Treatment Of Secondary Hyperparathyroidism Research Articles

#2823 High doses and levels of cholecalciferol for secondary hyperparathyroidism in hemodialysis patients

Abstract Background and Aims Vitamin D is crucial for musculoskeletal and general health. Low levels are associated with an increased risk of death and morbidity, including cancer, cardiovascular, autoimmune diseases and infections. In hemodialysis (HD) patients vitamin D deficiency plays additionally an important role in the pathogenesis of Chronic Kidney Disease–Mineral And Bone Disorder (CKD-MBD), including the development of secondary hyperparathyroidism (SHP). Determination of 25(OH)D levels in CKD patients and the administration of cholecalciferol according to the guidelines for the general population is recommended. The literature data show that therapy even with high doses of cholecalciferol appear to be safe and sufficient to increase 25(OH)D level > 30 ng/ml in HD patients. However, the prevailing opinion is that PTH lowering with cholecalciferol in CKD is unproven and clinically insignificant. The aim of the study was to evaluate the efficacy (including PTH concentration) and safety of increasing vitamin D levels from the recommended 30 ng/mL to >75 ng/mL in HD patients treated with high doses of cholecalciferol. Method 22 HD patients (16 M, 6 F)), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration 30–50 ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session) to reach the target serum 25(OH)D level > 75 ng/mL, but not longer than for 24 weeks. The baseline data on calcium, phosphate, 1,84 PTH, 25(OH)D and 1,25(OH)2D serum levels were compared with the data when 25(OH)D > 75 ng/mL was achieved or when the highest 25(OH)D levels were noted. Results A significant decrease in 1,84 PTH levels was observed during the study (542.36 ± 420.87 vs 230.99 ± 386.22 pg/mL; p < 0.005). No significant effect on calcium (8.91 ± 0.57 vs 9.03 ± 0.63 mg/dL; p = 0.23) and phosphate (4.6 ± 1.06 vs 4.81 ± 1.06 mg/dL; p = 0.93) concentrations was shown. There was also significant increase in 25(OH)D and 1,25(OH)2D levels (35.52 ± 8.26 vs 79.83 ± 21.38 ng/mL; p < 0.005, and 13.38 ± 7.26 vs 25.56 ± 12.80 pg/mL; p < 0.005, respectively). In the range of 25(OH)D levels 30-50 ng/mL 25(OH)D correlated positively with 1,25(OH)2D levels, r = 0.305. When 25(OH)D levels exceeded 50 ng/mL, there was negative correlation with 1,25(OH)2D levels (r = –0 .177 for 25(OH)D 50-75 ng/mL, and r = –0.262 for 25(OH)D >75 ng/mL). Conclusion Our study showed that the administration of high therapeutic doses of cholecalciferol to achieve 25(OH)D levels >75 ng/mL was safe, without the risk of hypercalcemia and hyperphosphatemia. Raising of 25(OH)D levels to the upper limit of the laboratory norm resulted in significant decrease in PTH levels. Cholecalciferol may be useful in the treatment of SHP in HD patients, but higher 25(OH)D levels seem to be crucial.

#1585 Ten years’ practice with calcimimetics and paricalcitol for the treatment of secondary hyperparathyroidism. Experience of one dialysis center

