Parathyroid Hormone: A Uremic Toxin.

Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]2D3). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]2D3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness.

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment.

The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade-off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca-sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.

Personalized Management of Bone and Mineral Disorders and Precision Medicine in End-Stage Kidney Disease.

Chronic kidney disease mineral bone disorder (CKD-MBD) is common in end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Mainstays of treatment include decreasing serum phosphorus level toward the normal range with dietary interventions and phosphate binders and treating increased parathyroid hormone levels with activated vitamin D and/or calcimimetics. There is significant variation in serum levels of mineral metabolism markers, intestinal absorption of phosphorus, and therapeutic response among individual patients and subgroups of patients with end-stage renal disease. This variation may be partly explained by polymorphisms in genes associated with calcium and phosphorus homeostasis such as the calcium-sensing receptor gene, the vitamin D-binding receptor gene, and genes associated with vascular calcification. In this review, we discuss how personalized medicine may be used for the management of CKD-MBD and how it ultimately may lead to improved clinical outcomes. Although genetic variants may seem attractive targets to tailor CKD-MBD therapy, complete understanding of how these polymorphisms function and their clinical utility and applicability to personalized medicine need to be determined.

Transcription factor MafB may play an important role in secondary hyperparathyroidism.

The transcription factor MafB is essential for development of the parathyroid glands, the expression of which persists after morphogenesis and in adult parathyroid glands. However, the function of MafB in adult parathyroid tissue is unclear. To investigate this, we induced chronic kidney disease (CKD) in wild-type and MafB heterozygote (MafB+/-) mice by feeding them an adenine-supplemented diet, leading to secondary hyperparathyroidism. The elevated serum creatinine and blood urea nitrogen levels in heterozygous and wild-type mice fed the adenine-supplemented diet were similar. Interestingly, secondary hyperparathyroidism, characterized by serum parathyroid hormone elevation and enlargement of parathyroid glands, was suppressed in MafB+/- mice fed the adenine-supplemented diet compared to similarly fed wild-type littermates. Quantitative RT-PCR and immunohistochemical analyses showed that the increased expression of parathyroid hormone and cyclin D2 in mice with CKD was suppressed in the parathyroid glands of heterozygous CKD mice. A reporter assay indicated that MafB directly regulated parathyroid hormone and cyclin D2 expression. To exclude an effect of a developmental anomaly in MafB+/- mice, we analyzed MafB tamoxifen-induced global knockout mice. Hypocalcemia-stimulated parathyroid hormone secretion was significantly impaired in MafB knockout mice. RNA-sequencing analysis indicated PTH, Gata3 and Gcm2 depletion in the parathyroid glands of MafB knockout mice. Thus, MafB appears to play an important role in secondary hyperparathyroidism by regulation of parathyroid hormone and cyclin D2 expression. Hence, MafB may represent a new therapeutic target in secondary hyperparathyroidism.

[Effect of cinacalcet combined with low-dose calcitriol on clinical outcome and bone metabolism in patients with severe secondary hyperparathyroidism].

OBJECTIVE: To observe the clinical outcome and the effect of the combination of cinacalcet hydrochloride with low-dose calcitriol on bone metabolism in maintenance hemodialysis (MHD) patients with severe secondary hyperparathyroidism (SHPT).
 Methods: Thirty SHPT patients were enrolled to receive treatment of cinacalcet combined with low-dose calcitriol, with inclusion criteria as follows: maintenance on MHD>6 months; serum intact parathyroid hormone (iPTH)>600 pg/mL; parathyroid glands with more than 1 nodules by ultrasonography; traditional therapy with no effects. All patients were given cinacalcet 25-75 mg and 0.5 µg calcitriol daily. Serum Ca, P, iPTH, bone metabolic markers and bone density were measured before and after treatment. The clinical symptoms and their changes were recorded.
 Results: The baseline levels of iPTH, Ca and P were (1787.3±1 321.0) pg/mL, (2.54±0.19) mmol/L, and (2.06±0.15) mmol/L, respectively. After 2 weeks of treatment, serum phosphorus decreased by 20%; after 1 and 3 months of treatment, iPTH decreased by 35% and 70%. Ca and P fell to (2.39±0.17) and (1.56±0.50) mmol/L (P<0.05), respectively. The symptoms of the patients relieved. The above indicators remained stable after 12 months. Moreover, after 6 months of treatment, the alkaline phosphatase, osteocalcin and ß-cross levels were decreased by 50%, 37% and 49%, respectively. The decline in patients' bone density was inhibited. No severe adverse events were observed.
 Conclusion: Cinacalcet hydrochloride combined with low dose calcitriol can improve high calcium, high phosphorus and high iPTH in MHD patients with severe SHPT, relieve symptoms, and improve bone metabolism. It can be used as a favorable choice for the treatment of SHPT.

