Reduction In Parathyroid Hormone Research Articles

Short-term therapy with R568 ameliorated secondary hyperparathyroidism but does not prevent aortic valve calcification in uremic rats

IntroductionRenal failure associated aortic valve calcification (AVC) is the result of hyperphosphatemia and hyperparathyroidism. Calcimimetics is an effective tool for management of secondary hyperparathyroidism. Our goal was to evaluate the effect of the medical intervention with calcimimetic R568 on the AVC process.Methods and resultsThe experimental design consisted of administering a uremia-inducing phosphate-enriched diet to rats for six weeks. Rats received a daily R568 injection at different times. Biochemical analysis demonstrated increased urea (34.72 ± 3.57 vs. 5.18 ± 0.15 mmol/L, p<0.05) and creatinine (293.93 ± 79.6 vs. 12.82 ± 1.56 µmol/L, p<0.05). R568 treatment markedly reduced parathyroid hormone (PTH) levels in both treated groups (192.63 ± 26.85, 301.23 ± 101.79 vs. 3570 ± 986.63 pg/mL, p<0.05), with no impact on serum calcium and phosphate. von Kossa staining showed increase in AVC in uremic rats compared to control (1409 ± 159.5 vs. 27.33 ± 25.83, p<0.05). AVC was not affected by R568 in both groups (3343 ± 2462, 1593 ± 792 vs. 1409 ± 159.5, NS). Similarly, the inflammatory marker CD68 was elevated in uremic rats (15592 ± 3792 vs. 181.8 ± 15.29, p<0.01), and was not influenced by R568 treatment (8453 ± 818.5, 9318 ± 2232 vs. 15592 ± 3792, NS). Runt-related transcription factor 2 (Runx2), the regulator of osteoblast differentiation, was upregulated in uremic rats (23186 ± 9226 vs. 3184 ± 2495), that accompanied by elevated levels of Osteopontin (158395 ± 45911 vs. 237.7 ± 81.5, p<0.05) and Osteocalcin (22203 ± 8525 vs. 489.7 ± 200.6, p<0.05). R568 had no impact on osteoblastic markers (Runx2: 21743 ± 3193, 23004 ± 10871 vs. 23186 ± 9226, NS; osteopontin: 57680 ± 19522, 137116 ± 60103 vs. 158395 ± 45911, NS; osteocalcin: 10496 ± 5429, 8522 ± 5031 vs. 22203 ± 8525, NS).ConclusionIn an adenine-induced uremic rat model, we showed that short-term R568 therapy had no effect on AVC. Treatment with R568 decreased PTH levels but had no effect on high phosphate levels. Regression of AVC necessitates not only a decrease in PTH levels, but also a decline in phosphate levels. To achieve improved outcomes, it is advisable to consider administering a combination of R568 with other medications, such as calcium supplements or phosphate binders. Additional studies are required for further evaluation of the potential treatment of chronic kidney disease (CKD)-associated AVC.

Vitamin D3 suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a knockout mice

Vitamin D3 is clinically used for the treatment of vitamin D3 deficiency or osteoporosis, partially because of its role in regulating phosphate (Pi) and calcium (Ca2+) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in Pi homeostasis; however, the role of vitamin D3 in hypophosphatemia has never been investigated. We administered vehicle or vitamin D3 to wild-type (WT) mice or hypophosphatemic Npt2a−/− mice. In contrast to WT mice, vitamin D3 treatment increased plasma Pi levels in Npt2a−/− mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca2+ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary Pi and Ca2+/creatinine ratios, in Npt2a−/− mice, Pi/creatinine was unchanged and Ca2+/creatinine drastically decreased, coinciding with the highest kidney Ca2+ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a−/− mice, vitamin D3 treatment completely diminished Npt2c abundance, so that mice resembled Npt2a/c double knockout mice. Abundance of intestinal Npt2b and claudin-3 (tight junctions protein) were reduced in Npt2a−/− only, the latter might facilitate the increase in plasma Pi in Npt2a−/− mice. Npt2a might function as regulator between renal Ca2+ excretion and reabsorption in response to vitamin D3.

#2793 Improvement of bone mineral density in kidney transplant recipients: it is just denosumab?

