Spurious Hyperphosphatemia in a Patient with Chronic Kidney Disease - a Rare Case of Alteplase Contamination.

Spurious hyperphosphatemia, a rare occurrence, typically arises from substances in a patient's blood interfering with the colorimetric method for serum phosphate measurement. We present a case of factitious hyperphosphatemia caused by alteplase-contaminated blood samples in an 88-year-old CKD patient on hemodialysis, leading to misleadingly high phosphorus levels. Thorough investigations ruled out other etiologies, highlighting the necessity of stringent adherence to blood collection protocols to prevent sample contamination and avert erroneous laboratory results. This unique cause of hyperphosphatemia should be considered in the differential diagnosis when encountering unexplained elevations in phosphorus levels, particularly in the context of normal blood calcium levels.

Reducing the risk of denosumab-induced hypocalcemia in patients with advanced chronic kidney disease: a quality improvement initiative.

Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision of denosumab in advanced CKD that reduced the risk of hypocalcemia by 37% at our hospital. Similar pathways could be adopted and tested in other centers. PURPOSE: There is an increased risk of hypocalcemia with denosumab in advanced chronic kidney disease (CKD). We aimed to reduce the proportion of patients with advanced CKD who experienced denosumab-induced hypocalcemia at our center. METHODS: We conducted a quality improvement (QI) project of patients with CKD stage 3b or less (i.e., estimated glomerular filtration rate <45 mL/min/1.73m2 including dialysis) who were part of the Osteoporosis and Bone Disease Program at St. Joseph's Health Care London (Canada) between December 2020 and January 2023. Our intervention was a clinical care pathway which optimized CKD mineral and bone disorder (CKD-MBD) and 25-hydroxyvitamin levels; provided calcium and vitamin D prophylaxis; promoted multidisciplinary communication between bone and kidney specialists; and carefully monitored calcium post-denosumab injection. Our primary outcome measure was the proportion of patients with hypocalcemia (defined by albumin-corrected serum calcium <1.9mmol/L) at 60 days. Process measures included the appropriate provision of calcium and vitamin D prophylaxis. Balance measures included the development of hypercalcemia and hyperphosphatemia following prophylaxis. We used plan-do-see-act cycles to study four tests of change and presented results using descriptive statistics and run charts. RESULTS: There were 6 patients with advanced CKD treated with denosumab prior to the implementation of our care pathway (March 2015-October 2020; 83% receiving dialysis). At the time of their denosumab injection, 83% were using 500-1000 mg of calcium, and 83% used 1000-2000 IU of vitamin D3. Fifty percent developed denosumab-induced hypocalcemia. Following the implementation of our care pathway, 15 patients (40% receiving dialysis) were treated with denosumab. Ninety-three percent received calcium at a daily dose of 350 to 2250 mg and 87% received 1000-2000 IU of vitamin D3. Thirteen percent developed denosumab-induced hypocalcemia. There was no hypercalcemia or hyperphosphatemia. CONCLUSIONS: A clinical care pathway focused on the safe provision of denosumab in advanced CKD reduced the risk of hypocalcemia in patients treated in our hospital. Similar pathways could be adopted and tested in other centers.

A 47-Year-Old Man with Hyperphosphatemia Due to Chronic Renal Failure Treated with Lanthanum Carbonate Tablets Presenting Acutely with Partial Large Bowel Obstruction.

BACKGROUND Hyperphosphatemia is a complication of chronic renal failure (CRF) due to reduction in the glomerular filtration rate. Lanthanum carbonate is a commonly used phosphate binder for patients with CRF and hyperphosphatemia, but has adverse effects if patients are not monitored. This report is of a 47-year-old man with hyperphosphatemia due to CRF treated with lanthanum carbonate tablets who presented acutely with partial large bowel obstruction. The incidence of lanthanum carbonate causing intestinal obstruction is rare, and few cases in the literature have described the course of the disease in detail. CASE REPORT A 47-year-old man diagnosed with diabetic nephropathy underwent hemodialysis treatment and was prescribed 0.5 g/day of chewable lanthanum carbonate tablets. After taking lanthanum carbonate for 5 months, the patient experienced symptoms of decreased bowel movements and exhaustion, which progressively worsened. Abdominal computed tomography (CT) revealed multiple hyperdensities in the large bowel, indicating the presence of lanthanum deposition. Lanthanum carbonate was promptly discontinued. After undergoing enema and catharsis treatment, the large bowel obstruction was relieved, and the hyperdensities in the abdominal CT disappeared. The colonoscopy and histologic examination revealed ulcerations and inflammatory changes in the large bowel mucosa. CONCLUSIONS This report highlights the rare association between the use of lanthanum carbonate tablets and intestinal obstruction. Healthcare providers should enhance their vigilance regarding lanthanum carbonate-induced serious gastrointestinal adverse reactions and actively seek to detect lanthanum deposition by abdominal CT or radiography (X-ray). After the occurrence of lanthanum deposition, drug withdrawal and promotion of defecation are primary treatment methods.

Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification.

Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, such as PiT-1/2, mediate depolarization, Ca2+ influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia.

Lanthanum masquerading as foreign body ingestion in a critically ill patient with end-stage renal disease.

PURPOSE: Medication use may affect imaging results. In this case study, we report a case of lanthanum ingestion resulting in imaging consistent with ingested metallic foreign bodies. SUMMARY: Hyperphosphatemia affects most patients with end-stage renal disease (ESRD) and is associated with morbidity and mortality. Lanthanum carbonate reduces daily phosphate absorption and is indicated as a non-calcium-based phosphate binder in patients with ESRD. A 58-year-old man with a medical history of stage 5 chronic kidney disease was admitted to the intensive care unit (ICU) for hyperkalemia and acute respiratory failure after a missed dialysis session. He required vasopressors, intubation, and continuous renal replacement therapy. Admission imaging demonstrated several ingested metallic foreign bodies within the colon. There was consideration of colorectal surgery and gastroenterology consultation. On the initial medication reconciliation, no medications that would have the radiographic appearance of ingested metallic foreign bodies were identified. On further review of prescription data available through the electronic medical record, it was noted that the patient had recently filled a prescription for lanthanum despite its apparent discontinuation on a previous admission. After interviewing the patient's wife, it was confirmed that the patient had continued taking lanthanum and that he was swallowing it whole and not chewing it. No consultations or interventions were performed, and the metallic foreign bodies were no longer present on further imaging after a period of 35 days. CONCLUSION: Escalation of care was avoided in this patient due to the performance of diligent medication reconciliation and recognition of the impact of lanthanum ingestion on imaging.

Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors.

This phase I study was designed to: (1) determine the maximum tolerated dose (MTD) and recommended dose (RD) of the fibroblast growth factor receptor (FGFR) inhibitor futibatinib in Japanese patients with advanced solid tumors, and (2) examine the antitumor activity of the RD in patients with gastric cancer (GC) or other advanced solid tumors who have FGFR or FGF/FGFR abnormalities, respectively. In the dose-escalation phase, patients were assigned to 21-day cycles of oral futibatinib 8-160 mg three times a week (TIW) or 16 or 20 mg once daily (QD). In the expansion phase, patients received oral futibatinib 56, 80, or 120 mg TIW, or 16 or 20 mg QD. Eighty-three patients received futibatinib TIW (n = 40) or QD (n = 43). No dose-limiting toxicities were observed according to the final study protocol definition, and the MTD was not reached. The most common adverse events with both regimens were hyperphosphatemia (TIW, 82.5%; QD, 100.0%) and decreased appetite (TIW, 40.0%; QD, 58.1%). Hyperphosphatemia was asymptomatic, not leading to futibatinib discontinuation. The overall response rate (ORR) was 11.5% in patients with FGF/FGFR abnormalities. Notably, in GC patients harboring FGFR2 copy number (CN) ≥10, the ORR was 36.4% versus 0 in patients with CN <10. Therefore, futibatinib had a generally predictable and manageable safety profile in patients with advanced solid tumors. Antitumor activity was seen in patients with FGF/FGFR abnormalities, particularly those with GC and high FGFR2 CNs. Thus, futibatinib 20 mg QD was chosen as the RD for phase II studies.

Liposomal amphotericin B related late-onset hyperphosphatemia in a pediatric patient with acute myeloid leukemia.

INTRODUCTION: Children with acute myeloid leukemia (AML) are at risk for serious electrolyte abnormalities. CASE REPORT: We reported a case of hyperphosphatemia in a child with acute myeloid leukemia who received liposomal amphotericin B (AMBL) for the treatment of an invasive fungal infection. The findings of this case suggest that cumulative dose accumulation due to long term AMBL treatment may result in late-onset hyperphosphatemia. MANAGEMENT AND OUTCOME: This is the first case report in the literature that of late-onset hyperphosphatemia (day 56) in a patient with low-dose AMBL treatment (3-5 mg/kg/day) and normal renal function. DISCUSSION: We highlight the importance of increasing awareness of AMBL related hyperphosphatemia among healthcare providers.

Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. METHODS: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. FINDINGS: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. INTERPRETATION: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. FUNDING: QED Therapeutics and Novartis.

