Early vs late initiation of sodium glycerophosphate: Impact on hypophosphatemia in preterm infants <32 weeks.

BACKGROUND & AIMS: Early electrolyte and mineral imbalances have emerged as a conspicuous problem in very preterm babies since the revision of nutrition guidelines and the eventual implementation of early aggressive parenteral nutrition (PN). We opted to carry out a study with the introduction of phosphorus as sodium glycerophosphate in PN from the first day onward to reveal the impact on serum phosphorus and calcium levels following the surge in the incidence of hypercalcemia and hypophosphatemia. METHODS: In this single-center, prospective, observational cohort study, inborn babies <32 gestational weeks and <1500 g between August 2017 and July 2018 were enrolled consecutively. Infants born in the first 6-month of this period were initiated PN (Early phosphorus group) containing phosphorus (1 mmol P as sodium glycerophosphate/100 ml PN) immediately after birth, and in the latter six-months, mineral-free standard PN (Control group) was commenced up until 48 h of life. Parenteral nutritional prescriptions of both groups were similar in terms of macro and micronutrient intakes except for early phosphorus, calcium, and sodium. Serum mineral and electrolyte levels were measured on Days 1-3-7 and compared between the groups. The primary outcome was the presence of hypophosphatemia in the first week of life. The secondary outcome was hypercalcemia, preterm morbidity, and mortality. RESULTS: A total of 261 infants were included in this study. There were 130 babies in Early phosphorus group and 131 in control group. Gestational ages (28.79 ± 2.1 vs 28.46 ± 2.2 weeks, respectively) and birth weights (1138 ± 273 vs 1090 ± 274 g, respectively) were similar in the groups. Mean serum phosphorus levels were higher on all days in Early phosphorus group (p < 0.001). Early phosphorus group had a lower incidence of hypophosphatemia on days 1-3 and 7 (p < 0.001). The percentage of hypercalcemic infants was significantly lower in Early phosphorus group on day 3 (p < 0.001). No difference was noted in terms of hypernatremia in the groups. CONCLUSIONS: Adding phosphorus to PN in the first hours of life reduced the frequency of hypophosphatemia and hypercalcemia without any surge in hypernatremia or morbidity. Nutrition guidelines need to be revised accordingly in terms of early mineral/electrolyte supplementation.

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis. Methods: Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations. Recommendations: The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

Severe hypercalcaemia and hypophosphataemia with an optimised preterm parenteral nutrition formulation in two epochs of differing phosphate supplementation.

OBJECTIVE: To compare in two epochs of differing phosphate provision serum calcium, phosphate, potassium, and sodium concentrations and the frequency of abnormality of these electrolytes and of sepsis in preterm infants who received an optimised higher amino acid-content formulation. DESIGN AND SETTING: Retrospective cohort study at a single tertiary-level neonatal unit. PATIENTS: Preterm infants given parenteral nutrition (PN) in the first postnatal week during two discrete 6-month epochs in 2013-2014. INTERVENTIONS: In epoch 1 the Ca2+:PO4 molar ratio of the PN formulation was ~1.3-1.5:1 (1.7 mmol Ca2+ and 1.1 mmol PO4 per 100 mL aqueous phase) and in epoch 2 was 1.0:1 via extra phosphate supplementation (1.7 mmol Ca2+ and 1.7 mmol PO4 per 100 mL). MAIN OUTCOME MEASURES: Peak calcium and nadir phosphate and potassium concentrations, and proportions with severe hypercalcaemia (Ca2+ >3.0 mmol/L), hypophosphataemia (PO4<1.5 mmol/L), and hypokalaemia (K+ <3.5 mmol/L) within the first postnatal week. RESULTS: In epoch 2, peak calcium concentrations were lower than in epoch 1 (geometric means: 2.83 mmol/L vs 3.09 mmol/L, p value<0.0001), fewer babies were severely hypercalcaemic (10/49, 20%, vs 31/51, 61%, p value<0.0001); nadir plasma phosphate concentrations were higher (means: 1.54 mmol/L vs 1.32 mmol/L, p value=0.006), and there were fewer cases of hypophosphataemia (17/49, 35% vs 31/51, 61%, p value=0.009) and hypokalaemia (12/49, 25% vs 23/51, 45%, p value=0.03). CONCLUSIONS: Reverting from a PN Ca2+:PO4 molar ratio of 1.3-1.5:1 to a ratio of 1.0:1 was associated with a lower incidence and severity of hypophosphataemia and hypercalcaemia. For preterm infants given higher concentrations of amino acids (≥2.5 g/kg/day) from postnatal day 1, an equimolar Ca2+:PO4 ratio may be preferable during the first postnatal week.

