Dietary Phosphate Research Articles

High phosphate impairs arterial endothelial function through AMPK-related pathways in mouse resistance arteries.

In patients with renal disease, high serum phosphate shows a relationship with cardiovascular risk. We speculate that high phosphate (HP) impairs arterial vasodilation via the endothelium and explore potential underlying mechanisms. Isolated vessel relaxation, endothelial function, glomerular filtration rate (GFR), oxidative stress status and protein expression were assessed in HP diet mice. Mitochondrial function and protein expression were assessed in HP-treated human umbilical vein endothelial cells (HUVECs). High phosphate (1.3%) diet for 12weeks impaired endothelium-dependent relaxation in mesenteric arteries, kidney interlobar arteries and afferent arterioles; reduced GFR and the blood pressure responses to acute administration of acetylcholine. The PPARα/LKB1/AMPK/eNOS pathway was attenuated in the endothelium of mesenteric arteries from HP diet mice. The observed vasodilatory impairment of mesenteric arteries was ameliorated by PPARα agonist WY-14643. The phosphate transporter PiT-1 knockdown prevented HP-mediated suppression of eNOS activity by impeding phosphorus influx in HUVECs. Endothelium cytoplasmic and mitochondrial reactive oxygen species (ROS) were increased in HP diet mice. Moreover HP decreased the expression of mitochondrial-related antioxidant genes. Finally, mitochondrial membrane potential and PGC-1α expression were reduced by HP treatment in HUVECs, which was partly restored by AMPKα agonist. HP impairs endothelial function by reducing NO bioavailability via decreasing eNOS activity and increasing mitochondrial ROS, in which the AMPK-related signalling pathways may play a key role.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis

Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. Multicenter, pragmatic, cluster-randomized clinical trial. HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL). Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. The trial is currently enrolling. HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome. Registered at ClinicalTrials.gov with study number NCT04095039.

Effects of Individualized Dietary Phosphate Control Program With a Smartphone Application in Hemodialysis Patients in Taiwan.

Hyperphosphatemia in end-stage renal disease patients is prevalent and associated with increasing cardiac mortality. Restricting dietary phosphate intake is a key element in controlling hyperphosphatemia, but most patients fail due to lack of knowledge and sustainability. In this study, we aimed to examine whether incorporating a smartphone application (APP) into a multidisciplinary caring system can decrease the prevalence of hyperphosphatemia in hemodialysis patients. We designed a quasi-experimental study to enroll patients undergoing regular hemodialysis and assigned them to receive APP-assisted caring program (ACP group, n = 30) or standard education caring program (SCP group, n = 30). Both caring programs targeting dietary phosphate control were administered. Patients' general characteristics, self-care efficacy scales, knowledge test of phosphate control, and results of monthly blood biochemistry were analyzed. Knowledge of diet phosphate control and self-care efficacy were significantly higher in the ACP group. Notably, the knowledge improvement was higher in patients aged over 60 years. Compared to the SCP group, the percentage of patients with successful hyperphosphatemia control was significantly higher in the ACP group (p = 0.0398). The APP-assisted caring program benefits patients with regular hemodialysis to achieve better dietary phosphate control without compromising proper protein intake.

Investigation of the transforming growth factor-beta 1 signalling pathway as a possible link between hyperphosphataemia and renal fibrosis in feline chronic kidney disease

Chronic kidney disease (CKD) is common in geriatric cats, and is characterised in the majority of cases by tubulointerstitial inflammation and fibrosis. Hyperphosphataemia is a frequent complication of CKD and is independently associated with severity of renal fibrosis and disease progression. Transforming growth factor-beta 1 (TGF-β1) signalling is thought to be a convergent pathway which mediates the progression of renal fibrosis in CKD. The aims of this study were to explore the interaction between increased extracellular phosphate and the TGF-β1 signalling pathway by investigating: (a) the effect of a commercially available, phosphate-restricted, diet on urinary TGF-β1 excretion in cats with CKD; and (b) the role of increased extracellular phosphate in regulating proliferation, apoptosis, and expression of genes related to TGF-β1 signalling and extracellular matrix (ECM) production in feline proximal tubular epithelial cells (FPTEC) and cortical fibroblasts from cats with azotaemic CKD (CKD-FCF).The dietary intervention study revealed no effect of dietary phosphate restriction on urinary active TGF-β1 excretion after 4–8 weeks (P=0.98), despite significantly decreasing serum phosphate (P<0.001). There was no effect of increased growth media phosphate concentration (from 0.95mM to 2mM and 3.5mM) on proliferation (P=0.99) and apoptotic activity in FPTEC (P=0.22), or expression of genes related to ECM production and the TGF-β1 signalling pathway in FPTEC and CKD-FCF (P>0.05). These findings suggest the beneficial effects of dietary phosphate restriction on progression of feline CKD may not occur through modulation of renal TGF-β1 production, and do not support a direct pro-fibrotic effect of increased extracellular phosphate on feline renal cells.