Effects of parathyroidectomy on bone metabolism in haemodialysis patients with secondary hyperparathyroidism.

OBJECTIVE: To evaluate the outcome of bone metabolism and bone mineral density (BMD) in haemodialysis patients after parathyroidectomy (PTX). METHODS: A total of 31 haemodialysis patients with secondary hyperparathyroidism (SHPT) were treated with PTX. BMD of lumbar spine (LS) and femoral neck (FN) was determined by dual energy X-ray absorptiometry. RESULTS: Parathyroidectomy ledds to significant decrease of serum ß-crosslaps (ß-CTX), osteocalcin (OC) and procollagen type I amino-terminal propeptide (PINP) while serum sclerostin (SOST) increased after surgery. BMD was markedly improved in both LS and FN after PTX. Z-scores analysis further confirmed that PTX significantly benefited bone metabolism in haemodialysis patients, which well correlated with the improvement of serum iPTH and OC. CONCLUSIONS: Parathyroidectomy leads to significant improvement of serum OC, PINP, ß-CTX and SOST, which may beneficially modify calcium-phosphorus metabolism and BMD in haemodialysis patients with SHPT.

2MD (DP001), a Single Agent in the Management of Hemodialysis Patients: A Randomized Trial.

BACKGROUND: Vitamin D analogs and calcimimetics are used to manage secondary hyperparathyroidism (SHPT) in dialysis patients. DP001 is an oral vitamin D analog that suppresses parathyroid hormone (PTH) in uremic rats, osteopenic women, and hemodialysis patients. The safety and effectiveness of DP001 suppressing PTH in dialysis patients previously managed with active vitamin D with or without a calcimimetic are presented. METHODS: A multicenter, randomized, double-blind study compared DP001 to placebo in hemodialysis patients with serum-intact PTH (iPTH) ≥300 pg/ml. The primary efficacy endpoint was the proportion of patients achieving 2 consecutive ≥30% decreases in iPTH levels during the 12 weeks of treatment. Calcium, phosphorus, calcium × phosphorus product and safety were also evaluated. The responses to DP001 were compared in patients previously treated with both active vitamin D and a calcimimetic to those previously on active vitamin D alone. RESULTS: Sixty-two patients were randomized (n = 34 DP001; n = 28 placebo). At week 12, 78% of all DP001-treated patients and 7% of all placebo-treated patients achieved the primary endpoint (p < 0.0001); iPTH fell 45% in the DP001 group and increased 37% in the placebo group. No patient exceeded the safety threshold of 2 consecutively corrected serum calcium levels ≥11.0 mg/dl. Patients previously on cinacalcet plus active vitamin D also responded to DP001 (n = 10) resulting in a 55% decrease in iPTH, while those on placebo (n = 9) increased by 70%. CONCLUSION: DP001 safely and effectively suppressed iPTH in hemodialysis patients with SHPT that were previously managed with active vitamin D alone or with a calcimimetic (www.clinicaltrials.gov, NCT01922843).

Impact of obesity on bone metabolism. / Influencia de la obesidad sobre el metabolismo óseo.

High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention.

Calcium gluconate supplementation is effective to balance calcium homeostasis in patients with gastrectomy.

UNLABELLED: We demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice. INTRODUCTION: Gastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification. METHODS: Undecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b-/-) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism. RESULTS: Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p < 0.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6 months (p < 0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria. CONCLUSION: Gastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.

The uses and abuses of Vitamin D compounds in chronic kidney disease-mineral bone disease (CKD-MBD).

Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering.

Abnormal mineral metabolism and mortality in hemodialysis patients with secondary hyperparathyroidism: evidence from marginal structural models used to adjust for time-dependent confounding.