Rapid progression of vascular and soft tissue calcification while being managed for severe and persistent hypocalcemia induced by denosumab treatment in a patient with multiple myeloma and chronic kidney disease.

We herein present the case of a patient with myeloma and chronic kidney disease (CKD) who developed rapidly progressive vascular and soft tissue calcification during the course of treatment for severe hypocalcemia induced by the administration of denosumab for myeloma and hypercalcemia. Because a large amount of supplementation with active vitamin D and calcium was required to correct the severe hypocalcemia, rapidly progressive vascular calcification developed. Seeing that patients with CKD are prone to developing severe and prolonged hypocalcemia after denosumab treatment, physicians should closely monitor the patients' serum calcium levels and manage their hypocalcemia appropriately so as to avoid the development of significant ectopic calcification.

Effect of lanthanum carbonate versus calcium-based phosphate binders in dialysis patients: a meta-analysis.

BACKGROUND: The effects of lanthanum carbonate (LC) vs. calciumbased phosphate binders in dialysis patients have been a matter of debate. METHODS: We electronically searched PubMed, Embase, CENTRAL, and CBM for all randomized controlled trials comparing LC with calcium-based phosphate binders in adult dialysis patients. Quality assessment was performed using the Cochrane risk of bias tool. Metaanalysis was conducted by RevMan 5.2. RESULTS: Nine studies were eligible for our meta-analysis. There was no significant difference in all-cause mortality (RR 0.84, 95% CI 0.25 - 2.83) and cardiovascular events (RR 0.84, 95% CI 0.55 - 1.29) between LC and calcium-based phosphate binders. LC was associated with similar proportions of phosphate-controlled patients (RR 0.63, 95% CI 0.27 - 1.44) and lower incidence of hypercalcemia (RR 0.13, 95% CI 0.05 - 0.35) in comparison to calcium-based phosphate binders. Compared with calcium salts, LC was associated with significantly lower serum calcium, similar serum Ca x P product and higher serum iPTH. CONCLUSION: Despite the trends observed, we found no statistically significant differences in all-cause mortality and cardiovascular events between LC and calcium-based phosphate binders in dialysis patients. The conclusion was limited by lack of large sample and long-term trials. LC could reduce the incidence of hypercalcemia while comparable with calcium-based phosphate binders in reducing serum phosphorus level.

Combination of oral vitamin D3 with photodynamic therapy enhances tumor cell death in a murine model of cutaneous squamous cell carcinoma.

Photodynamic therapy (PDT), in which 5-ALA (a precursor for protoporphyrin IX, PpIX) is administered prior to exposure to light, is a nonscarring treatment for skin cancers. However, for deep tumors, ALA-PDT is not always effective due to inadequate production of PpIX. We previously developed and reported a combination approach in which the active form of vitamin D3 (calcitriol) is given systemically prior to PDT to improve PpIX accumulation and to enhance PDT-induced tumor cell death; calcitriol, however, poses a risk of hypercalcemia. Here, we tested a possible strategy to circumvent the problem of hypercalcemia by substituting natural dietary vitamin D3 (cholecalciferol; D3 ) for calcitriol. Oral D3 supplementation (10 days of a 10-fold elevated D3 diet) enhanced PpIX levels 3- to 4-fold, and PDT-mediated cell death 20-fold, in subcutaneous A431 tumors. PpIX levels and cell viability in normal tissues were not affected. Hydroxylated metabolic forms of D3 were only modestly elevated in serum, indicating minimal hypercalcemic risk. These results show that brief oral administration of cholecalciferol can serve as a safe neoadjuvant to ALA-PDT. We suggest a clinical study, using oral vitamin D3 prior to PDT, should be considered to evaluate this promising new approach to treating human skin cancer.

Comparative efficacy and safety of different doses of ergocalciferol supplementation in patients with metabolic syndrome.