Stress, inflammation, depression, and dementia associated with phosphate toxicity.

Depression and dementia are predicted to increase within aging global populations. Pathophysiological effects of phosphate toxicity, dysregulated amounts of accumulated phosphorus in body tissue, are under-investigated in association with stress, inflammation, depression, and dementia. A comparative analysis of concepts in cited sources from the research literature was used to synthesize novel themes exploring the disease-oriented neuroscience effects of phosphate toxicity. Phosphate toxicity is associated with activation of cellular stress response systems and inflammation. Cortisol released by the hypothalamic-pituitary-adrenal axis responds to stress and inflammation associated with phosphate toxicity and depression. In a reciprocal interaction, phosphate toxicity is capable of harming adrenal gland function, possibly leading to adrenal insufficiency and depression. Furthermore, Alzheimer's disease is associated with hyperphosphorylated tau which self-assembles into neurofibrillary tangles from excessive amounts of phosphate in the brain and central nervous system. Future research should investigate dietary phosphate modification to reduce potential pathophysiological effects of phosphate toxicity in stress, inflammation, depression, and cognitive decline which affects global populations.

Vitamin D supplementation improves bone mineralisation independent of dietary phosphate in male X-linked hypophosphatemic (Hyp) mice.

The disorder of X-linked hypophosphatemia (XLH), results in the supressed renal production of active 1α,25-dihydroxyvitamin D (1,25(OH)2D) due to elevated fibroblast growth factor-23 (FGF23) levels. While adequate 25(OH)D levels are generally associated with improved mineralisation of the skeleton independent of circulating 1,25(OH)2D levels, it is unclear whether raising 25(OH)D to sufficiently high levels through dietary vitamin D3 administration contributes to improving bone mineralisation in the murine homolog for XLH, Hyp mice. Three-week-old male Hyp mice were fed one of four diets containing either 1000IU (C) or 20,000IU (D) vitamin D3/kg diet with either 0.35% phosphate or 1.25% phosphate (P) until 12weeks of age (n=12/group). When compared to C-fed mice, D-fed mice significantly elevated serum 25(OH)D levels to 72.8±4.9nmol/L (2-fold, p<0.001) and increased both cortical bone mineral density (15%, p<0.01), and vertebral trabecular BV/TV% (80%, p<0.001), despite persistent hypophosphatemia and normocalcemia. The increase in bone volume was associated with improved Tb.Th (12%, p<0.01) and Tb.N (63%, p<0.001). Unlike with D-diet, P-fed mice resulted in increased femoral (15%, p<0.001) and vertebral (12%, p<0.001) length, and a 34% increase in vertebral trabecular BV/TV% when compared to control fed animals (p<0.001). However, the addition of the high P diet to the high D diet did not result in additive effects on bone mineralisation when compared to the effects of D diet alone, despite serum 25(OH)D levels elevated to 118.8±8.6nmol/L. In D-fed mice, the increase in bone mineral density and volume was associated with reduced osteoid volume, reduced ObS/BS, and a trend for reduced serum PTH levels, suggesting reduced bone turnover in these animals. Thus, elevating serum 25(OH)D levels independently improves bone mineralisation in Hyp mice without causing hypercalcemia, suggesting that further studies are required in XLH patients to establish the role of increasing 25(OH)D levels in improving bone mineralisation.