Abstract Background and Aims Post-transplant bone disease is a common complication after a kidney transplant. Several factors, including pre-existing CKD-MBD, steroid, and CNI immunosuppressive treatment, contribute to this condition and increase the risk of bone loss and fractures. Among various therapeutic strategies, Denosumab, a human monoclonal antibody against RANK-L, can decrease the risk of fracture in Kidney Transplant Recipients (KTRs). The most reported side effects are episodes of hypocalcemia, which are associated with an increase in parathyroid hormone (PTH) levels. The FDA recommends treating these episodes with calcium supplements and cholecalciferol; another alternative is the use of receptor activators (VDRa). To our knowledge, there are only a few case reports in the literature analyzing the effect of combined treatment with VDRa and Denosumab. In this observational study, we evaluated changes in laboratory data and bone density (BMD) assessed by DXA in KTRs that received Denosumab with or without VDRa supplementation. Method This retrospective study evaluated 18 kidney transplant recipients who started Denosumab therapy after transplantation. The patients were divided into two groups: those who started or increased vitamin D receptor agonist therapy within the first 6 months before the second dose of Denosumab, and those who did not. We analyzed at baseline (T0) and after 1 year from first Denosumab administration (T1) creatinine, calcium, phosphate, PTH, bone alkaline phosphatase (BALP), osteocalcin (OC), carboxy-terminal cross-linked telopeptides of type 1 collagen (CTX), and 25-OH vitamin D and BMD at vertebral lumbar spine, femoral neck and total Hip. Furthermore, we evaluated Trabecular Bone Score (TBS). We performed ANOVA and Kruskal-Wallis for continuous variables based on distribution and Fisher's test for categorical variables. To assess the correlation between variables, we used linear regression and the Pearson correlation coefficient. Additionally, we conducted logistic regression to analyze the outcomes. Results A total of 18 patients were included in the study cohort. Of these, 66.7% were females, and 33.3% were males, with an average age of 67 years (Table 1). 13 patients started or uptitrated VDRa within the first 6 months (VDRa group), while 5 did not (Control group). At baseline, the VDRa group had a lower eGFR and higher PTH compared to the Control group, although both were at the threshold of statistical significance (37.38 vs 52.20 mL/min/1.73 m², p = 0.060 and 106.77 vs 72.60 pg/mL, p = 0.069). However, they had significantly lower serum calcium levels (8.96 vs 9.90 mg/dL, p = 0.039). In terms of baseline bone structure, there were no significant differences between the two groups at any of the three sites examined. At 1 year the VDRa group had a significantly greater gain at the Total Hip (+0.08 vs −0.03 g/cm3, p = 0.048 and +10.81 vs −4.16%, p = 0.037). Additionally, the VDRa group had an increase in TBS, while the Control group had a reduction, and this absolute and percentage variation between the two was statistically significant (+0.07 vs −0.02, p = 0.034 and +6.14 vs −1.62, p = 0.043) (Table 2). In linear correlation analysis higher doses of VDRa were significantly and positively associated with Delta BMD at the Total Hip (r = 0.65, p = 0.003). However, a significant correlation was highlighted between VDRa dosage and PTH reduction (r = −0.51, p = 0.027). Finally, in univariate logistic regression analysis, the dosage of VDRA was significantly and positively associated with 5% BMD gain at the Total Hip (OR = 1.54, CI 1.08 to 1.89, p = 0.046) (Fig. 1). Conclusion After conducting our study, we found that the use of Denosumab had a positive impact on bone mineral density. In addition to that, we observed that the association with VDRa led to further improvement in BMD and better control of PTH. Despite having a small sample size, our study demonstrates that VDRa not only helps in correcting hypocalcemia but also enhances the effect of Denosumab.

Extended-Release Calcifediol: A Data Journey From Phase 3 Studies to Real-world Evidence Highlights the Importance of Early Treatment of Secondary Hyperparathyroidism.