BACKGROUND: Vitamin D deficiency is a common problem worldwide. Several studies have shown an association between vitamin D deficiency and the increased risk of metabolic syndrome. No previous study has compared the efficacy and safety of ergocalciferol at 40,000 versus 20,000 IU/week in patients with metabolic syndrome. OBJECTIVE: To evaluate the efficacy of ergocalciferol supplementation on serum 25-hydroxyvitamin D [25(OH)D] concentrations and to examine safety parameters in metabolic syndrome patients. SETTING: Outpatient department of Phramongkutklao Hospital, Bangkok, Thailand. METHOD: A randomized, double-blinded, parallel study was conducted in metabolic syndrome patients with vitamin D deficiency [25(OH)D <20 ng/mL]. Ninety patients were randomly assigned into three groups of 30 patients each. Group 1 was given two capsules of placebo/week, group 2 was given ergocalciferol 20,000 IU/week, and group 3 was given ergocalciferol 40,000 IU/week for 8 weeks. MAIN OUTCOME MEASURE: serum 25(OH)D concentrations, serum calcium, safety, and corrected QT (QTc) interval. RESULTS: Of the 90 patients enrolled, 84 patients completed the study. At the end of the study, the mean serum 25(OH)D in groups 2 and 3 significantly increased from the baseline (15.1 and 14.3 to 26.8 and 30.0 ng/mL, respectively). The increase in serum 25(OH)D in groups 2 and 3 were comparable and significantly greater than that of the placebo group. The percentage number of patients achieving normal vitamin D levels in groups 1, 2 and 3 were 3.3, 33.3, and 60.0 %, respectively, which were significantly different between groups (p < 0.001). Adverse reactions in both ergocalciferol treatment groups were not different from the placebo group (p > 0.05). Serum calcium levels did not change within and between groups of treatment. No significant change in QTc was observed in any patient. CONCLUSIONS: Both 20,000 and 40,000 IU/week of ergocalciferol supplementation for 8 weeks were able to increase serum 25(OH)D concentrations significantly. However, more patients in the ergocalciferol 40,000 IU/week treatment group achieved a normal serum 25(OH)D level than in the group which received 20,000 IU/week. Clinicians would have informed of choosing the dosing regimen of ergocalciferol in metabolic syndrome patients.

Calcium and vitamin D in sarcoidosis: is supplementation safe?

Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.

Humoral hypercalcemia caused by uterine corpus carcinosarcoma consisting of squamous cell carcinoma in its epithelial component.

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome primarily caused by a tumor-producing parathyroid hormone-related protein (PTH-rP). We describe the first reported case of a uterine carcinosarcoma causing HHM. A 70-year-old patient was transferred to our hospital for a uterine tumor accompanied by impaired consciousness. The laboratory tests indicated anemia, malnutrition, elevated serum calcium and elevated PTH-rP. Emergency surgery, including abdominal hysterectomy and bilateral salpingo-oophorectomy, was performed due to uncontrollable uterine bleeding. The pathological diagnosis was carcinosarcoma consisting of pure squamous cell carcinoma in its epithelial component. Postoperatively, chemotherapy with paclitaxel and carboplatin was performed. The patient had recurrent tumors at the para-aortic lymph nodes 11 months after the initial surgery and underwent a pelvic and para-aortic lymphadenectomy, which removed all of the recurrent tumors.

Effect of lanthanum carbonate vs. calcium carbonate on serum calcium in hemodialysis patients: a crossover study.

BACKGROUND: Lanthanum carbonate (LC) is a non-calcium-containing phosphate binder and shows a comparable effect with other phosphate binders on hyperphosphatemia in dialysis patients. LC also contributes to a reduced oral calcium load compared with calcium carbonate (CaC) treatment. However, no crossover studies which compare the influence on serum calcium level between treatments with LC and CaC in hemodialysis (HD) patients have been carried out. METHODS: After washout for 2 weeks, 50 patients on HD were randomized (1 : 1) to receive LC or CaC for 3 months. Thereafter, patients underwent a second 2-week washout period and were switched to the alternative binder for the next 3 months. Mineral and bone metabolism markers were measured with the changes of vitamin D doses. RESULTS: The serum phosphate level showed a similar decrease from baseline to 3 months in both groups. During the study periods, hypercalcemia was observed only in patients taking CaC. The dose of vitamin D analogue was increased more frequently in the patients of the LC group compared with LC group. The iPTH level showed a significant decrease in the CaC group, but not in the LC group. Serum levels of BAP, TRAP5b, and ALP were significantly elevated in the LC group, whereas the FGF-23 level showed a significant decrease. CONCLUSION: LC effectively reduced the serum phosphate level (like CaC) and allowed the vitamin D analogue dosage to be increased without hypercalcemia in HD patients. LC is one of the useful phosphate binders without hypercalcemia. (UMIN-CTR registration number: UMIN000002331).