Calciprotein particle-induced cytotoxicity via lysosomal dysfunction and altered cholesterol distribution in renal epithelial HK-2 cells

Dietary phosphate overload induces chronic kidney disease (CKD), and calciprotein particles (CPPs), a form of nanoparticle comprising calcium phosphate and serum proteins, has been proposed to cause renal toxicity. However, the mechanism of CPP cytotoxicity in renal tubular cells is unknown. Here we show that in renal proximal tubular epithelial HK-2 cells, endocytosed CPPs accumulate in late endosomes/lysosomes (LELs) and increase their luminal pH by ~ 1.0 unit. This results in a decrease in lysosomal hydrolase activity and autophagic flux blockage without lysosomal rupture and reactive oxygen species generation. CPP treatment led to vulnerability to H2O2-induced oxidative stress and plasma membrane injury, probably because of autophagic flux blockage and decreased plasma membrane cholesterol, respectively. CPP-induced disruption of lysosomal homeostasis, autophagy flux and plasma membrane integrity might trigger a vicious cycle, leading to progressive nephron loss.

The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy.

As a gut-restricted, nonabsorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, nonabsorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end-stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357, possessing optimized bile acid (BA) and phosphate sequestration characteristics. Long-term treatment of T2D obese cZucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) with SAR442357 resulted in enhanced sequestration of BAs and phosphate in the gut, improved glycemic control, lowering of serum cholesterol, and attenuation of diabetic kidney disease (DKD) progression. In comparison, colesevelam, a BAS with poor phosphate binding properties, did not prevent DKD progression, whereas losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Analysis of hepatic gene expression levels of the animals treated with SAR442357 revealed upregulation of genes responsible for the biosynthesis of cholesterol and BAs, providing clear evidence of target engagement and mode of action of the new sequestrant. Additional hepatic gene expression pathway changes were indicative of an interruption of the enterohepatic BA cycle. Histopathological analysis of ZSF1 rat kidneys treated with SAR442357 further supported its nephroprotective properties. Collectively, these findings reveal the pharmacological benefit of simultaneous sequestration of BAs and phosphate in treating T2D and its associated comorbidities and cardiovascular complications. SIGNIFICANCE STATEMENT: A new nonabsorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering, and attenuation of DKD progression in a single therapeutic agent.

Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats.

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5mg/day) or Bactrim (250mg/day). Urine and fecal pellets were collected over 6, 12 and 18weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

Phosphate and Oxysterols May Mediate an Inverse Relationship Between Atherosclerosis and Cancer

The peer-reviewed literature has reported an inverse relationship between atherosclerosis and cancer for almost 100 years, but no causative mechanism has been established to explain this puzzling relationship. More recent research has reported an association between tumourigenesis and phosphate toxicity from dysregulated phosphate metabolism, and an association has also been reported between atherosclerosis and cholesterol oxidation products or oxysterols. The present review article synthesises these research findings and proposes that an inverse relationship between the associated risk of cancer and atherosclerosis may be mediated by tumourigenic and atherogenic dietary patterns containing inverse proportions of dietary phosphate and oxysterols. Low-fat animal-based foods generally have reduced cholesterol and oxysterol levels and relatively higher protein and phosphate levels, and dietary patterns containing these foods are associated with reduced atherosclerosis risk and increased cancer risk. By comparison, full-fat animal-based foods are higher in cholesterol and oxysterols and relatively lower in protein and phosphate, and dietary patterns containing these foods are associated with increased atherosclerosis risk and reduced cancer risk. Fruits, vegetables, and plant-based fats generally have lower phosphate levels and no cholesterol, and dietary patterns associated with increased amounts of these foods, such as the Mediterranean diet, reduce risk for both cancer and cardiovascular disease.

Murine Fetal Serum Phosphorus is Set Independent of FGF23 and PTH, Except in the Presence of Maternal Phosphate Loading.