BACKGROUND: Hemodialysis patients with mineral and bone disorders (MBDs) have an abnormally high relative risk of death, but their absolute risk of death is unknown. Further, previous studies have not accounted for possible time-dependent confounding of the association between MBD markers and death due to the effect of markers of MBD on treatments, which subsequently may affect MBD markers. STUDY DESIGN: Multicenter, 3-year, prospective, case-cohort study. SETTING & PARTICIPANTS: 8,229 hemodialysis patients with secondary hyperparathyroidism (parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators) at 86 facilities in Japan. PREDICTORS: Serum phosphorus, calcium, and parathyroid hormone levels. OUTCOME: All-cause mortality. MEASUREMENTS: Marginal structural models were used to compute absolute differences in all-cause mortality associated with different levels of predictors while accounting for time-dependent confounding. RESULTS: The association between phosphorus level and mortality appeared U-shaped, although only higher phosphorus level categories reached statistical significance: compared to those with phosphorus levels of 5.0-5.9 mg/dL (1.61-1.93 mmol/L), patients with the highest (≥9.0 mg/dL [≥2.90 mmol/L]) phosphorus levels had 9.4 excess deaths/100 person-years (rate ratio, 2.79 [95% CI, 1.26-6.15]), whereas no association was found for the lowest phosphorus category (<3.0 mg/dL [<0.97 mmol/L]; rate ratio, 1.54 [95% CI, 0.87-2.71]). Similarly, hypercalcemia (≥10.0 mg/dL [≥2.50 mmol/L]) was associated with excess deaths, and the highest level of hypercalcemia (≥11.0 mg/dL [≥2.75 mmol/L]) was associated with 5.8 excess deaths/100 person-years (rate ratio, 2.38 [95% CI, 1.77-3.21]) compared to those with levels of 9.0-9.4 mg/dL (2.25-2.37 mmol/L). Abnormally high parathyroid hormone levels were not associated with excess deaths. LIMITATIONS: Possible residual confounding. CONCLUSIONS: These results reinforce the idea that serum calcium (in addition to phosphorus) level is an important predictor of the absolute risk of death in hemodialysis patients with secondary hyperparathyroidism.

Klotho and chronic kidney disease.

Through alternative splicing, Klotho protein exists both as a secreted and a membrane form whose extracellular domain could be shed from the cell surface by secretases and released into the circulation to act as endocrine factor. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23) to modulate FGF23 signal transduction, soluble Klotho is a multifunction protein present in the biological fluids including blood, urine and cerebrospinal fluid and plays important roles in antiaging, energy metabolism, inhibition of Wnt signaling, antioxidation, modulation of ion transport, control of parathyroid hormone and 1,25(OH)2VD3 production, and antagonism of renin-angiotensin-aldosterone system. Emerging evidence from clinical and basic studies reveal that chronic kidney disease is a state of endocrine and renal Klotho deficiency, which may serve as an early biomarker and a pathogenic contributor to chronic progression and complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. Supplementation of exogenous Klotho and/or upregulation of endogenous Klotho production by using rennin angiotensin system inhibitors, HMG CoA reductase inhibitors, vitamin D analogues, peroxisome proliferator-activated receptors-gamma agonists, or anti-oxidants may confer renoprotection from oxidation and suppression of renal fibrosis, and also on prevention or alleviation of complications in chronic kidney disease. Therefore, Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.

The efficacy of cinacalcet combined with conventional therapy on bone and mineral metabolism in dialysis patients with secondary hyperparathyroidism: a meta-analysis.

Cinacalcet, the first calcimimetic to be approved for the treatment of secondary hyperparathyroidism (SHPT) in the chronic kidney disease patients, offers a novel therapeutic approach to SHPT. The aim of this meta-analysis is to access the efficacy and safety of cinacalcet on bone and mineral metabolism disorders in the dialysis patients with SHPT. Randomized controlled trials on cinacalcet combined with vitamin D and/or phosphate binders in the dialysis patients with SHPT were identified in Pubmed, Sciencedirect, and the Cochrane library. Data were analyzed with RevMan software. We compared the proportion of patients achieving the biochemical targets recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and the incidence of adverse events between the cinacalcet and control groups. Six trials involving 2,548 patients were included. A greater proportion of patients in the cinacalcet group compared with the conventional group achieved the KDOQI targets. The relative risks (RRs) were parathyroid hormone (PTH) (RR = 3.51, 95 % CI: 2.38-5.17), calcium (RR = 2.04, 95 % CI: 1.76-2.37), phosphorus (RR = 1.15, 95 % CI: 0.83-1.60), and calcium-phosphorus product (Ca × P) (RR = 1.41, 95 % CI: 1.18-1.69), the number of patients simultaneously achieving the KDOQI targets for PTH + Ca × P was also greater (RR = 3.89, 95 % CI: 2.36-6.41), with p < 0.001 for each. The most common adverse events were nausea, vomiting, diarrhea, and hypocalcemia, which had a higher incidence in the cinacalcet group, but were usually mild to moderate in severity and transient. Compared with conventional therapy, treatment with cinacalcet results in more patients achieving KDOQI targets and offers an effective and safety therapeutic option for controlling mineral and bone disorders in the dialysis patients with SHPT.