[Vitamin D for prevention of diseases?]. / Vitamin D zur Prävention von Erkrankungen?

Vitamin D3 shows a multitude of possible preventive effects in various diseases. Calcitriol, the biologically active form of vitamin D3, affects not only bone metabolism but also acts on the renal renin secretion, the pancreatic insulin production in the beta cells, growth and proliferation of smooth and cardiac muscle cells and the function of lymphocytes and macrophages. Although the human body can synthesise vitamin D3 itself, vitamin D deficiency is common in the German population. Numerous trials studied the association between vitamin D deficiency and different diseases. It is known that even mild forms of vitamin D deficiency increase the risk for cardiovascular diseases or diabetes mellitus. Furthermore, an association with cancer such as pancreatic or colorectal cancer was observed. This is attributed to the influence of vitamin D on cell differentiation, angiogenesis, DNA repair mechanisms and the transcription of numerous genes. In addition, effects of vitamin D deficiency in diseases such as Parkinson's disease, multiple sclerosis and autoimmune diseases are discussed. However, up to now the level of evidence of all these observations is low. There are missing confirmatory randomized controlled trials. Noting the possible preventive effects of vitamin D, a moderate exposure to sunlight to increase vitamin D synthesis can be recommended. Even a controlled supplementation of vitamin D in patients with vitamin D deficiency is considered as reasonable. However, an uncritical substitution of high-dose vitamin D should be avoided because of the risk of hypercalcaemia.

Effectiveness of treatment with oral paricalcitol in patients with pre-dialysis chronic kidney disease.

PURPOSE: Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease. Treatment with paricalcitol, a selective vitamin D receptor (VDR) activator, has shown benefits in these patients by adequately reducing PTH levels with minimal changes in serum calcium and phosphorus. The aim of this study was to assess the effectiveness and safety of paricalcitol in chronic renal disease patients (CKD grades 3 and 4). METHODS: A study of our experience with paricalcitol was conducted in normal clinical practice in patients over 18 years diagnosed with grade 3 or 4 chronic kidney disease. Patients were periodically evaluated every 3 months. The primary endpoint of effectiveness was to obtain two consecutive decreases of ≥30% in iPTH with respect to baseline values. The secondary endpoints were fulfilment of the objectives in accordance with the Spanish Society of Nephrology (SEN) and Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, as well as the relationship between the effectiveness of the treatment and different patient variables. Safety was studied by means of hypercalcaemia events. RESULTS: The primary study endpoint was achieved in 54.3% of patients. In addition, another 16.3% of patients had reduced iPTH by more than 30% at the 3rd visit. Therefore, 70.6% of patients reduced their iPTH levels by more than 30% in 6 months. The relationship between treatment success and both glomerular filtration rate and body mass index was significant. There were few adverse events, although hypercalcaemia was found in 5.4% of patients. CONCLUSIONS: Treatment with paricalcitol is effective in controlling secondary hyperparathyroidism in non-dialysed patients with a wide safety margin.

Effectiveness and cost-efficacy of phosphate binders in hemodialysis.