Abstract Background and Aims Secondary hyperparathyroidism (SHPT) remains one of the main problems in patients with chronic kidney disease (CKD), associated with deterioration in quality of life, progression of cardiovascular complications and mortality. Method Patients on HD (n = 2517) were treated from 2012 to 2023 years in our dialysis center with secondary SHPT were included in this study. All patients were divided into 2 groups: 1 gr. included −1536 (61%) patients whose PTH levels remained in the target range from 300 to 600 pg/ml, without therapy or with low doses of alfacalcidol (0.75-5 μg/week ); 2 gr. included - 981 (39%) patients with PTH levels >600 pg/ml were treated with calcimimetics (doses of cinacalcet used from 30 mg to 90 mg/day, doses of etelcalcetide used from 5 to 15 mg/week) as monotherapy or in combination with paricalcitol (5–15 μg/week). Phosphorus levels were controlled by an adequate dose of dialysis and administration of phosphate binders (sevelamer and sucrose iron oxyhydroxide). Results The average PTH level in 2 gr. of patients at the time of treatment initiation was 916.7 ± 879.9 pg/ml (601-2500 pg/ml). During the treatment the level of PTH decreased to target values and amounted 523.4 ± 216.7 pg/ml (63-594 pg/ml) in 73% of patients. Monotherapy with calcimimetics was effective in 41%; the remaining of patients (59%) were required the addition of paricalcitol to therapy to achieve target PTH values. Therapy of SHPT was also carried out in 15 (0.6%) patients with identified parathyroid adenomas (volume more than 1 cm3) and PTH levels >1000 pg/ml; the effect was achieved in 9 patients (60%), 6 patients underwent parathyroidectomy. During the previous years of observation, parathyroidectomy was required in all patients with SHPT with similar changes in the parathyroid glands. Conclusion In the overwhelming majority of patients with CKD5D and SHPT, the administration of calcimimetics as monotherapy or in combination with paricalcitol during the progression of SHPT allowed us to achieve target PTH values and maintain it for a long time (from 1 to 10 years), as well as reduce the number of surgical interventions for parathyroid glands, compared to the previous period.

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.

Capsiate ameliorates secondary hyperparathyroidism by improving insulin sensitivity and inhibiting angiogenesis.

Secondary hyperparathyroidism has a significant impact on the overall well-being of the body. Capsiates, known for their antioxidant and metabolic properties, have emerged as a promising alternative treatment for secondary hyperparathyroidism. This study aims to evaluate the effects and mechanisms of capsiates in the treatment of secondary hyperparathyroidism. To achieve our research objectives, we conducted a study on patients' serum and examined changes in metabolic markers using serum metabolomics. We induced secondary hyperparathyroidism in rat through dietary intervention and divided them into four groups. The first group, referred to as the Parathyroid Hormone (PTH) group, received a low-calcium and high-phosphate diet (0.2% calcium, 1.2% phosphorus). The second group served as the control group, receiving a standard phosphate and calcium diet (0.6% calcium, 0.6% phosphorus). The third group, called the capsiates group, consisted of rat from the control group treated with capsiates (intraperitoneal injection of 2 mg/kg capsiates for 2 weeks after 2 weeks of dietary intervention). The fourth group was the capsiates-treated PTH group. Subsequently, we conducted ribose nucleic acid (RNA) sequencing on parathyroid gland cells and evaluated serum thyroxine levels, oxidative stress, expression of proteins associated with vascular neogenesis, measurement of SOD, GSH and 3-nitrotyrosine, micro-CT and histological staining. The serum metabolomic data revealed a significant decrease in capsiate levels in the secondary hyperparathyroidism group. Administration of capsiates to PTH rat resulted in increased calcium levels compared to the PTH group. Additionally, the PTH + Capsiates group showed significantly lower levels of PTH and phosphate compared to the PTH group. The PTH group exhibited a notable increase in the quantity and size of mitochondria compared to the control group. Following capsiates administration to the PTH group, there was a significant reduction in the number of mitochondria and length of microvilli, but an increase in the size of mitochondria compared to the PTH group. Sequencing analysis revealed that vascular endothelial growth factor (VEGF) and Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) play crucial roles in this process. Vascular-related variables and downstream signalling were significantly elevated in hyperthyroidism and were alleviated with capsaicin treatment. Finally, combining capsiates with the PTH group improved bone mineral density, Tb.N, BV.TV, Cs.Th, Tt.Ar, OPG, Ob.TV and Oc.TV, as well as the mineral apposition rate, but significantly decreased Tb.Sp and Receptor Activator for Nuclear Factor-κ B Ligand (RANKL) compared to the PTH group. The findings suggest that capsiates can improve secondary hyperparathyroidism and ameliorated osteoporosis outcomes by inhibiting angiogenesis and reducing oxidative stress.