Early secondary hyperparathyroidism (SHPT) diagnosis and treatment are crucial to delay the progression of SHPT and related complications, in particular, cardiovascular events and bone fractures. Extended-release calcifediol (ERC) has been developed for the treatment of SHPT in patients with stage 3/4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI). This review compares baseline characteristics and treatment responses of SHPT patients receiving ERC in Phase 3 studies with those treated with ERC in a real-world study. Mean ± standard deviation baseline parathyroid hormone (PTH) levels were 147 ± 56 pg/mL and 148 ± 64 pg/mL in the Phase 3 ERC cohorts, and 181 ± 98 pg/mL in the real-world study. Other baseline laboratory parameters were consistent between the clinical and real-world studies. ERC treatment increased 25-hydroxyvitamin D [25(OH)D] and significantly reduced PTH levels, regardless of baseline CKD stage, in all studies. In the pooled Phase 3 per-protocol populations, 74% of the ERC cohort were up-titrated to 60 μg/day after 12 weeks at 30 μg/day, 97% attained 25(OH)D levels ≥30 ng/mL, and 40% achieved ≥30% PTH reduction. Despite a much lower rate of uptitration in the real-world study, 70% of patients achieved 25(OH)D levels ≥30 ng/mL, and 40% had a ≥30% reduction in PTH. These data establish a 'continuum' of clinical and real-world evidence of ERC effectiveness for treating SHPT, irrespective of CKD stage, baseline PTH levels, and ERC dose. This evidence supports early treatment initiation with ERC, following diagnosis of SHPT, VDI, and stage 3 CKD, to delay SHPT progression.

A prospective cross-sectional study on hypocalcemia after total thyroidectomy in patients with Graves' disease: insights on secondary hyperparathyroidism.

To investigate the parathyroid function and calcium (Ca) levels in the secondary hyperparathyroidism (SHPT) state in patients with Graves' disease. We examined 31 consecutive patients with Graves' disease without chronic kidney disease, who were treated with total thyroidectomy. The patients were divided into a normal parathyroid hormone (PTH) group (NPTH group; n = 19) with a PTH level ≤ 65pg/mL, and a secondary hyperparathyroidism group (SHPT group; n = 12), with a PTH level > 65pg/mL. The PTH and Ca-related parameters were examined and the risk factors for postoperative hypocalcemia were analyzed. The preoperative Ca level was significantly lower (2.24 ± 0.06 vs. 2.31 ± 0.07mmol/L, p < 0.05) in the SHPT group than in the NPTH group. The reduction in PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D), and Ca levels from the preoperative day to the next morning was significantly greater in the SHPT group than in the NPTH group (p < 0.05). When intraoperative factors were included, the decrease in the PTH level alone was significant. SHPT was a significant factor in determining the extent of PTH reduction. Hyperfunctioning parathyroid glands in the SHPT state were more susceptible to postoperative PTH reduction, which, combined with low preoperative Ca levels, increased the risk of postoperative hypocalcemia in patients with Graves' disease.

Etelcalcetide use During Maintenance Hemodialysis and Incidence of Parathyroidectomy After Kidney Transplantation

Etelcalcetide is an i.v. calcimimetic agent, effectively reducing parathyroid hormone levels in patients on maintenance hemodialysis (HD). The clinical impact of discontinuing etelcalcetide at the time of kidney transplantation is unknown. We retrospectively reviewed all patients on HD meeting predefined criteria who received a kidney transplant at our institution between January 1, 2015, and December 12, 2022. The incidence of parathyroidectomy and the evolution of calcium, phosphate, and intact parathyroid hormone (iPTH) levels after transplantation was analyzed according to the type of calcimimetic treatment before transplantation (cinacalcet vs. etelcalcetide vs. none). Overall, 372 patients (aged 53 years; interquartile range [IQR]: 42-62 years) were included. At the time of transplantation, 35, 75, and 262 patients were under etelcalcetide, cinacalcet, or no calcimimetic, respectively. After 1064 (IQR: 367-1658) days, the incidences of parathyroidectomy in the etelcalcetide, cinacalcet, no calcimimetic groups were 29%, 12%, and 1%, respectively (P< 0.001). Etelcalcetide was associated with an increased incidence of parathyroidectomy after adjustment for age, sex, and HD vintage (hazard ratio [HR]: 97.0, 95% confidence interval [CI]: 19.1-493.9, P< 0.001). The incidence of parathyroidectomy was related to etelcalcetide dosage (6/11 [54.6%] in patients with≥ 10 mg vs. 4/24 [16.7%] in patients with< 10 mg, P= 0.02). Moreover, peak calcium levels were higher (P< 0.001) and parathyroidectomy was performed earlier (median 80 vs. 480 days, P< 0.001) in the etelcalcetide compared with the cinacalcet group. Long-term graft function, graft loss, and mortality were similar. Etelcalcetide use during maintenance HD is associated with an increased incidence of early parathyroidectomy after transplantation compared to cinacalcet or no calcimimetic.

AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients.

Pruritus is a common and distressing symptom that affects patients with chronic kidney disease. The concentration of protein bounded uremic toxin was associated with the uremic pruritus. The aim is to assess the efficacy of AST-120 for uremic pruritus in hemodialysis patients. The participants were enrolled and then divided into the AST-120 treatment group and control group with a ratio of 2:1. All participants underwent pre-observation screenings two weeks before the study with three visits. In the treatment phase (week 1 to week 4), the treatment group added 6g/day of AST-120 along with routine anti-pruritic treatment. Visual analog scale (VAS) and biochemical parameters were measured. The VAS score began to be lower in the AST-120 treatment group after the 5th visiting (p < 0.05). The reduction in indoxyl sulfate (IS) at 5th week along with TNF-alpha. The reduction ratio of indoxyl sulfate correlated with reduction of parathyroid hormone. This study has demonstrated that the four-week treatment of AST-120 decreased the severity of uremic pruritus in patients with ESRD. The concentration of IS and TNF-alpha decreased in the AST-120 treatment group. The reduction of iPTH correlated with the reduction of IS in the AST-120 treatment.

Neck Reoperation for Recurrent or Persistent Renal Hyperparathyroidism.

Patients with renal hyperparathyroidism undergoing parathyroidectomy may experience relapse. Reoperation for persistent or recurrent disease, particularly in the neck region, is challenging and has a high complication rate because of difficult exploration. We aimed to evaluate the effectiveness of neck reoperation in renal hyperparathyroidism. Patients with recurrent or persistent renal hyperparathyroidism who underwent neck reoperation between January 2015 and August 2022 were investigated, focusing on operative findings, perioperative biochemical changes, and significance of intraoperative parathyroid hormone (PTH) measurements. During reoperation, 35 parathyroid glands were identified and removed from the 26 enrolled patients, with one, two, and three glands retrieved from 19 (73.2%), five (19.2%), and two (7.6%) patients, respectively. Most removed glands (68.6%) were located in the lower neck, followed by the mediastinum, carotid sheath, and upper neck. Successful resection, defined as a postoperative PTH level of <300pg/mL, was achieved in 21 patients (80.8%). The remaining four (15.4%) and one (3.9%) patients were classified as having persistent and recurrent disease, respectively. The extent of PTH reduction was correlated with specimen weight, specimen volume, and preoperative alkaline phosphatase (ALP) level. The mean intraoperative PTH ratio (10 min after excision/pre-excision) was 0.23, and all patients with persistent or recurrent disease had a PTH ratio >0.3. Severe hypocalcemia (<7.5mg/dL) occurred in 19 (73.0%) patients after reoperation. Neck reoperation is an effective therapeutic option in patients with recurrent or persistent renal hyperparathyroidism. A decrease in PTH level by >70% during reoperation (PTH ratio <0.3) predicts successful resection.

Transoral Endoscopic Thyroidectomy Vestibular Approach Versus Gasless Transaxillary Endoscopic Thyroidectomy for Patients With Unilateral Papillary Thyroid Carcinoma: A Retrospective Study.