The Rising Risk of Chronic Kidney Disease (CKD) and How it is Dealt with: A Review of Current and Potential Phosphate Binders (PB).

It is estimated that by 2040, Chronic Kidney Disease (CKD) will be the 5th main cause of global deaths. It has been suggested that hyperphosphatemia is among the main factors leading to the increased risk of death. This review focuses on potential and currently used Phosphate Binders (PB). Aluminum hydroxide is presently not recommended due to potential aluminum toxicity. Calciumcontaining phosphate binders (CCPB) can cause calcium overload, resulting in hypercalcemia and an increased risk of cardiovascular diseases. Magnesium and calcium complexes were suggested to be as effective as sevelamer in the reduction of serum phosphate, with the potential to slow down the process of calcification. However, limited studies have been conducted in this area. Although sevelamer seemed to have a positive influence on cardiovascular calcification and arterial stiffness, its influence on mortality was unclear. Sevelamer crystal accumulation in the Gastrointestinal tract (GI) can cause gastrointestinal bleeding. Lanthanum carbonate seemed to lower all-cause mortality and reduce the chance of hypercalcemia, even though a deposit in the GI tract was observed. Colestilan, like sevelamer, reduced LDL cholesterol. Sucroferric oxyhydroxide had a lower pill burden than other PBs and it seemed to reduce serum FGF-23. Ferric citrate improved parameters that are related to anemia but can cause iron overload. Bixalomer appeared to have fewer gastrointestinal side effects than sevelamer. Nano-lanthanum hydroxide and SBR759 may have an interesting future as PBs. In conclusion, the development of new PBs should also take into consideration their potential to function as protection modifiers.

Alfacalcidol vs Calcitriol in the Management of Patient With Hypoparathyroidism: A Randomized Controlled Trial.

CONTEXT: Alfacalcidol and calcitriol are commonly used for managing hypoparathyroidism. Their relative merits have not been systematically assessed. OBJECTIVE: We compared the effect of alfacalcidol and calcitriol on phosphatemic control, hypercalciuria, and associated factors in idiopathic-hypoparathyroidism (IH). DESIGN AND SETTING: Open-label randomized controlled trial, tertiary care center. SUBJECTS AND METHODS: IH patients with optimal calcemic control on alfacalcidol were continued on the same (n = 20) or switched to calcitriol (n = 25) at half of the ongoing alfacalcidol dose. The dose was adjusted during follow-up to maintain serum total calcium between 8.0 and 9.5 mg/dL. Serum calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24-h urine calcium-to-creatinine ratio, and fractional excretion of phosphorus (FEPh) were measured at baseline and 6 months. Plasma intact-FGF23 was measured at final follow-up. RESULT: Patients receiving alfacalcidol and calcitriol had comparable serum calcium at 6 months (8.7 ±â€…0.4 vs 8.9 ±â€…0.4 mg/dL, P = 0.13). Their median [interquartile range (IQR)] dose at 6 months was 2.0 (1.0-2.5) and 0.75 (0.5-1.0) µg/d, respectively. Serum 1,25(OH)2D levels were physiological in both (35.3 ±â€…11.6 and 32.3 ±â€…16.9 pg/mL). Serum phosphate and calcium excretion were comparable in 2 arms. A majority had hyperphosphatemia (75% vs 76%), hypercalciuria (75% vs 72%), and elevated FGF23 (116 ±â€…68 and 113 ±â€…57 pg/mL). Age showed significant independent association with plasma FGF23 (ß = 1.9, P = 0.001). Average FEPh was low despite high FGF23. CONCLUSION: At optimal calcium control, both alfacalcidol and calcitriol lead to comparable but high serum phosphate levels, hypercalciuria, physiological circulating 1,25(OH)2D, and elevated FGF23. Further studies are required to systematically investigate other treatment options.

Adsorptivity of cationic cellulose nanocrystals for phosphate and its application in hyperphosphatemia therapy.

Nanocellulose has gained much attention because of its excellent properties. Cationic cellulose nanocrystals (cCNC) shows good adsorptivity toward negative ions and molecules. Phosphate binders are most used to treat hyperphosphatemia and it is significant to develop its alternatives with high specific and low cost in the clinic. Herein, we prepared cCNC and characterized it by FTIR, TEM, dynamic light scattering, and viscosity method. We simulated the binding process of cationic cellulose for phosphate and used it as phosphate binder for hyperphosphatemia therapy to study the phosphate binding effect and evaluate the oral toxicity. Cationic cellulose improved the conditions of mice models and efficiently decreased the level of phosphate in the serum. cCNC had a better binding effect than cationic microcrystalline cellulose both in vitro and in vivo. cCNC could be used as alternatives to phosphate binder for therapy of chronic renal failure and hyperphosphatemia.