Fibroblast growth factor 23 (FGF23) appears to play no role until after birth, given unaltered phosphate and bone metabolism in Fgf23- and Klotho-null fetuses. However, in those studies maternal serum phosphorus was normal. We studied whether maternal phosphate loading alters fetal serum phosphorus and invokes a fetal FGF23 or parathyroid hormone (PTH) response. C57BL/6 wild-type (WT) female mice received low (0.3%), normal (0.7%), or high (1.65%) phosphate diets beginning 1 week prior to mating to WT males. Fgf23+/- female mice received the normal or high-phosphate diets 1 week before mating to Fgf23+/- males. One day before expected birth, we harvested maternal and fetal blood, intact fetuses, placentas, and fetal kidneys. Increasing phosphate intake in WT resulted in progressively higher maternal serum phosphorus and FGF23 during pregnancy, while PTH remained undetectable. Fetal serum phosphorus was independent of the maternal phosphorus and PTH remained low, but FGF23 showed a small nonsignificant increase with high maternal serum phosphorus. There were no differences in fetal ash weight and mineral content, or placental gene expression. High phosphate intake in Fgf23+/- mice also increased maternal serum phosphorus and FGF23, but there was no change in PTH. WT fetuses remained unaffected by maternal high-phosphate intake, while Fgf23-null fetuses became hyperphosphatemic but had no change in PTH, skeletal ash weight or mineral content. In conclusion, fetal phosphate metabolism is generally regulated independently of maternal serum phosphorus and fetal FGF23 or PTH. However, maternal phosphate loading reveals that fetal FGF23 can defend against the development of fetal hyperphosphatemia.

Dietary casein, egg albumin, and branched-chain amino acids attenuate phosphate-induced renal tubulointerstitial injury in rats

Dietary phosphate intake is closely correlated with protein intake. However, the effects of the latter on phosphate-induced organ injuries remain uncertain. Herein, we investigated the effects of low (10.8%), moderate (23.0%), and high (35.2%) dietary casein and egg albumin administration on phosphate-induced organ injuries in rats. The moderate and high casein levels suppressed renal tubulointerstitial fibrosis and maintained mitochondrial integrity in the kidney. The serum creatinine levels were suppressed only in the high casein group. Phosphate-induced muscle weakness was also ameliorated by high dietary casein. The urinary and fecal phosphate levels in the early experiment stage showed that dietary casein did not affect phosphate absorption from the intestine. High dietary egg albumin showed similar kidney protective effects, while the egg albumin effects on muscle weakness were only marginally significant. As the plasma branched-chain amino acid levels were elevated in casein- and egg albumin-fed rats, we analyzed their effects. Dietary supplementation of 10% branched-chain amino acids suppressed phosphate-induced kidney injury and muscle weakness. Although dietary protein restriction is recommended in cases of chronic kidney disease, our findings indicate that the dietary casein, egg albumin, and branched-chain amino acid effects might be reconsidered in the era of a phosphate-enriched diet.

A review of phosphorus homeostasis and the impact of different types and amounts of dietary phosphate on metabolism and renal health in cats.

Elevated concentrations of serum phosphate are linked with progression and increased case fatality rate in animals and humans with chronic kidney disease. Elevated concentrations of serum phosphate can be a risk factor for development of renal and cardiovascular diseases or osteoporosis in previously healthy people. In rodents, an excess intake of dietary phosphorus combined with an inverse dietary calcium : phosphorus ratio (<1 : 1) contributes to renal calcification. Renal injury also has occured in cats fed experimental diets supplemented with highly soluble phosphate salts, especially in diets with inverse calcium : phosphorus ratios. However, not all phosphorus sources contribute similarly to this effect. This review, which focuses on cats, summarizes the published evidence regarding phosphorus metabolism and homeostasis, including the relative impact of different dietary phosphorus sources, and their impact on the kidneys. No data currently shows that commercial cat foods induce renal injury. However, some diets contain high amounts of phosphorus relative to recommendations and some have inverse Ca : P ratios and so could increase the risk for development of kidney disease. While limiting the use of highly soluble phosphates appears to be important, there are insufficient data to support a specific upper limit for phosphate intake. This review also proposes areas where additional research is needed in order to strengthen conclusions and recommendations regarding dietary phosphorus for cats.

Risk Assessment of the Dietary Phosphate Exposure in Taiwan Population Using a Total Diet Study.

Phosphorus and calcium are essential nutrients for the human body. However, excessive intake of phosphates and a low calcium:phosphorus ratio can lead to disorders in calcium-phosphorus metabolism, kidney disease, or osteoporosis. In this study, a total diet study (TDS) was used. The total phosphorus concentrations of foods were combined with the average dietary consumption to calculate the estimated daily intake, which was compared with the maximum tolerable daily intake (MTDI) to assess the resulting health risk of total phosphorus exposure. The calcium concentration in food and total calcium intake were also analyzed and estimated to calculate the calcium:phosphorus ratio. In conclusion, the phosphate exposure risks for the Taiwanese population are acceptable. However, the calcium:phosphorus ratio in the Taiwanese population (0.51–0.63) is lower than the reference calcium:phosphorus ratio (1.25).