Surgical treatment of secondary hyperparathyroidism in children with chronic kidney disease. Experience in 19 patients.

Secondary hyperparathyroidism (sHPT) is an important contributor to bone disease and cardiovascular calcifications in children with chronic kidney disease (CKD). When conservative measures are ineffective, parathyroidectomy is indicated. The aim of our study was to evaluate the efficacy and safety of subtotal parathyroidectomy (sPTX) in pediatric and adolescent patients, and to provide a rationale for considering this aggressive treatment in CKD patients with uncontrolled sHPT. We retrospectively analyzed the medical records of 19 pediatric CKD patients on dialysis with refractory sHPT who underwent sPTX at our institution between 2010 and 2020. All patients had clinical, radiological, and biochemical signs of renal osteodystrophy. One year after sPTX, parathyroid hormone (PTH) levels (median and interquartile range (IQR)) dropped from 2073 (1339-2484) to 164 (93-252) pg/mL (p=0.0001), alkaline phosphatase (ALP) levels from 1166 (764-2373) to 410 (126-421) IU/L (p=0.002), and the mean (±SDS) calcium-phosphate (Ca*P) product from 51±11 to 41±13mg2/dL2 (p=0.07). Postoperatively, all patients presented with severe hungry bone syndrome (HBS) and required intravenous and oral calcium and calcitriol supplementation. None of them had other postoperative complication. Histological findings had a good correlation with preoperative parathyroid ultrasound imaging (n: 15) in 100 % and with technetium-99m (99mTc) sestamibi scintigraphy (n: 15) in 86.6 %. Clinical and radiological signs of bone disease improved in all patients. Pediatric sPTX is effective and safe to control sHPT and calcium-phosphate metabolism in children with CKD on dialysis and may mitigate irreversible bone deformities and progression of cardiovascular disease.

Cost-Effectiveness and Clinical Outcomes of Secondary Hyperparathyroidism Treatments in Patients with Chronic Kidney Disease.

The study addresses the challenge of treating secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, focusing on the cost-effectiveness of surgical versus pharmacological interventions. Conducting a retrospective analysis on 152 CKD patients with SHPT at the Third People's Hospital of Chengdu, the study matched 80 patients into two groups: 40 undergoing parathyroidectomy with autotransplantation (PTX + AT) and 40 treated with calcimimetics. PTX + AT was more effective in alleviating symptoms, particularly bodily pain, and demonstrated greater cost-effectiveness over a long-term period compared to calcimimetics. This was especially significant in patients with PTH levels > 1800 pg/mL and hyperphosphatemia. Despite similar initial costs, PTX + AT led to a substantial decrease in expenses during the 2-5 years post-treatment period, PTX + AT results in an ICER of -RMB 26.71/QALY for the first post-treatment year and -RMB-111.9k/QALY for the 2-5 year period, indicating cost-effectiveness with reduced long-term costs. The study also found an increased economic burden in managing patients with hyperphosphatemia. Surgical intervention (PTX + AT) is advocated as the primary treatment strategy for severe SHPT in CKD patients, owing to its long-term economic and clinical advantages. The results underscore the need for a severity-based approach in treating SHPT.

Secondary hyperparathyroidism combined with thyroid disease.