OBJECTIVES: Worldwide, incidence rates of chronic renal insufficiency have clearly increased over the past decade, especially in people of older age. Hyperphosphatemia is the strongest independent risk factor for mortality in renal patients. In order to reduce serum phosphate concentrations to recommended values, phosphate binders (P binders) are used to bind ingested phosphate in the digestive tract. Besides the traditional therapies with calcium and aluminium salts, sevelamer and lanthanum represent recent developments on the market. The purpose of the present health technology assessment (HTA) report was to compare the effectiveness and safety of different P binders in patients with chronic renal insufficiency. METHODS: Based on a systematic literature search followed by a two-part selection process with predefined criteria 18 publications were included in the assessment. RESULTS: All P binders effectively controlled serum phosphate, calcium and parathyroid hormone concentrations. The numbers of hypercalcemic episodes were higher when using calcium-containing P binders compared to sevelamer and lanthanum. Regarding mortality rate, cardiovascular calcification and bone metabolism no definite conclusions could be drawn; however, sevelamer seemed to be more effective than calcium in certain patient subgroups, such as older patients and patients with preexisting arterial calcification. CONCLUSIONS: From a medical point of view, sevelamer showed superiority over calcium-containing P binders at least for special indications.

1α,24(S)(OH)2D2 normalizes bone morphology and serum parathyroid hormone without hypercalcemia in 25-hydroxyvitamin D-1-hydroxylase (CYP27B1)-deficient mice, an animal model of vitamin D deficiency with secondary hyperparathyroidism.

BACKGROUND: Vitamin D compounds are effective in managing elevated PTH levels in secondary hyperparathyroidism (SHPT) of renal failure. However, undesired increases in serum calcium and phosphorus associated with compounds such as calcitriol [1,25(OH)2D3] has prompted a search for compounds with improved safety profiles. 1alpha,24(S)(OH)2D2 (1,24(OH)2D2) is a vitamin D2 metabolite with low calcium-mo bilizing activity in vivo. We studied the efficacy of 1,24(OH)2D2 in mice lacking the CYP27B1 enzyme [25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase)], a novel vitamin D deficiency model with SHPT. MATERIALS AND METHODS: 1alpha-OHase-deficient (-/-) mice and normal (+/-) heterozygous littermates re ceived 1,24(OH)2D2 (100, 300, 1000, and 3000 pg/g/day) or 1,25(OH)2D3 (30, 300, and 500 pg/g/day) for 5 weeks via daily sc injection. Control groups received vehicle. RESULTS: Vehicle-treated 1alpha-OHase-deficient mice were hypocalcemic and had greatly elevated serum PTH. 1,24(OH)2D2 at doses above 300 pg/g/day normalized serum calcium, serum PTH, bone growth plate morphology, and other bone parameters. No hy percalcemia was observed at any dose of 1,24(OH)2D2 in normal or 1alpha-OHase-deficient animals. In contrast, 1,25(OH)2D3 at only 30 pg/g/day normalized calcemia, serum PTH, and bone parameters, but at higher doses completely suppressed PTH and caused hypercalcemia in both 1alpha-OHase-deficient and normal mice. Treatment with 500 pg/g/day of 1,25(OH)2D3 also induced osteomalacia in normal animals. CONCLUSION: 1,25(OH)2D3 was maximally active at 10-fold lower doses than 1,24(OH)2D2, but induced hypercalcemia and osteomalacia at high doses. 1,24(OH)2D2 normalized serum calcium, serum PTH, and bone histomorphometry without hypercalcemia in 1alpha-OHase-deficient mice with SHPT.

Calcium requirements after parathyroidectomy in patients with refractory secondary hyperparathyroidism.

BACKGROUND/AIMS: Calcium supplements are often required following successful parathyroidectomy (PTX) in order to prevent overt hypocalcemia. The current study aims to quantify these calcium needs and to identify predictors of a high calcium need present at the time of surgery. METHODS: Charts of 42 patients with chronic kidney disease stage 5D, who underwent a successful subtotal PTX, were reviewed in detail. Biochemical indices of mineral metabolism available within a time frame of 4 weeks before and 6 weeks after the surgery were registered. Details concerning active vitamin D (1-alpha-calcidiol and calcitriol) and calcium supplementation were recorded as well. RESULTS: Serum calcium, phosphorus and PTH levels declined whereas total alkaline phosphatase levels increased significantly in the early post-PTX period. Transient hypocalcemia was observed in 83% of the patients. The median daily postoperative elemental calcium requirements amounted to 3.2 g during week 1, and declined to 2.4 g during week 6. A high preoperative PTH level and a low serum calcium level were identified as independent predictors of a high postoperative calcium need. CONCLUSION: Substantial amounts of elemental calcium are required following successful subtotal PTX in order to avoid frank hypocalcemia, especially in patients with a high PTH level and a low calcium level before surgery.