Transoral endoscopic thyroidectomy vestibular approach (TOETVA) and gasless transaxillary endoscopic thyroidectomy (GTET) are 2 newly applied technologies. This study is to compare the 2 approaches from the aspects of effectiveness and safety. A total of 339 patients who underwent TOETVA or GTET with unilateral papillary thyroid carcinoma were enrolled in this study from March 2019 to February 2022. The 2 groups were compared in terms of patient characteristics, perioperative clinical results, and postoperative outcomes. The operative time of the TOETVA group was significantly longer than the GTET group (141.39±16.11 vs. 98.45±12.24, P<0.05). The TOETVA group had advantages over GTET group when the reduction of parathyroid hormone was compared (19.18±17.43 vs. 23.07±15.72, P<0.05). Meanwhile, more parathyroids were detected in central neck specimens in GTET group (40/181 vs. 21/158, P<0.05). TOETVA had an advantage on total number of central lymph nodes over GTET (7.65±3.11 vs. 4.99±2.45, P<0.05), whereas the number of positive central lymph nodes was similar (P>0.05). No differences were found between the 2 groups on other data. TOETVA and GTET are both safe and effective for unilateral papillary thyroid carcinomas. TOETVA has advantage on protection of inferior parathyroid glands and harvest of central lymph node dissection. Meanwhile, GTET can save more time compared with TOETVA. Surgeons and patients should freely choose the approaches based on their demands.

Paricalcitol and Extended Release Calcifediol for Treatment of Secondary Hyperparathyroidism in Non-Dialysis Chronic Kidney Disease: Results From a Network Meta-Analysis.

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. 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 biomarkers PTH, calcium and Phosphate in patients with non-dialysis CKD (ND CKD). A systematic literature research (SLR) 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. Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on two overlapping networks, due to non-reporting 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 to ERC (0.2 mg/dl increase, 95% CI: -0.37 to -0.05 mg/dl). No differences in effects on phosphate were observed. This NMA 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.

The rationale for intermittent administration of PTH in the management of mineral and bone disorder of chronic kidney disease.

A major complication of chronic kidney disease is the derangement of mineral metabolism, leading to increased risk of fractures and cardiovascular mortality. Current therapeutic regimens are focused on reducing parathyroid hormone levels caused by secondary hyperparathyroidism, and the active vitamin D metabolite l,25(OH)2D, with limited success. It may be a more effective approach, however, if we could target the delayed response of parathyroid hormone in the early retention of phosphate following loss of renal function.We propose intermittent administration (even in stage 2 chronic kidney disease) of parathyroid hormone, known for its bone anabolic effects compared to the catabolic effects of the continuously elevated parathyroid hormone associated with the hyperparathyroid state, to mitigate the retention of phosphate. This approach may prevent the compensatory responses of the other two major calcium- and phosphate-regulating hormones (FGF-23 and l,25(OH)2D) that lead to further worsening of the derangement of mineral metabolism.In addition to its strong theoretical basis, there are data supporting the need for further research focused on the use of intermittent parathyroid hormone in the management of chronic kidney disease-mineral bone disorder.

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics

Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

ODP118 PTH (1-34) Replacement Therapy for Hypoparathyroidism due to Sporadic Calcium Sensing Receptor Gain-of-Function Point Mutation