To retrospectively analyze the diagnosis and treatment of secondary hyperparathyroidism (SHPT) combined with thyroid disease, and to investigate the correlation between SHPT and papillary thyroid carcinoma (PTC), SHPT and thyroid disease, and the importance of preoperative localization diagnosis in patients with SHPT. Clinical data of 101 patients who underwent surgical treatment for SHPT at the Third Hospital of Hebei Medical University were collected from August 2014 to May 2023, and patients were divided into SHPT without PTC group (n = 94) and SHPT with PTC group (n = 7) according to their postoperative pathology. Patients were divided into SHPT without thyroid disease group (n = 32) and SHPT with thyroid disease group (n = 69) according to their preoperative ultrasound diagnosis and postoperative pathology. The differences between the 2 groups were compared to explore the association between SHPT and PTC and between SHPT and thyroid disease. Of the 101 patients with SHPT, 65 were male and 36 were female with a mean age of (44.26 ± 11.16) years. There were 69 patients (68.32%) with concomitant thyroid disease and 32 patients (31.68%) without concomitant thyroid disease, including 7 patients (6.93%) with PTC. The results of univariate analysis showed that the differences in age and preoperative PTH levels between the SHPT without PTC group and the SHPT with PTC group were statistically significant (P < 0. 05),There were no significant differences in age, gender, preoperative PTH, preoperative alkaline phosphatase, preoperative serum calcium, preoperative serum phosphorus, preoperative serum creatinine, duration of dialysis disease, and whether they were accompanied by hypertension or not between the SHPT without thyroid disease group and the SHPT with thyroid disease group (P > 0. 05), logistic regression analysis showed that there was a correlation between the age of patients with SHPT and the level of preoperative PTH with PTC. In patients with SHPT, concomitant thyroid disease is more common, so patients with SHPT should be screened for thyroid disease at the same time as routine preoperative ultrasonography combined with nuclear scan for localized diagnosis, and surgical resection is preferred if concomitant PTC is present.

Teriparatide and etelcalcetide improve bone, fibrosis, and fat parameters in chronic kidney disease model rats

ObjectivesChronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) is associated with an increased risk of fragility fractures. Etelcalcetide (EC) is a treatment for SHPT that reduces serum parathyroid hormone (PTH) levels. However, the effects of combined treatment with osteoporosis drugs such as teriparatide (TPTD) remain unclear. This study investigates the combined effects of EC and TPTD on bone in CKD model rats. MethodsThe CKD model was established in 8-week-old male Wistar rats by feeding them a 0.75% adenine diet for 4 weeks. At 20 weeks of age, the rats were divided into 4 groups (N = 9–10 in each group): CKD group (vehicle administration), TPTD group (30 μg/kg, 3 times/week), EC group (0.6 mg/kg, daily), and Comb group (TPTD and EC combined). EC was injected for 12 weeks starting at 20 weeks of age, and TPTD was injected for 8 weeks starting at 24 weeks of age. After treatment, the followings were evaluated: bone mineral density, bone strength, biochemical tests, bone and fat histomorphometry, and micro-computed tomography. ResultsIn CKD model rats, the combination of EC and TPTD was more effective in increasing cortical bone thickness and bone strength and inhibiting porosity. In addition, the combined treatment decreased bone marrow adiposity and fibrosis, and it increased bone mass and improved bone microstructure in trabecular bone. ConclusionsWith the observed benefits such as improved bone mass, bone strength, structural properties, and bone marrow adiposity, combination therapy may be a potential way to improve bone fragility in CKD.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n=55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Secondary hyperparathyroidism in chronic kidney disease: pathomechanism and current treatment possibilities.

Secondary hyperparathyroidism (SHPT) is one of the most common metabolic complications resulting from chronic kidney disease (CKD). The complexity of calcium and phosphate disorders associated with CKD is defined by the Kidney Disease Improvement Global Outcomes (KDIGO) working group as CKD-related mineral and bone disorders (CKD-MBD). The last update of the KDIGO guidelines on the conduct in CKD-MBD was published in 2017. The treatment of SHPT is based on 2 strategies: counteracting hyperphosphataemia and suppressing parathyroid hormone (PTH) secretion. Therapy should be based on optimally selected drugs, taking into account additional effects to reduce the risk of chronic complications and side effects. The creation of new drugs with a better safety profile, significant reduction of side effects, and greater efficiency in achieving target serum phosphorus and PTH values forces the gradual replacement of existing treatment with new pharmacotherapies. The aim of this study is to discuss the latest issues (in connection with the latest KDIGO guidelines) regarding the pathomechanism of secondary hyperparathyroidism and the current directions of the therapy in these disorders.

