Understudied Hyperphosphatemia (Chronic Kidney Disease) Treatment Targets and New Biological Approaches.

Hyperphosphatemia is a secondary disorder of chronic kidney disease that causes vascular calcifications and bone-mineral disorders. As per the US Centers for Disease Control and Prevention, renal damage requires first-priority medical attention for patients with COVID-19; according to a Johns Hopkins Medicine report, SARS-CoV-2 can cause renal damage. Therefore, addressing the research inputs required to manage hyperphosphatemia is currently in great demand. This review highlights research inputs, such as defects in the diagnosis of hyperphosphatemia, flaws in understanding the mechanisms associated with understudied tertiary toxicities, less cited adverse effects of phosphate binders that question their use in the market, socioeconomic challenges of renal treatment and public awareness regarding the management of a phosphate-controlled diet, novel biological approaches (synbiotics) to prevent hyperphosphatemia as safer strategies with potential additional health benefits, and future functional food formulations to enhance the quality of life. We have not only introduced our contributions to emphasise the hidden aspects and research gaps in comprehending hyperphosphatemia but also suggested new research areas to strengthen approaches to prevent hyperphosphatemia in the near future.

To what extent can we achieve mineral bone metabolism treatment targets suggested by the KDIGO guidelines among chronic kidney disease stage 3 - 5 non-dialysis patients?

INTRODUCTION: Real-life data on the predialysis management of chronic kidney disease (CKD) is scarce. In this study, our aim was to investigate the current clinical practice and compliance among nephrologists with the KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guidelines. MATERIALS AND METHODS: In this multicenter cross-sectional study, we recruited stage 3 - 5 non-dialysis (ND) CKD patients and recorded the data related to CKD-MBD from two consecutive outpatient clinical visits 3 - 6 months apart. We calculated the therapeutic inertia for hyperphosphatemia, hypocalcemia, hyperparathyroidism, and hypovitaminosis D, in addition to overtreatment for hypophosphatemia, hypercalcemia, hypoparathyroidism, and hypervitaminosis D. RESULTS: We examined a total of 302 patients (male: 48.7%, median age: 67 years). The persistence of low 25-hydroxy vitamin D levels was the most common laboratory abnormality related to CKD-MBD (61.7%), followed by hyperparathyroidism (14.8%), hyperphosphatemia (7.9%), and hypocalcemia (0.0%). According to our results, therapeutic inertia seems to be a more common problem than overtreatment for all the CKD-MBD laboratory parameters that we examined. Therapeutic inertia frequency was highest for hypovitaminosis D (81.1%), followed by hypocalcemia (75.0%), hyperparathyroidism (59.0%), and hyperphosphatemia (30.4%). CONCLUSION: We concluded that CKD-MBD is not optimally managed in CKD stage 3 - 5 ND patients. Clinicians should have an active attitude regarding the correction of MBD even at the earlier stages of CKD.

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

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Multicenter, pragmatic, cluster-randomized clinical trial. SETTING & PARTICIPANTS: 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. INTERVENTION: 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). OUTCOMES: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. RESULTS: The trial is currently enrolling. LIMITATIONS: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. CONCLUSIONS: 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. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04095039.

State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective.

Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.

Modification and Validation of the Phosphate Removal Model: A Multicenter Study.

BACKGROUND: Our research group has previously reported a noninvasive model that estimates phosphate removal within a 4-h hemodialysis (HD) treatment. The aim of this study was to modify the original model and validate the accuracy of the new model of phosphate removal for HD and hemodiafiltration (HDF) treatment. METHODS: A total of 109 HD patients from 3 HD centers were enrolled. The actual phosphate removal amount was calculated using the area under the dialysate phosphate concentration time curve. Model modification was executed using second-order multivariable polynomial regression analysis to obtain a new parameter for dialyzer phosphate clearance. Bias, precision, and accuracy were measured in the internal and external validation to determine the performance of the modified model. RESULTS: Mean age of the enrolled patients was 63 ± 12 years, and 67 (61.5%) were male. Phosphate removal was 19.06 ± 8.12 mmol and 17.38 ± 6.75 mmol in 4-h HD and HDF treatments, respectively, with no significant difference. The modified phosphate removal model was expressed as Tpo4 = 80.3 × C45 - 0.024 × age + 0.07 × weight + ß × clearance - 8.14 (ß = 6.231 × 10-3 × clearance - 1.886 × 10-5 × clearance2 - 0.467), where C45 was the phosphate concentration in the spent dialysate measured at the 45th minute of HD and clearance was the phosphate clearance of the dialyzer. Internal validation indicated that the new model was superior to the original model with a significantly smaller bias and higher accuracy. External validation showed that R2, bias, and accuracy were not significantly different than those of internal validation. CONCLUSIONS: A new model was generated to quantify phosphate removal by 4-h HD and HDF with a dialyzer surface area of 1.3-1.8 m2. This modified model would contribute to the evaluation of phosphate balance and individualized therapy of hyperphosphatemia.

Management of Hyperphosphatemia in End-Stage Renal Disease: A New Paradigm.

Bone and mineral metabolism becomes dysregulated with progression of chronic kidney disease (CKD), and increasing levels of parathyroid hormone serve as an adaptive response to maintain normal phosphorus and calcium levels. In end-stage renal disease, this response becomes maladaptive and high levels of phosphorus may occur. We summarize strategies to control hyperphosphatemia based on a systematic literature review of clinical trial and real-world observational data on phosphorus control in hemodialysis patients with CKD-mineral bone disorder (CKD-MBD). These studies suggest that current management options (diet and lifestyle changes; regular dialysis treatment; and use of phosphate binders, vitamin D, calcimimetics) have their own benefits and limitations with variable clinical outcomes. A more integrated approach to phosphorus control in dialysis patients may be necessary, incorporating measurement of multiple biomarkers of CKD-MBD pathophysiology (calcium, phosphorus, and parathyroid hormone) and correlation between diet adjustments and CKD-MBD drugs, which may facilitate improved patient management.

