, and serum 1,25(OH)2 D3 levels. Spearman's correlation analysis illustrated the positive correlation between NFIB levels and BMD scores. At receiver operator characteristic (ROC) curve analysis, the cutoff of 1.6508 for NFIB was able to identify patients with sHPT from healthy controls; meanwhile, NFIB could also discriminate sHPT among CRF patients as well (cutoff = 1.4741). Furthermore, we found that during 6 months of treatment, NFIB levels were gradually increased, while PTH and serum P levels were decreased. CONCLUSIONS: Serum NFIB was a highly accurate tool to identify sHPT from healthy controls and CRF patients. Due to its simplicity, specificity, and sensitivity, this candidate can be proposed as a first-line examination in the diagnostic workup in sHPT.
Subject(s)
Biomarkers/blood , Calcium/blood , Hyperparathyroidism, Secondary/diagnosis , NFI Transcription Factors/blood , Vitamin D/blood , Case-Control Studies , Female , Follow-Up Studies , Humans , Hyperparathyroidism, Secondary/blood , Male , Middle Aged , Prognosis , ROC Curve , Retrospective StudiesABSTRACT
INTRODUCTION: Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. METHODS: In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. RESULTS: The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. CONCLUSIONS: The CKD5 patients' baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.
Subject(s)
Heart Rate/physiology , Parathyroid Hormone/blood , Parathyroidectomy , Renal Insufficiency, Chronic/blood , Adult , Case-Control Studies , China , Cross-Sectional Studies , Female , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/surgery , Male , Middle Aged , Regression AnalysisABSTRACT
Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.
Subject(s)
Cytochrome P-450 CYP3A/genetics , Graft Rejection/prevention & control , Kidney Failure, Chronic/therapy , Kidney Transplantation/adverse effects , Tacrolimus/pharmacokinetics , Adult , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Female , Graft Rejection/immunology , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Hyperparathyroidism, Secondary/metabolism , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Middle Aged , Parathyroid Hormone/blood , Parathyroid Hormone/metabolism , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Retrospective Studies , Tacrolimus/administration & dosageABSTRACT
BACKGROUND: Renal hyperparathyroidism is a disease entity that is complex and poorly understood. Although there are guidelines regarding how to manage this patient group, evidence is scarce. Therefore, this survey-based study aims to map the physicians' attitude in terms of preference for management of renal hyperparathyroidism and the influence of patient and respondent factors. METHODS: A survey was sent to Dutch societies of nephrology, endocrinology, and surgeons with interest in endocrine surgery. The survey consisted of eight case vignettes of renal hyperparathyroidism patients who were on hemodialysis and suitable for kidney transplantation, and varied in one of three patient variables import for decision making: age (40 vs. 65 years), parathyroid hormone (40 vs. 90 pmol/L), and serum calcium level (2.25 vs. 2.8 mmol/L). For each case, respondents could choose between maintaining conservative treatment (active vitamin D metabolites), calcimimetics, or subtotal parathyroidectomy as their treatment of choice. Categorical multilevel logistic models were used to investigate the association of patient and respondent variables with treatment preference. The influence of patient variables was determined independently of each other and by means of logistic regression the probabilities of treatment choice were calculated. RESULTS: In total, 115 surveys were included in the analysis. In 6 out of 8 cases, less than two-thirds of respondents agreed on the most favoured treatment. Among patient characteristics, the main disincentive for respondents not to choose conservative therapy was an elevated serum calcium level (subtotal parathyroidectomy vs conservative OR 93.1, 95%-CI: 48.39-179.07 and calcimimetics vs conservative OR 31.2 95%-CI: 18.58-52.30). Additionally, the most significant treatment differences were found between medical specialties and the experience of the respondents, expressed as the amount of cases the physician was involved in during the past year. CONCLUSIONS: Elevated serum calcium levels were widely recognized and the prime reason for respondents to abandon conservative treatment. However, considerable disagreement in treatment preferences remained throughout the cases, demonstrating the current literature available being inconclusive in guiding physicians. Therefore, a high-quality trial comparing subtotal parathyroidectomy to medical treatment is needed to determine optimal treatment.