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Increase in phosphaturia by inhibition of renal sodium-dependent phosphate cotransporter NPT2a

Numerous mechanisms are involved in maintaining serum phosphate concentration in the normal range, mainly by regulating phosphate absorption in the gut and tubular phosphate reabsorption in the kidney. In the gut, phosphate is absorbed by passive paracellular diffusion and active transcellular transport, mainly via NPT2b, the major sodium phosphate cotransporter in the small intestine.1 Active phosphate absorption is enhanced by 1,25(OH)2 vitamin D. Intestinal phosphate absorption can be reduced by several approaches,1 including reduction of dietary phosphate intake, chelation of phosphate in the gut lumen,2 specific inhibition of NPT2b activity by small-molecule inhibitors,3 nonspecific inhibition of NPT2b by niacin or its derivative nicotinamide,2 and reduction of passive paracellular phosphate flux via inhibition of the sodium/hydrogen exchanger 3.

Cardiovascular problems in dialysis patients - focus on correcting hyperphosphatemia

Mineral-bone disorder in chronic kidney disease (CKD-MBD) is one of the most important factor determining prognosis in dialysis patients. CKD-MBD syndrome occurs at the CKD stage 2 and reaches its maximum in patients with end-stage renal disease. Currently, hyperphosphatemia plays a central role in the pathogenesis of CKD-MBD(the so-called “phosphate-centric paradigm”). In turn, hyperphosatemia leads to an increase in the level of phosphaturic hormone - fibroblast growth factor type 23 (FGF23). FGF23 causes remodeling and fibrosis of the myocardium, renal parenchyma, the development of calcification and vascular atherosclerosis. Thus, hyperphosphatemia, indirectly, through an increase in the level of FGF23, is one of the most important manifestation of progressive CKD and a significant factor of high overall and cardiovascular morbidity and mortality in this cohort of patients. Given that cardiovascular events are the main cause of mortality in patients on renal replacement therapy with dialysis, correction of hyperphosphatemia is a prerequisite for successful monitoring of this group of patients and influencing prognosis. The review presents the main approaches for the correction of hyperphosphatemia in CKD, such as nutritional correction, modification of dialysis methods, and prescribing of phosphate binders. The advantages of calcium-free phosphate-binding agents are considered in details and had compared with effects of containing calcium phosphate binders. The treatment of hyperphosphatemia should be approached comprehensively, using optimal dialysis therapy regimens, training and monitoring dietary phosphate consumption with the obligatory use of phosphate binders that are most effective and well tolerated.

Phosphate binders usage, patients knowledge, and adherence. A cross-sectional study in 4 centers at Qassim, Saudi Arabia.

Objectives:To assess phosphate binders’ usage, knowledge regarding their utilization, and adherence among hemodialysis patients in Qassim, Saudi Arabia.Methods:A prospective cross-sectional study conducted at 4 dialysis centers in Qassim, Saudi Arabia with inclusion of 237 patients’ undergoing hemodialysis between November 2018 to January 2019. The study involved interviewing the patients, reviewing their medical records for biomarkers used to assess kidney function, and assessing the patients’ knowledge-based regarding dietary phosphate control, as well as adherence to phosphate binders’ usage.Results:Out of 237 included patients, male to female ratio was 54:46. The prevalence of prescribing non-calcium phosphate binders was 82.7% whereas prescribing calcium phosphate binders was 73.8%. A total of 63% of patients showed a medium level of adherence to phosphate binders. Although adherence level was not poor, therapeutic efficacy was affected by other factors such as administration time adherence positively correlated with the serum phosphate level (p=0.00).Conclusion:Phosphate binders usage is frequent among hemodialysis patients in Qassim centers. Circulating phosphate level was affected by the extent of patients’ knowledge of dietary control and adherence to the usage of phosphate binders. Thus, we recommend enhancing patient education in reference to high- and low- phosphate-rich diet to take wise dietary decisions, lower pill burden, and improve adherence toward the control of hyperphosphatemia

Clinical Evaluation of the Safety, Efficacy and Tolerability of Lanthanum Carbonate in the Management of Hyperphosphatemia in Patients with End-Stage Renal Disease.