Efficacy and safety of radiofrequency ablation for primary and secondary hyperparathyroidism: a retrospective study

There is now growing interest in the use of Ultrasound-guided radiofrequency ablation (RFA) to treat hyperparathyroidism. But the efficacy and limitations of this treatment have not been described in sufficient detail. Assessing and contrasting the effectiveness and safety of RFA in treating primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). This retrospective study included 57 HPT patients (48 for PHPT and 9 for SHPT) who underwent RFA between January 2017 and April 2021. The serum intact parathyroid hormone (iPTH) and calcium, hyperplastic parathyroid volume, volume reduction rate (VRR) before and after RFA, clinical success rate, symptoms, and complications were analyzed and compared. In SHPT group, bone pain (7/9, 77.8%), skin pruritus (4/9, 44.4%), and multiple hyperplastic parathyroid glands (4/9, 44.4%) were more common compared to the PHPT group. After 12 months of follow-up, the serum iPTH, calcium, and the volume of PHPT and SHPT groups had decreased by more than 60%, 10%, and 90%, respectively (P < 0.05). In the VRR, 13 glands of SHPT (72.2%) and 42 glands of PHPT (87.5%) had achieved the clinical success. In addition, the preoperative and postoperative serum iPTH were higher in the SHPT group than in the PHPT group (P < 0.05). In terms of the serum iPTH and calcium, the PHPT group had substantially higher rates of clinical success, with 42 patients (87.5%) and 46 patients (95.8%) meeting the criteria, respectively compared to 3 patients (33.3%) and 6 patients (66.7%) of SHPT group (P < 0.05). After RFA, the clinical symptoms improved in both groups. The overall incidence of complications (hoarseness and postoperative hematoma) of RFA in the two groups was 10.5% (6/57), and hoarseness (3/9, 33.3%) of SHPT group was more common than PHPT group. All the complications were resolved spontaneously within 12 months after symptomatic treatments. In the treatment of PHPT and SHPT, ultrasound-guided RFA is both successful and safe. PHPT patients have better results in restoring normal iPTH by RFA, and have no considerable difference with the SHPT patients in terms of serum calcium, the volume of the ablation area, and the VRR.

Misdiagnosis of chronic kidney disease and parathyroid hormone testing during the past 16 years

Chronic kidney disease (CKD) is a prevalent pathological condition worldwide. Parathyroid hormone (PTH) is an important index related to bone metabolism in CKD patients and has not received enough attention. This study was performed to investigate the incidence and diagnostic rate of CKDin hospital as well as PTH testing and treatment for secondary hyperparathyroidism (SHPT) in patients with stage 3 to 5 CKD. The data of patients who visited Zhejiang Provincial People's Hospital from February 2006 to April 2022 were retrieved from the hospital database. All data were divided into three subgroups using PTH testing and SHPT treatment as major comparative indicators for analysis. The data were then analyzed for overall PTH testing, CKD incidence, and diagnostic rate. Among 5,301,391 patients, the incidence of CKD was 13.14%. The missed diagnosis rate for CKD was 65.76%. The total PTH testing rate was 1.22%, of which 15.37% of PTH testing was performed in patients with stage 3 to 5 CKD. The overall diagnosis rate of SHPT in patients with stage 3 to 5 CKD was 31.0%. The prophylactic medication rate was 7.4%, and the rate of post-diagnostic drug therapy was 22.2% in patients who underwent SHPT treatment. The high misdiagnosis rate and low PTH testing rate of CKD requires prompt attention from clinicians. SHPT treatment should be considered especially in patients with stage 3 to 5 CKD.

Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl.