Subject(s)
Hyperparathyroidism, Secondary/therapy , Kidney Failure, Chronic/complications , Practice Patterns, Physicians' , Adult , Aged , Calcimimetic Agents/therapeutic use , Calcium/blood , Clinical Decision-Making , Conservative Treatment , Health Care Surveys , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/therapy , Netherlands , Parathyroid Hormone/blood , Parathyroidectomy , Renal Dialysis , Vitamin D/therapeutic use , Vitamins/therapeutic useABSTRACT
Persistent or recurrent renal hyperparathyroidism may occur after total parathyroidectomy and transcervical thymectomy with forearm autograft under continuous stimulation due to uremia. Parathyroid hormone (PTH) levels may reflect persistent or recurrent renal hyperparathyroidism because of the enlarged autografted parathyroid glands in the forearm or remnant parathyroid glands in the neck or mediastinum. Detailed imaging requires predictive localization of causative parathyroid glands. Casanova and simplified Casanova tests may be convenient. However, these methods require avascularization of the autografted forearm for >10 min with a tourniquet or Esmarch. The heavy pressure during avascularization can be incredibly painful and result in nerve damage. An easier method that minimizes the burden on patients in addition to predicting the localization of causative parathyroid glands was developed in this study. Ninety patients who underwent successful re-parathyroidectomy for persistent or recurrent renal hyperparathyroidism after parathyroidectomy between January 2000 and July 2019 were classified according to the localization of causative parathyroid glands (63 and 27 patients in the autografted forearm and the neck or mediastinum groups, respectively). Preoperatively, intact PTH levels were measured from bilateral forearm blood samples following a 5-min avascularization of the autografted forearm. Cutoff values of the intact PTH ratio (intact PTH level obtained from the non-autografted forearm before re-parathyroidectomy/intact PTH level obtained from the autografted forearm before re-parathyroidectomy) were investigated with receiver operating characteristic curves to localize the causative parathyroid glands. Intact PTH ratios of <0.310 with an area under the curve (AUC) of 0.913 (95% confidence interval [CI]: 0.856-0.970; P < 0.001) and >0.859 with an AUC 0.744 (95% CI: 0.587-0.901; P = 0.013) could predict causative parathyroid glands in the autografted forearm and the neck or mediastinum with diagnostic accuracies of 81.1% and 83.3%, respectively. Therefore, we propose that the intact PTH ratio is useful for predicting the localization of causative parathyroid glands for re-parathyroidectomy.
Subject(s)
Hyperparathyroidism, Secondary/diagnosis , Kidney Failure, Chronic/diagnosis , Parathyroid Glands/transplantation , Parathyroid Hormone/blood , Postoperative Complications/diagnosis , Reoperation/adverse effects , Female , Forearm/surgery , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/etiology , Male , Mediastinum/surgery , Middle Aged , Parathyroid Glands/surgery , Parathyroidectomy , Postoperative Complications/blood , Postoperative Complications/etiology , ROC Curve , Recurrence , Retrospective Studies , Transplantation, AutologousABSTRACT
[Figure: see text].
Subject(s)
Fibroblast Growth Factor-23/blood , Hydroxycholecalciferols/therapeutic use , Hypertrophy, Left Ventricular/drug therapy , Peptides/therapeutic use , Renal Dialysis , Renal Insufficiency, Chronic/therapy , Death, Sudden, Cardiac/prevention & control , Disease Progression , Female , Humans , Hydroxycholecalciferols/administration & dosage , Hydroxycholecalciferols/adverse effects , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Hypertrophy, Left Ventricular/blood , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/etiology , Hypocalcemia/chemically induced , Intention to Treat Analysis , Klotho Proteins/blood , Magnetic Resonance Imaging , Male , Middle Aged , Parathyroid Hormone/blood , Peptides/administration & dosage , Peptides/adverse effects , Phosphates/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Single-Blind MethodABSTRACT
BACKGROUND: Secondary hyperparathyroidism is a common complication of end-stage renal disease (ESRD), which may be associated with cardiovascular diseases. Thus, this study aimed to explore myocardial damage using non-contrast cardiovascular magnetic resonance (CMR) in ESRD patients undergoing hemodialysis and further investigate its relationship with parathyroid hormone (PTH) toxicity. METHODS: Seventy-two adult ESRD patients receiving regular hemodialysis and 30 healthy subjects underwent CMR examination. Continuous CMR cine sections from the mitral valve level to the left ventricular (LV) apex in the short-axis plane, cine series of vertical two-chamber long-axis plane, and horizontal four-chamber plane were acquired. Native T1 mapping was obtained using modified Look-Locker inversion recovery (MOLLI) sequences. Native T1 values and myocardial strain were analyzed. Immunoreactive parathyroid hormone (iPTH) was obtained from all enrolled patients. RESULTS: Forty (55.6%) hemodialysis ESRD patients were found to have increased iPTH levels. LV ejection fraction (LVEF) of both ESRD patients with targeted and increased iPTH levels was decreased compared with healthy subjects (55.9 ± 12.0% vs. 65.0 ± 4.5%; 51.7 ± 12.8 vs. 65.0 ± 4.5%, both P < 0.05). The mean peak radial strain (PRS), peak circumferential strain (PCS), and peak longitudinal strain (PLS) were lowest in ESRD patients with increased iPTH; however, no significant difference was observed among these three groups. Segmentally, from base to apex, the native T1 of ESRD patients with increased iPTH levels tended to be higher than those with targeted iPTH and healthy subjects (all P < 0.05). In ESRD patients with targeted iPTH, both native T1 of basal and middle segments were significantly higher than normal subjects (basal, 1304 ± 41 ms vs. 1238 ± 36 ms, P = 0.001; middle, 1300 ± 43 ms vs. 1242 ± 50 ms, P < 0.001). Comparing global native T1 values in the three groups, ESRD patients with targeted and increased iPTH level showed increased native T1 (1305 ± 41 ms vs. 1251 ± 49 ms, P = 0.001; 1334 ± 40 ms vs. 1251 ± 49 ms, P < 0.001, respectively). Native T1 values of the basal segment and global native T1 were moderately associated with iPTH (r = 0.4, P < 0.001; r = 0.5, P < 0.001). Multiple linear regression analysis showed that global native T1 values (beta = 1.0, P = 0.01) were independently associated with iPTH. CONCLUSIONS: Elevated iPTH level was associated with and was an independent risk factor for myocardial damage in ESRD patients undergoing maintenance hemodialysis. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ) ChiCTR-DND-17012976, 13/12/2017, retrospectively registered.