Patients with progressive chronic kidney disease (CKD) commonly develop mineral and bone abnormalities and extraskeletal calcifications with following increased cardiovascular risk. A key pathophysiological role is played by hyperphosphatemia. Since diet and dialysis are often insufficient to control serum phosphorus levels, many patients require treatment with phosphate binders. Among them is lanthanum carbonate, an aluminum-free non-calcium-based compound. The present review summarizes the most recent literature data concerning the safety, efficacy and tolerability of lanthanum carbonate in patients with end-stage renal disease and hyperphosphatemia. The drug is taken orally as chewable tablets or powder with only minimal gastrointestinal absorption and resulting reduced risk of tissue deposition and systemic drug interactions. The dissociation of the drug in the acid environment of the upper gastrointestinal tract induces the release of lanthanum ions, which bind to dietary phosphate forming insoluble complexes then excreted in the feces. Even though there is no clear evidence that lowering serum phosphorus levels can improve patient-centered outcomes, a mortality benefit with all phosphate binders, especially non-calcium containing ones, is not excluded. Lanthanum carbonate has been suggested to decrease all-cause mortality but not cardiovascular event rate compared to other phosphate binders. It induces a lower suppression of bone turnover than calcium carbonate and calcium acetate and may improve systolic function and cardiac dimension compared to calcium carbonate. Moreover, the use of lanthanum carbonate has been associated with better nutritional status compared to other phosphate binders, lower risk for hypercalcemia than calcium-containing binders, and amelioration of mild metabolic acidosis contrary to sevelamer hydrochloride. Main adverse effects include nausea, alkaline gastric reflux, gastric deposition of lanthanum, gastrointestinal obstruction, subileus, ileus, perforation, fecal impaction, and reduction of gastrointestinal absorption of some drugs including statins, angiotensin-converting enzyme inhibitors and some antibiotics such as fluoroquinolones or tetracyclines.

A combined microRNA and target protein-based panel for predicting the probability and severity of uraemic vascular calcification: a translational study.

Vascular calcification (VC) increases the future risk of cardiovascular events in uraemic patients, but effective therapies are still unavailable. Accurate identification of those at risk of developing VC using pathogenesis-based biomarkers is of particular interest and may facilitate individualized risk stratification. We aimed to uncover microRNA (miRNA)-target protein-based biomarker panels for evaluating uraemic VC probability and severity. We created a three-tiered in vitro VC model and an in vivo uraemic rat model receiving high phosphate diet to mimic uraemic VC. RNAs from the three-tiered in vitro and in vivo uraemic VC models underwent miRNA and mRNA microarray, with results screened for differentially expressed miRNAs and their target genes as biomarkers. Findings were validated in original models and additionally in an ex vivo VC model and human cells, followed by functional assays of identified miRNAs and target proteins, and tests of sera from end-stage renal disease (ESRD) and non-dialysis-dependent chronic kidney disease (CKD) patients without and with VC. Totally 122 down-regulated and 119 up-regulated miRNAs during calcification progression were identified initially; further list narrowing based on miRNA-mRNA pairing, anti-correlation, and functional enrichment left 16 and 14 differentially expressed miRNAs and mRNAs. Levels of four miRNAs (miR-10b-5p, miR-195, miR-125b-2-3p, and miR-378a-3p) were shown to decrease throughout all models tested, while one mRNA (SULF1, a potential target of miR-378a-3p) exhibited the opposite trend concurrently. Among 96 ESRD (70.8% with VC) and 59 CKD patients (61% with VC), serum miR-125b2-3p and miR-378a-3p decreased with greater VC severity, while serum SULF1 levels increased. Adding serum miR-125b-2-3p, miR-378a-3p, and SULF1 into regression models for VC substantially improved performance compared to using clinical variables alone. Using a translational approach, we discovered a novel panel of biomarkers for gauging the probability/severity of uraemic VC based on miRNAs/target proteins, which improved the diagnostic accuracy.