Contribution of calcium, phosphorus and 25-hydroxyvitamin D to the excessive severity of secondary hyperparathyroidism in African-Americans with CKD.

BACKGROUND: Parathyroid hormone (PTH) levels in African-American (AA) chronic kidney disease (CKD) patients exceed those in patients of other races; mechanisms are unknown. METHODS: We performed a cross-sectional analysis of initial laboratory data collected on 2028 CKD patients (505 AA) from US practices using a laboratory CKD service. Serum calcium (Ca), phosphorus (P), 25-hydroxyvitamin D (25-D) and plasma PTH levels were compared between the two groups. RESULTS: Mean PTH for AA exceeded PTH for non-AA in Stages 2-5 (P<0.001, all four stages). 25-D levels were higher for non-AA in Stages 1-3 (P<0.001). Serum Ca and P did not differ between groups at any stage. Full adjustment for these variables using multivariable generalized linear modeling did not remove the effect of AA race: AA PTH values exceeded non-AA values in CKD Stages 2-5 (P<0.02, all four stages). Serum Ca, P and 25-D were all inversely correlated with PTH levels irrespective of race, but all factors combined accounted for ∼42% of the variance in PTH. CONCLUSIONS: PTH rises with progressive CKD stage far more in AA than in non-AA patients, and only a moderate component of the rise in PTH is explained by changes in serum Ca, P and 25-D in either group. These findings concur with those from other large CKD cohorts and support the need for further study to determine other factors responsible for this racial difference.

Parathyroidectomy for the attainment of NKF-K/DOQI™ and KDIGO recommended values for bone and mineral metabolism in dialysis patients with uncontrollable secondary hyperparathyroidism.

PURPOSE: The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI™) 2003 and Kidney Disease: Improving Global Outcomes (KDIGO) 2009 have established guidelines for the treatement of secondary hyperparathyroidism. This study evaluated the impact of parathyroidectomy to achieve recommended values for parathyroid hormone, calcium, phosphorus and CaxPO(4) product in dialysis patients with severe secondary hyperparathyroidism that is resistant to medical treatment. METHODS: This study included 43 consecutive patients who underwent parathyroidectomy for a severe form of secondary hyperparathyroidism (SHPT) that is unresponsive to medical treatment. The serum iPTH, calcium and phosphorus levels were measured prior to surgery, every morning after surgery for 5 days and on the first, sixth and eighth postoperative months. RESULTS: Following parathyroidectomy, a significant decline in iPTH values was observed in all patients; however, after the 8-month study period, only one of these patients achieved a serum iPTH concentration within the K/DOQI recommended target range. Unlike iPTH, targeting for calcium, phosphorus and CaxPO(4) at the last follow-up were 55.8%, 60.5% and 93%, respectively. These values indicated a significant improvement in comparison to preoperative percentages. In regards to the KDIGO recommended guidelines, the iPTH levels did not significantly change at the end of our study compared to preoperative values; however, calcium levels significantly declined and phosphorus levels significantly improved compared to preoperative values. CONCLUSIONS: Although the majority of patients fail to reach recommended iPTH values, parathyroidectomy remains a valuable tool to attain these NKF-K/DOQI recommendations for serum calcium, phosphorus and CaxPO(4) in dialysis patients with secondary hyperparathyroidism resistant to medical therapy. Parathyroidectomy was shown to be an inadequate intervention for achieving KDIGO recommendations.

A mathematical model of calcium and phosphorus metabolism in two forms of hyperparathyroidism.