Subject(s)
Heart Diseases/diagnostic imaging , Hyperparathyroidism, Secondary/blood , Kidney Failure, Chronic/therapy , Magnetic Resonance Imaging, Cine , Myocardium/pathology , Parathyroid Hormone/blood , Renal Dialysis , Adult , Aged , Biomarkers/blood , Case-Control Studies , Female , Heart Diseases/etiology , Heart Diseases/pathology , Heart Diseases/physiopathology , Humans , Hyperparathyroidism, Secondary/diagnosis , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/diagnosis , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Renal Dialysis/adverse effects , Risk Assessment , Risk Factors , Stroke Volume , Time Factors , Treatment Outcome , Up-Regulation , Ventricular Function, LeftABSTRACT
BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.
Subject(s)
Calcitriol/analogs & derivatives , Hyperparathyroidism, Secondary/drug therapy , Peptides/therapeutic use , Vascular Calcification/prevention & control , Adult , Aged , Aged, 80 and over , Calcitriol/therapeutic use , Cognition/drug effects , Hand Strength , Humans , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Middle Aged , Prospective Studies , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Vascular Calcification/blood , Young AdultABSTRACT
Minerals perform several functions in the body, such as coagulation actions, muscle contraction, enzymatic and hormonal production, among others. This study aims to evaluate the effect of a 150 days chelated and not chelated mineral supplementation with and without potassium oxalate on serological parameters and bone mineral density of horses. Twenty-four crossbred yearlings (12 females and 12 males) with an average age of 21±3 months and body weight of 330.8±37.9kg were divided into four groups containing six equines in each (three females and three males) in a completely randomized design with repeated measurements in a 2x2 factorial arrangement. Treatments were: 1 - chelated minerals compound; 2 - chelated minerals compound and potassium oxalate; 3 - not chelated minerals compound; and 4 - not chelated minerals compound and potassium oxalate. Clinical signs of nutritional secondary hyperparathyroidism (NSH) were observed only in treatment 4. Results showed no treatment effect in bone biopsy for calcium, phosphorus and bone density. There were significant reductions of parathyroid hormone (PTH) means concentrations in treatments 2 and 4 during supplementation. Animals supplemented with chelated minerals compounds avoided mineral imbalances and NSH even when in dietary potassium oxalate challenged.(AU)
Os minerais desempenham diversas funções no organismo, como ações de coagulação, contração muscular, produção enzimática e hormonal, entre outras. O objetivo deste estudo foi avaliar o efeito da suplementação de minerais quelatados e não quelatados, por 150 dias, com e sem oxalato de potássio, sobre parâmetros sorológicos e densidade mineral óssea em equinos. Vinte e quatro filhotes mestiços (12 fêmeas e 12 machos), com idade média de 21±3 meses e peso corporal de 330,8±37,9kg, foram divididos em quatro grupos contendo seis equinos cada (três fêmeas e três machos), em delineamento inteiramente ao acaso, com repetição medida em arranjo fatorial 2x2. Os tratamentos foram: 1 - composto mineral quelatado; 2 - composto mineral quelatado e oxalato de potássio; 3 - composto mineral não quelatado; e 4 - composto mineral não quelatado e oxalato de potássio. Os sinais clínicos do hiperparatireoidismo secundário nutricional (NSH) foram observados apenas no tratamento 4. Os resultados não mostraram efeito de tratamento na biópsia óssea para cálcio, fósforo e densidade óssea. Houve redução significativa do hormônio da paratireoide (PTH) em concentrações médias nos tratamentos 2 e 4 durante a suplementação. Os animais suplementados com compostos minerais quelatados evitaram desequilíbrios minerais e NSH, mesmo quando desafiados no oxalato de potássio na dieta.(AU)