Cinacalcet (I), sold as hydrochloride salt, is a calcimimetic drug which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Here, an improved method for the synthesis of 3-(3-trifluoromethylphenyl)propanal (II), a key intermediate for the preparation of I, is described. The protocol required a Mizoroki-Heck cross-coupling reaction between 1-bromo-3-(trifluoromethyl)benzene and acroleine diethyl acetal, catalyzed by Pd(OAc)2 in the presence of nBu4NOAc (tetrabutylammonium acetate), followed by the hydrogenation reaction of the crude mixture of products in a cascade process. Palladium species, at the end of the reaction, were efficiently recovered as Pd/Al2O3. The procedure was developed under conventional heating conditions as well as under microwave-assisted conditions. The obtained mixture of 1-(3,3-diethoxypropyl)-3-(trifluoromethyl)benzene (III), impure for ethyl 3-(3-trifluoromethylphenyl) propanoate (IV), was finally treated, under mild conditions, with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) to obtain after hydrolysis 3-(3-trifluoromethylphenyl)propanal (II), in an excellent overall yield and very high purity. Microwave conditions permitted a reduction in reaction times without affecting selectivity and yield. The final API was obtained through reductive amination of (II) with (R)-(+)-1-(1-naphthyl)ethylamine (V) using a catalyst prepared by us with a very low content of precious metal.

Observation of the efficacy of parathyroidectomy for secondary hyperparathyroidism in hemodialysis patients: a retrospective study

PurposeParathyroidectomy (PTX) is commonly performed as a treatment for secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease (ESRD). We aimed to evaluate the efficacy of PTX in patients with SHPT who underwent hemodialysis.MethodsThis retrospective study analyzed the clinical treatment of 80 hemodialysis patients with SHPT who underwent either total PTX with forearm auto transplantation (TPTX + AT) or subtotal parathyroidectomy (SPTX). We compared the changes in biochemical indices before and after surgery as well as the attenuation of intact parathyroid hormone (iPTH) in the TPTX and SPTX groups. We also evaluated clinical symptoms and quality of life using the Visual Analog Scale (VAS) and the Short Form-36 Questionnaire (SF-36) before and at 3, 6, and 12 months after surgery.ResultsSerum iPTH and serum phosphorus levels decreased significantly after surgery in 80 patients with SHPT (P < 0.05). Within one month of surgery, there was a difference in iPTH levels between the TPTX + AT and SPTH groups, but there was no difference over time. Patients experienced significant improvement in their clinical symptoms of restless leg syndrome, skin itching, bone pain, and joint pain at 1 week post operation (P < 0.001). Quality of life significantly improved after surgery, as assessed by SF-36 scores (P < 0.05). Hypocalcemia was the most common postoperative complication, occurring in 35% of patients. Within the first 12 months post surgery, 5 patients had a recurrence.ConclusionPTX is effective in rapidly reducing iPTH levels, improving calcium and phosphorus metabolism disorders, and enhancing patients’ quality of life by safely and effectively relieving clinical symptoms.

Pharmacological profile of upacicalcet, a novel positive allosteric modulator of calcium-sensing receptor, in vitro and in vivo

Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca2+) concentration without exhibiting an agonistic action when the extracellular Ca2+ level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca2+. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03–3mg/kg and 0.3–30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca2+ levels; however, the effect of upacicalcet on the reduction in serum Ca2+ disappeared at extracellular Ca2+ levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.

Treatment of Secondary Hyperparathyroidism and Posttransplant Tertiary Hyperparathyroidism