Abstract Background The calcium sensing receptor (CASR) regulates parathyroid hormone secretion in response to extracellular calcium concentration. A gain-of-function mutation of the CASR lowers the set point for extracellular calcium sensing, resulting in both reduced parathyroid hormone secretion and increased urinary calcium excretion compared to other causes of hypoparathyroidism. Clinical Case After presenting with hypocalcemia-associated seizures at the age of two years, our patient had an undetectable serum parathyroid hormone level. He was started on calcitriol and calcium supplementation, however continued to have recurrent seizures throughout childhood. On ultrasound at age four, he exhibited nephrocalcinosis. DNA sequence analysis revealed a heterozygous T383G mutation nucleotide substitution on exon 3, resulting in the replacement of phenylalanine with cysteine at amino acid position 128. Our patient's base substitution likely represents a de novo mutation as we have confirmed that he has no family history of hypocalcemia. Notably, a different missense mutation at the same codon (F128L) co-segregated with autosomal dominant hypocalcemia in a large family, and functional studies confirm that mutation of this phenylalanine provides gain-of-function to the CASR. After enrolling in a clinical trial for continuous recombinant parathyroid hormone infusion at age seven, his symptoms of hypocalcemia abated. His seizures stopped, and anti-epileptic drugs were discontinued at age eight. After the clinical trial concluded, he was switched to teriparatide 10 micrograms three times daily, and serum calcium was maintained between 7.5 and 8.5 mg/dL. With the goal to minimize hypercalciuria and reduce the frequency of injections, teriparatide was discontinued, and recombinant parathyroid hormone (Natpara) 50 micrograms daily was started. This led to symptomatic hypocalcemia with muscle cramping and cognitive changes, and he was thus restarted on teriparatide with calcium carbonate supplementation. Despite maintenance of 24-hour urine calcium excretion ranging 325-388 mg, he developed bilateral flank pain. Computed tomography images revealed worsening nephrocalcinosis and bilateral nephrolithiasis. To reduce hypercalciuria and risk of stone formation, he was started on chlorthalidone, switched to calcium citrate, and encouraged to reduce dietary sodium intake. Conclusion This patient has a novel T383G activating mutation in CASR gene resulting in hypoparathyroidism and type 5 Bartter syndrome that has not been previously published in the literature. His hypocalcemia has remained stable on teriparatide for over 18 years, which to our knowledge, is the longest treatment duration using recombinant human parathyroid hormone for this purpose. We demonstrate a unique clinical challenge to balance treatment of hypoparathyroidism and hypocalcemia with teriparatide and supplemental calcium, while minimizing hypercalciuria and associated nephrocalcinosis. Presentation: No date and time listed

LBSAT229 Extended-release Calcifediol Effectively Raised 25-hydroxyvitamin D In CKD Despite Obesity

Abstract Inadequate levels of serum total 25-hydroxyvitamin D (25D) in chronic kidney disease (CKD) are associated with an increased risk of secondary hyperparathyroidism (SHPT). Serum 25D can be difficult to raise sufficiently with vitamin D supplements (cholecalciferol or ergocalciferol) to effectively lower elevated parathyroid hormone (PTH) levels especially in overweight patients. Obesity is common in CKD and requires attention when vitamin D repletion is considered. Vitamin D supplements are fat-soluble molecules which accumulate in adipose tissue. They have low affinity for serum vitamin D binding protein and are poorly mobilized from adipose tissue into circulation for hepatic activation. Recent studies suggest that serum 25D levels of ≥50 ng/mL are necessary to produce significant PTH reductions in nondialysis patients. Data were analyzed from two identical randomized clinical trials investigating the efficacy and safety of treating adult nondialysis patients with extended-release calcifediol (ERC; n=285) or placebo (n=144) to see if ERC raised 25D to at least 50 ng/mL in all body weight categories, with subgroup analyses by race, gender and age. On enrollment, subjects had eGFR of ≥15 and &amp;lt;60 mL/min/1.73 m2, PTH ≥85 and &amp;lt;500 pg/mL, serum 25D ≥10 and &amp;lt;30 ng/mL, corrected serum calcium ≥8.4 and &amp;lt;9.8, serum phosphorus ≥2. 0 and &amp;lt;5. 0, absence of nephrotic range proteinuria (&amp;gt;3 mg/mg creatinine) and no history of parathyroidectomy or renal transplantation. These subjects had mean (SD) age of 65.4 (10.9) years, serum 25D at baseline of 19.6 (5.4) ng/mL, body weight of 97.8 (24.3) kg and BMI of 34.7 (7.9) kg/m2. Fifty percent were male, 64. 0% White, 32.9% African-American or Black, and 3.1% Other, and 20% were Hispanic. A total of 356 subjects completed a 20- to 26-week treatment period per-protocol and were included in the analysis. Enrolled subjects ingested a 30 mcg capsule of ERC (OPKO Pharmaceuticals, Miami) daily for 12 weeks followed by one or two capsules (30 or 60 mcg) daily for a 14 more weeks. Control subjects received matching placebo. Mean (SD) serum 25D remained unchanged with placebo treatment but rose progressively with ERC treatment to 67.1 (21.6) ng/mL (mean of weeks 20-26). The observed increases in serum 25D were inversely related to body weight but exceeded 50 ng/mL in all body weight categories, irrespective of race (White vs. African-American or black), gender or age (&amp;lt;70 vs. ≥70 years). Side effects observed at these levels were similar to placebo. These data showed that ERC successfully raised mean serum 25D to at least 50 ng/mL irrespective of body weight, race, gender or age. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Randomized Control Study on Hemoperfusion Combined with Hemodialysis versus Standard Hemodialysis: Effects on Middle-Molecular-Weight Toxins and Uremic Pruritus