High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling.

Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of p62-Luc and myogenin-Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation in vitro and promotes muscle atrophy in vivo through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.

Oxidative stress by Ca2+ overload is critical for phosphate-induced vascular calcification.

Hyperphosphatemia is the primary risk factor for vascular calcification, which is closely associated with cardiovascular morbidity and mortality. Recent evidence showed that oxidative stress by high inorganic phosphate (Pi) mediates calcific changes in vascular smooth muscle cells (VSMCs). However, intracellular signaling responsible for Pi-induced oxidative stress remains unclear. Here, we investigated molecular mechanisms of Pi-induced oxidative stress related with intracellular Ca2+ ([Ca2+]i) disturbance, which is critical for calcification of VSMCs. VSMCs isolated from rat thoracic aorta or A7r5 cells were incubated with high Pi-containing medium. Extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin were activated by high Pi that was required for vascular calcification. High Pi upregulated expressions of type III sodium-phosphate cotransporters PiT-1 and -2 and stimulated their trafficking to the plasma membrane. Interestingly, high Pi increased [Ca2+]i exclusively dependent on extracellular Na+ and Ca2+ as well as PiT-1/2 abundance. Furthermore, high-Pi induced plasma membrane depolarization mediated by PiT-1/2. Pretreatment with verapamil, as a voltage-gated Ca2+ channel (VGCC) blocker, inhibited Pi-induced [Ca2+]i elevation, oxidative stress, ERK activation, and osteogenic differentiation. These protective effects were reiterated by extracellular Ca2+-free condition, intracellular Ca2+ chelation, or suppression of oxidative stress. Mitochondrial superoxide scavenger also effectively abrogated ERK activation and osteogenic differentiation of VSMCs by high Pi. Taking all these together, we suggest that high Pi activates depolarization-triggered Ca2+ influx via VGCC, and subsequent [Ca2+]i increase elicits oxidative stress and osteogenic differentiation. PiT-1/2 mediates Pi-induced [Ca2+]i overload and oxidative stress but in turn, PiT-1/2 is upregulated by consequences of these alterations.NEW & NOTEWORTHY The novel findings of this study are type III sodium-phosphate cotransporters PiT-1 and -2-dependent depolarization by high Pi, leading to Ca2+ entry via voltage-gated Ca2+ channels in vascular smooth muscle cells. Cytosolic Ca2+ increase and subsequent oxidative stress are indispensable for osteogenic differentiation and calcification. In addition, plasmalemmal abundance of PiT-1/2 relies on Ca2+ overload and oxidative stress, establishing a positive feedback loop. Identification of mechanistic components of a vicious cycle could provide novel therapeutic strategies against vascular calcification in hyperphosphatemic patients.

Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1-3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3-altered Advanced/Metastatic Urothelial Carcinoma.

BACKGROUND: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition. OBJECTIVE: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC. INTERVENTION: Oral infigratinib 125 mg/d for 21 d every 28 d. DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical outcomes were compared in groups with/without hyperphosphatemia. RESULTS AND LIMITATIONS: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size. CONCLUSIONS: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial. PATIENT SUMMARY: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.

TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells.

OBJECTIVE: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (Pi) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC. METHODS AND RESULTS: Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by Pi and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of RUNX2 (Runt-related transcription factor 2), a well-established driver of Pi-mediated VC, is reduced in TDAG51-/- VSMCs. To explain these observations, we identified that TDAG51-/- VSMCs express reduced levels of the type III sodium-dependent Pi transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular Pi uptake. Significantly, in response to hyperphosphatemia induced by vitamin D3, medial VC was attenuated in TDAG51-/- mice. CONCLUSIONS: Our studies highlight TDAG51 as an important mediator of Pi-induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.

Hypervitaminosis D has no positive effects on goat tuberculosis and may cause chronic renal lesions.