Parathyroid hormone (PTH) plays a critical role in calcium and phosphorus metabolism. Interestingly, in two forms of hyperparathyroidism (excessive amount of PTH in the serum), the metabolic disturbances in patients with chronic kidney disease (CKD) significantly differ from those with primary hyperparathyroidism (PHP). Since an intuitive understanding of these PTH-linked regulatory mechanisms are hardly possible, we developed a mathematical model using clinical data (1586 CKD and 40 PHP patients). The model was composed of a set of ordinary differential equations, in which the regulatory mechanism of PTH together with other key factors such as 1,25-Dihydroxyvitamin D (1,25(OH)2D) and calcium was described in the tissues including bone, the kidney, the serum, and the parathyroid glands. In this model, an increase in PTH was induced by its autonomous production in PHP, while PTH in CKD was elevated by a decrease in feedback inhibition of 1,25(OH)2D in the serum, as well as an increase in stimulation by phosphorus in the serum. The model-based analysis revealed characteristic differences in the outcomes of hyperparathyroidism in CKD and PHP. The calcium exchange in bone, for instance, was predicted significantly higher in PHP than CKD. Furthermore, we evaluated the observed and predicted responses to the administration of calcimimetics, a recently developed synthetic drug that modulated efficacy of calcium-sensing receptors. The results herein support the notion that the described model would enable us to pose testable hypotheses about the actions of PTH, providing a quantitative analytical tool for evaluating treatment strategies of PHP and CKD.

Efficacy and safety of cinacalcet for the treatment of secondary hyperparathyroidism in patients with advanced chronic kidney disease before initiation of regular dialysis.

AIM: To evaluate the compassionate use of cinacalcet for the management of secondary hyperparathyroidism in patients who are not on dialysis. METHODS: Patients with stage 4-5 chronic kidney disease (CKD) who were not on dialysis, had an intact parathyroid hormone (iPTH) level greater than 300 pg/mL, and had not responded satisfactorily to treatment with phosphate binders and vitamin D were prospectively studied. Patients received 6 months of compassionate treatment with cinacalcet, which was initiated at a dose of 30 mg/day orally and flexibly dosed thereafter based on iPTH levels. RESULTS: Twenty-six patients with a mean age±standard deviation (SD) of 58.8±16.1 years were enrolled in the study and included in the statistical analysis. The mean percentage change in iPTH levels from baseline after 6 months of treatment was -67.9±17.0%, with 92.3% (95% confidence interval (CI), 75.9-97.9) of patients showing an iPTH level within the limits recommended by Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. The mean serum calcium concentrations had decreased significantly at the end of the study (-8.0±6.9%), while the mean serum phosphorus concentration had significantly increased (+8.3±17.0%). CONCLUSION: Our results suggest that cinacalcet may be a useful alternative for the treatment of secondary hyperparathyroidism in pre-dialysis patients who are unresponsive to other treatments. The hypocalcemia and hyperphosphatemia reported in previous studies may not occur if a moderate dose of calcimimetics is used in patients with marginal glomerular filtration rates, especially if combined with vitamin D analogues and calcium-based phosphate binders.

Exposure-clinical response analysis of paricalcitol in patients with chronic kidney disease (stage 5) on hemodialysis or peritoneal dialysis.

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

The surgical management of renal hyperparathyroidism.

Secondary and tertiary hyperparathyroidism (HPT) develop in patients with renal failure due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1,25-dihydroxy vitamin D levels. Patients present with various bone disorders, cardiovascular disease, and typical laboratory abnormalities. Medical treatment consists of controlling hyperphosphatemia, vitamin D/analog and calcium administration, and calcimimetic agents. Improved medical therapies have led to a decrease in the use of parathyroidectomy (PTX). The surgical indications include parathyroid hormone (PTH) levels >800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Transplant recipients often show decreased PTH, calcium and phosphorus levels, but some will have persistent HPT. Evidence suggests that PTX may cause deterioration in renal graft function in the short-term calling into the question the indications for PTX in these patients. Pre-operative imaging is only occasionally helpful except in re-operative PTX. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages and disadvantages which are discussed. Intraoperative PTH monitoring has a high positive predictive value of cure but a poor negative predictive value and therefore is of limited utility. Hypocalcemia is the most common complication requiring aggressive calcium administration. Benefits of surgery may include improved survival, bone mineral density and alleviation of symptoms.

Chronic kidney disease--mineral and bone disorder: a complex scenario.

The chronic kidney disease-bone and mineral disorders (CKD-MBD) represents a dinamic area of research. Recently, new factors such as FGF-23 have been added to the classic list of regulators of bone metabolism, which include calcium, phosphorus, PTH and calcitriol. Vascular calcification, one of the most important complication of CKD-MBD is regulated by a complex variety of  promoters and inhibitors. The relationship between vascular calcification, bone loss and mortality, together with the existence of likely common signaling pathways are subject of interesting investigations.