Introduction: Classic hemodialysis schedules present inadequate middle-molecular-weight toxin clearance due to limitations of membrane-based separation processes. Accumulation of uremic retention solutes may result in specific symptoms (e.g., pruritus) and may affect clinical outcome and patient’s quality of life. Hemoperfusion (HP) is a blood purification modality based on adsorption that can overcome such limitations, and thus, it may be interesting to test the efficacy of at least one session per week of HP combined with hemodialysis. This is a randomized, open-label trial, controlled, multicenter clinical study to investigate the effect of long-term HP combined with hemodialysis on middle-molecular-weight toxins and uremic pruritus in maintenance hemodialysis (MHD) patients. Methods: 438 MHD patients from 37 HD centers in China with end-stage kidney disease (63.9% males, mean age 51 years) suffering from chronic intractable pruritus were enrolled in the study. Eligible patients were randomized into four groups: low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), HP + LFHD, and HP + HFHD at a 1:1:1:1 ratio. Beta-2 microglobulin (β2M) and parathyroid hormone (PTH) were measured at baseline, 3–6, and 12 months. At the same time points, the pruritus score was evaluated. The primary outcome was the reduction of β2M and PTH, while the secondary outcome was the reduction of the pruritus score. Results: In the two groups HP + LFHD and HP + HFHD, there was a significant decrease of β2M and PTH levels after 12 months compared to the control groups. No significant differences were noted between HP + LFHD and HP + HFHD. Pruritus score reduction was 63% in the HP + LFHD group and 51% in the HP + HFHD group, respectively. Conclusion: The long-term HP + HD can reduce β2M and PTH levels and improve pruritus in MHD patients independently on the use of high- or low-flux dialyzers, showing that the results are linked to the effect of adsorption.

Systemic lupus erythematosus as a rare cause of hypercalcemia: A case report

Hypercalcemia is a rare manifestation in systemic lupus erythematosus (SLE) patients. In this case report, a thirty-five-year-old woman with a 3-year-old history of lupus was reported. Our case had symptoms of SLE flare, including joint pain, hair loss, photosensitivity, high level of calcium and creatinine, and lymphadenopathy. In her brain magnetic resonance imaging, intracranial hemorrhage was detected. Given her high serum level of calcium and phosphorus, reduced parathyroid hormone, and normal level of vitamin D, her hypercalcemia was attributed to the presence of stimulating parathyroid hormone receptor autoantibody. Regarding the findings of this study, it is suggested to consider SLE as a rare but possiblecause of severe hypercalcemia.

Cortical porosity development and progression is mitigated after etelcalcetide treatment in an animal model of chronic kidney disease.

Chronic kidney disease (CKD) leads to increased bone fragility and risk of fracture. Cortical deteriorations, including cortical porosity, are key factors in fracture susceptibility in CKD. Since secondary hyperparathyroidism is common in CKD individuals and contributes to cortical deterioration, we hypothesized that reducing parathyroid hormone (PTH) may modulate CKD-induced cortical porosity. The goal of this pilot study was to assess the effects of lowering PTH, via the preclinical analogue of the FDA-approved calcimimetic etelcalcetide (KP-2326), on the development and progression of cortical pores in the setting of CKD. Male Cy/+ Sprague Dawley rats with clinical biochemistries consistent with CKD (N=8) were assigned to the study. At 30-32weeks of age, cortical bone was assessed via In vivo μCT and blood collected for biochemistries to create baseline measures. Calcimimetic treatment with KP-2326 (KP) was then administered 3× weekly for 2-4weeks. Cortical bone and biochemical parameters were repeated at study endpoint (33-37 wks of age). A group of age- and cohort-matched CKD rats (N=4) were utilized as untreated controls. Untreated CKD rats had significantly increased cortical porosity over time, while porosity in KP-treated CKD rats was not significantly changed over time. Individual pore analysis revealed that pore area was significantly higher for expanding pores in untreated CKD rats compared to KP-treated CKD rats. Mechanical properties of KP-treated animal femora were similar to historical values of age-matched CKD animals and lower than those of age-matched non-diseased animals. Our pilot preclinical study demonstrates that etelcalcetide treatment can mitigate the progression of cortical bone changes in an animal model of CKD through suppression of pre-existing cortical pore expansion and limiting the size of new pore development. While stabilization of porosity is beneficial it remains likely that infilling of porosity will be needed to positively affect mechanical properties of bones in the setting of CKD.