BACKGROUND: There is evidence for a link between vitamin D deficiency and active tuberculosis (TB). In human beings, several trials have evaluated the role of vitamin D supplementation in TB treatment with conflicting results. However, the role of vitamin D supplementation in animal TB control has received less attention. The authors evaluated the benefit of vitamin D supplementation for preventing mycobacterial infection or reducing TB lesions (TBL) in a controlled trial with goats naturally exposed to Mycobacterium caprae. METHODS: Two groups of goats, a vitamin D-supplemented group and a non-supplemented control group, were housed for 10 months in direct contact with M caprae-infected adult goats. Upon contact with the infected adult goats, all animals were TB-tested every two months. RESULTS: No experimental evidence of a protective effect of vitamin D supplementation based on M caprae culture prevalence, TBL prevalence, median TBL score or the proportion of single versus multiple organs presenting TBL was observed. CONCLUSION: The results indicate that, in the conditions used in this study, vitamin D supplementation in goats does not reduce TB infection risk nor the diffusion and severity of TBL. In addition, vitamin D-supplemented goats presented hyperphosphataemia and renal injury with calcifications suggestive of vitamin D intoxication.

Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study.

BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib. METHODS: We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50-800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited. FINDINGS: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration. INTERPRETATION: Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment. FUNDING: Bayer AG.

Phosphate supplementation for hypophosphatemia during continuous renal replacement therapy in adults.

BACKGROUND: Hypophosphatemia is common during continuous renal replacement therapy (CRRT) in critically ill patients and can cause generalized muscle weakness, prolonged respiratory failure, and myocardial dysfunction. This study aimed to investigate the efficacy and safety of adding phosphate to the dialysate and replacement solutions to treat hypophosphatemia occurring in intensive CRRT in critically ill patients. METHODS: We retrospectively analyzed 73 patients treated with intensive CRRT (effluent flow ≥35 ml/kg/hr) in the intensive care unit. The control group (group 1, n = 22) received no phosphate supplementation. The treatment groups received dialysate and replacement solution phosphate supplementation at 2.0 mmol/L (group 2, n = 26) or 3.0 mmol/L (group 3, n = 25). RESULTS: The CRRT-induced hypophosphatemia incidence was 59.0%. Correction of hypophosphatemia with phosphate supplementation changed the mean serum phosphorus levels to 1.24 ± 0.37 and 1.44 ± 0.31 mmol/L in groups 2 and 3, respectively (p = .02). The time required for correction was 1.65 ± 0.80 and 1.39 ± 1.43 days for groups 2 and 3, respectively and was significantly longer in group 2 (p = .02). After supplementation, hypophosphatemia, and hyperphosphatemia both occurred in 7% of group 2. Group 3 developed no hypophosphatemia, but 20% developed hyperphosphatemia. The serum phosphate levels in hyperphosphatemia cases returned to normal within 2.0 days (group 2) and 1.0 day (group 3) after stopping phosphate supplementation. CONCLUSION: Phosphate supplementation effectively corrected CRRT-induced hypophosphatemia in critically ill patients with an acute kidney injury. The use of 2 mmol/L phosphate is appropriate in patients with CRRT-induced hypophosphatemia, but a different concentration could be required to prevent hypophosphatemia at the start of CRRT.

Auditing the Efficacy and Safety of Alfacalcidol and Calcium Therapy in Idiopathic Hypoparathyroidism.

CONTEXT: Patients with hypoparathyroidism are treated with vitamin D and calcium. PTH is an emerging option because of its physiological action. It is important to assess the efficacy and shortcomings of conventional therapy. OBJECTIVE: We assessed the efficacy and safety of alfacalcidol in a large cohort of patients with idiopathic hypoparathyroidism (IH) and identified a subset who could be treated without oral calcium. DESIGN AND SETTING: Observational study at tertiary care center. SUBJECTS AND METHODS: We assessed 92 patients with IH who were receiving alfacalcidol and oral calcium to maintain an optimal serum total calcium level of 8.0 to 8.5 mg/dL during routine follow-up. Patients with suboptimal control were provided free medicines and followed up frequently. Oral calcium and alfacalcidol doses were titrated sequentially to determine the minimum doses for optimal calcium control. Serum phosphate level, 1,25-dihydroxyvitamin D, fractional excretion of phosphorus (FEPh), and hypercalciuria (urine calcium-to-creatinine ratio, >0.2) were assessed at each step of titration. RESULTS: Only 38% of patients had optimal calcium control during routine follow-up. With good compliance, all achieved optimal serum calcium and 1,25-dihydroxyvitamin D levels and 43% of patients could stop taking oral calcium. Hyperphosphatemia, hypercalciuria, and low FEPh persisted at all stages of therapy. Serum phosphorus levels normalized when the serum calcium level increased to 9.9 mg/dL, but this level of serum total calcium was associated with hypercalciuria in 90% of patients. CONCLUSION: Alfacalcidol is effective in achieving calcemic control in IH. Calcemic control without oral calcium was achieved in 43% of patients receiving alfacalcidol. However, optimal calcium control was associated with hyperphosphatemia and hypercalciuria in most patients.