IntroductionSecondary hyperparathyroidism (sHPT) is prevalent in dialysis patients and can lead to tertiary hyperparathyroidism (tHPT) after kidney transplantation. We aimed to assess the association of pretransplant sHPT treatment on posttransplant outcomes. MethodsWe reviewed kidney transplant patients treated with parathyroidectomy or cinacalcet for sHPT. We compared patients biochemical and clinical parameters, and outcomes based on sHPT treatment. ResultsA total of 41 patients were included: 18 patients underwent parathyroidectomy and 23 patients received cinacalcet prior to transplantation. There were no significant differences between demographics, comorbidities, allograft characteristics or pre-sHPT intervention parathyroid hormone (PTH) and calcium levels. Patients that underwent parathyroidectomy were on dialysis for longer, although not significantly (71.9 versus 42.3 mo, P = 0.051). At time of transplantation, patients treated by parathyroidectomy had increased rates of controlled sHPT (88.9%; 16/18 versus 47.8%; 11/23, P = 0.008). Patients treated by parathyroidectomy had decreased development of tHPT (5.9%; 1/17; versus 42.1%; 8/19, P = 0.020) as well as decreased rates of posttransplant treatment with cinacalcet (11.1%; 2/18 versus 52.2%; 12/23, P = 0.008). Three patients treated with cinacalcet underwent parathyroidectomy after transplantation. Median PTH after transplant remained lower in patients treated by parathyroidectomy prior to transplant compared to those treated with cinacalcet (60.7 [interquartile range 39.7-133.4] versus 170.0 [interquartile range 128.4-292.7], P = 0.001). Allograft function and survival were similar for parathyroidectomy and cinacalcet, with median follow-up after transplantation of 56.7 and 34.2 mo, respectively. ConclusionssHPT treated by parathyroidectomy is associated with controlled PTH levels at transplantation and decreased rates of tHPT. Long-term outcomes should be studied on a larger scale.

Cinacalcet use in secondary hyperparathyroidism: a machine learning-based systematic review.

This study aimed to systematically review research on cinacalcet and secondary hyperparathyroidism (SHPT) using machine learning-based statistical analyses. Publications indexed in the Web of Science Core Collection database on Cinacalcet and SHPT published between 2000 and 2022 were retrieved. The R package "Bibliometrix," VOSviewer, CiteSpace, meta, and latent Dirichlet allocation (LDA) in Python were used to generate bibliometric and meta-analytical results. A total of 959 articles were included in our bibliometric analysis. In total, 3753 scholars from 54 countries contributed to this field of research. The United States, Japan, and China were found to be among the three most productive countries worldwide. Three Japanese institutions (Showa University, Tokai University, and Kobe University) published the most articles on Cinacalcet and SHPT. Fukagawa, M.; Chertow, G.M.; Goodman W.G. were the three authors who published the most articles in this field. Most articles were published in Nephrology Dialysis Transplantation, Kidney International, and Therapeutic Apheresis and Dialysis. Research on Cinacalcet and SHPT has mainly included three topics: 1) comparative effects of various treatments, 2) the safety and efficacy of cinacalcet, and 3) fibroblast growth factor-23 (FGF-23). Integrated treatments, cinacalcet use in pediatric chronic kidney disease, and new therapeutic targets are emerging research hotspots. Through a meta-analysis, we confirmed the effects of Cinacalcet on reducing serum PTH (SMD = -0.56, 95% CI = -0.76 to -0.37, p = 0.001) and calcium (SMD = -0.93, 95% CI = -1.21to -0.64, p = 0.001) and improving phosphate (SMD = 0.17, 95% CI = -0.33 to -0.01, p = 0.033) and calcium-phosphate product levels (SMD = -0.49, 95% CI = -0.71 to -0.28, p = 0.001); we found no difference in all-cause mortality (RR = 0.97, 95% CI = 0.90 to 1.05, p = 0.47), cardiovascular mortality (RR = 0.69, 95% CI = 0.36 to 1.31, p = 0.25), and parathyroidectomy (RR = 0.36, 95% CI = 0.09 to 1.35, p = 0.13) between the Cinacalcet and non-Cinacalcet users. Moreover, Cinacalcet was associated with an increased risk of nausea (RR = 2.29, 95% CI = 1.73 to 3.05, p = 0.001), hypocalcemia (RR = 4.05, 95% CI = 2.33 to 7.04, p = 0.001), and vomiting (RR = 1.90, 95% CI = 1.70 to 2.11, p = 0.001). The number of publications indexed to Cinacalcet and SHPT has increased rapidly over the past 22 years. Literature distribution, research topics, and emerging trends in publications on Cinacalcet and SHPT were analyzed using a machine learning-based bibliometric review. The findings of this meta-analysis provide valuable insights into the efficacy and safety of cinacalcet for the treatment of SHPT, which will be of interest to both clinical and researchers.