Non-Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

ABSTRACTChronic kidney disease‐mineral and bone disorder (CKD‐MBD) increases cardiovascular calcification and skeletal fragility in part by increasing systemic oxidative stress and disrupting mineral homeostasis through secondary hyperparathyroidism. We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before end‐stage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKD‐MBD, the Cy/+ rat, beginning early in CKD with the NADPH oxidase (NOX1/4) inhibitor GKT‐137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KP‐2326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased C‐terminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8‐OHdG in the serum or aorta. KP treatment reduced aortic 8‐OHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet.

ObjectiveThe aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone‐ and calcium (Ca) metabolism.MethodsTwo groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25‐OH vitamin D (25‐OH vit D), 1,25‐OH vitamin D (1,25‐OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N‐terminal propeptide (P1NP) and C‐terminal telopeptide collagen type 1 (CTX‐1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle‐stimulating hormone), sex hormone‐binding globulin, and leptin.ResultsAfter 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX‐1, P1NP, 1,25‐OH vit D, and leptin. There was a significant increase in 25‐OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (≥25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant.SignificanceTwelve weeks of MAD treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies.

Cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR) reduces parathyroid hormone (PTH) secretion by increasing the sensitivity of the CaSR on parathyroid cells. We conducted a systematic review and meta-analysis on the safety and efficacy of cinacalcet in Primary Hyperparathyroidism (PHPT). MEDLINE, Embase, BIOSIS, and the Cochrane Library were searched for published articles (from database inception to Sept 2020). All double-blind RCTs and cohort studies that reported data on the efficacy and safety of cinacalcet therapy in individuals ≥ 18 with PHPT were included. Random effect meta-analysis was performed to estimate the efficacy of cinacalcet in lowering serum calcium and PTH levels compared with placebo. 4 RCTs (177 participants) and 17 cohort studies (763 participants) were eligible for final analysis. Pooled results from the RCTs suggest that, when compared to placebo and administered for up to 28weeks, cinacalcet normalizes serum calcium (≤ 10.3mg/dl) in patients with PHPT [RR 20 (95% CI 6.04 - 68.52, I2 = 0%, pheterogeneity < 0·00001)]. Serum PTH levels decreased significantly after 2weeks and up to 28weeks after treatment with cinacalcet. In the pooled analysis of the 17 cohort studies, serum calcium levels normalized in 76% (95% CI 66% to 86%; I2 = 92%, pheterogeneity < 0·00001) of patients regardless of the duration of treatment. In most studies, PTH levels decreased by 13% to 55%. No RCT reported on BMD as a primary or secondary outcome, and no improvement in BMD was noted in the 2 non-randomized studies that reported densitometric findings. No significant difference in urinary calcium was noted with cinacalcet therapy in either the RCTs or non-randomized studies. There was no significant difference in overall adverse events (AE) (RD 0.01, 95% CI -0.07 to 0.26) compared to placebo noted in the RCTs. In the non-randomized studies, pooled weighted AE rate was 45% (95% CI 32 to 59%). Risk of bias was low in 2/4 RCTs and 6/17cohort studies; risk was intermediate in 2/4 RCTs and 8/17 cohort studies, and risk was high in 3/17 cohort studies. In PHPT, cinacalcet lowers serum calcium and PTH with greater effects on calcium than on PTH in the short term. In the doses reported, the drug is safe with tolerable side effects. These findings can help inform targeted medical therapy of PHPT in those for whom lowering the serum calcium is indicated and for whom parathyroidectomy is not an option.