Multidisciplinary approach to patients with heart failure and kidney disease: preliminary experience of an integrated cardiorenal unit.

Cardiorenal programs have emerged to improve the management of cardiorenal disease (CRD). Evidence about the benefits of these programs is still scarce. This work aims to evaluate the performance of a novel cardiorenal program and describe the clinical profile and outcomes of patients with CRD. We conducted a retrospective observational study of patients with CRD attended in a cardiorenal unit (CRU) from February 2021 to February 2022. Demographics and laboratory tests were collected and events (all-cause death and cardiovascular hospitalizations) were evaluated. Optimization of comorbidities and protective therapies was also assessed. Eighty-two patients were included, with a mean age of 76.8years [standard deviation (SD) 8.5] and 72% were men. A total of 58.5% (n=47) had left ventricular ejection fraction <50%. The mean follow-up was 11months (SD 4.0). Almost 54% of the patients (n=44) required hospitalization, 30.5% for heart failure (HF) decompensation. Total hospitalizations significantly decreased after CRU inclusion: 0.70 versus 0.45 admissions/year (P<.02). Global mortality was 17.1% (n=14). The percentage of patients with HF with reduced ejection fraction on quadruple therapy increased by 20%, and up to 60% of the patients were on three drugs. A total of 39% of the patients with HF and preserved ejection fraction started treatment with sodium-glucose co-transporter inhibitors. Hyperkalaemia required the use of potassium binders in 12.2% of the patients and treatment of secondary hyperparathyroidism was started in 42.7% and renal anaemia in 23.2%. Renal replacement therapy was initiated in 10% of the patients (n=8). CRD confers a considerable risk of adverse outcomes. Cardiorenal programs may improve cardiorenal syndrome management by optimizing therapies, treating comorbidities and reducing hospitalizations.

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

Prevalence and current approaches to the treatment of secondary hyperparathyroidism and its complications in chronic kidney disease: a literature review

There is a universal trend towards increase of patients with chronic kidney disease by 7% on average. In the Russian Federation, the annual increase is even higher, at about 10%. The average age of patients receiving renal replacement therapy is 60 years in the Tomsk region and 56 years in Russia, which is relatively lower than in European countries and the United States. With increasing age of patients receiving dialysis treatment, a progressive increase in the incidence of secondary hyperparathyroidism is recorded. Mineral and bone disorders, hyperphosphatemia, hypercalcemia all lead to premature vascular calcification, increase the risk of cardiovascular complications and death. At the same time, elderly patients are characterized by an increase in risks immediately after the start of dialysis therapy. There is a global tendency towards increase in the target level of parathyroid hormone. Parathyroidectomy is recognized as a gold standard for treatment of drug-resistant hyperparathyroidism across the world. As the development of hyperplasia in the parathyroid glands does not proceed synchronously, instead progressing at different rates and in the selective glands, methods of local influence on the altered glands have recently been developed in order to gradually control secondary hyperparathyroidism. Alternative to the total parathyroidectomy are minimally invasive non-surgical methods, attractive due to a smaller number of complications, such as bleeding and paresis of the recurrent laryngeal nerve. Examples of minimally invasive methods are local injections of preparations of the active form of vitamin D, which lead to apoptosis of parathyroid gland cells instead of their destruction, and are safer in relation to surrounding tissues. This article presents current data on the prevalence of secondary hyperparathyroidism in chronic kidney disease. An analysis of clinical trials was carried out based on articles indexed in the Scopus database, the Russian Science Citation Index, PubMed and Web of Science.