Hyperphosphataemia in 2019: have we made progress?

PURPOSE OF REVIEW: This review describes recent developments in the management of serum phosphate in dialysis patients, with a focus on the development of recent trials which randomize patients to different levels of control. RECENT FINDINGS: We review the uncertainties around clinical benefits of serum phosphate control and alternative approaches to current management, as well as a multinational attempt to conduct randomized controlled trials in this area. We discuss novel methods of limiting oral phosphate absorption. SUMMARY: Although numerous guidelines and target ranges for serum phosphate management exist, they are largely based on observational data and there is no definitive evidence that good control improves the length or quality of life of dialysis patients. New phosphate binders continue to appear on the market with increasing financial cost but without additional meaningful outcome data. Two recently published trials have demonstrated the feasibility of a large-scale study of differing phosphate levels to test the hypothesis that reduction of serum phosphate is beneficial to dialysis patients. Restriction of oral phosphate intake should not be overlooked.

Mineral disorders in pediatric pre-emptive kidney transplantation.

BACKGROUND: Pre-emptive kidney transplantation (PEKT) is beneficial for patients, improves graft survival and minimizes the complications associated with chronic kidney disease. Reports on pediatric PEKT, however, are limited, and little is known about the parathyroid hormone (PTH) abnormalities and calcium-phosphorus disorders (CPD) in this condition. This study was the first to report on mineral disorders in pediatric PEKT patients during a 1 year period. METHODS: We conducted a comparative examination of the abnormalities in calcium, phosphorus, calcium-phosphorus products and PTH before and 1 year after living donor kidney transplantation in PEKT and non-PEKT patients. RESULTS: Thirty-one patients were included. The patients were divided into two groups: PEKT (n = 11; 5 months in CKD stage 4-5) and non-PEKT (n = 20; 31.5 months in dialysis). Mean age at transplantation was 9.4 ± 5.0 years. Hypercalcemia and hyperphosphatemia were observed before and after transplantation in the PEKT and non-PEKT groups, and >15% of patients in each group had bone disorder and ectopic calcification associated with mineral disorder. Mineral disorder was present for approximately 3 months after transplantation in both treatment groups. CONCLUSIONS: No significant differences in PTH or CPD were noted between PEKT and non-PEKT groups; moreover, normalization of abnormal values did not differ between the PEKT and non-PEKT groups. Compared with non-PEKT, PEKT did not improve the course of mineral metabolism disorders. Mineral and bone disorder treatment was likely insufficiently provided to pediatric PEKT patients. To obtain the maximum advantage of PEKT, calcium and phosphorus levels should be strictly controlled before kidney transplantation.

Prevention and treatment of hyperphosphatemia in chronic kidney disease.

Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field.

Dialysis as a Treatment Option for a Patient With Normal Kidney Function and Familial Tumoral Calcinosis Due to a Compound Heterozygous FGF23 Mutation.

Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.

Should phosphate management be limited to the KDIGO/ KDOQI guidelines?

Hyperphosphatemia is a common complication of CKD. Prior to development of overt hyperphosphatemia, there are several adaptive mechanisms that occur to maintain normal phosphorus equilibrium in patients with CKD. These include an early and progressive rise in fibroblast growth factor 23 (FGF 23), followed by an increase in parathyroid hormone (PTH) with a decrease in 1,25-dihydroxyvitamin D (1,25 Vit D). Over the last 20 years, a large number of studies have shown that hyperphosphatemia is a strong predictor of adverse clinical outcomes including increased incidence of vascular calcification, cardiovascular disease, and all-cause mortality in both individuals with CKD as well as those with normal kidney function. In addition, elevations of both FGF 23 and PTH are independently associated with increased morbidity and mortality. Therefore, phosphorus lowering therapies are a vital part of the treatment strategy for patients with CKD and include dietary phosphorus restriction, treatment with phosphate binders and removal with dialysis. However, there has been a lack of high quality evidence demonstrating beneficial effects of phosphate lowering therapy on clinical outcomes. Furthermore, we do not have definitive data as to whether effective phosphate control with phosphate binders will prevent elevations in FGF 23, and whether lowering FGF 23 levels will lead to improved patient outcomes. As a result of the presently available data (or lack thereof) clinical guidelines recommend treatment only after hyperphosphatemia develops and in dialysis patients; KDOQI recommends a treatment target of less than 5.5 mg/dL, whereas KDIGO recommends treating "towards normal." We are left with a clinical dilemma, being whether these recommendations are adequate, or should we be more aggressive in phosphate management. In this article, our goal is to discuss some of the studies concerning the adverse consequences of phosphate excess and as well as elevated FGF 23 levels, and present our opinion on what we believe the goal of treatment should be.

Phosphate Removal During Conventional Hemodialysis: a Decades-Old Misconception.

BACKGROUND/AIMS: Hyperphosphatemia is associated with high mortality rate in patients on dialysis. Conventional hemodialysis (HD) is a limit technique in removing phosphate (P). There is a widespread belief that P is removed mainly in the first hour of HD. The aim of this study was to certify the percentage of 1-hour removal of P as compared to the entire procedure. METHODS: data from the first dialysis of the week of 21 patients (13 men, age 44±15 years), for 3 consecutive dialysis sessions were evaluated. Fresh dialysate samples were collected at 1 hour and at the end of the session from a partial spent dialysate collection method. RESULTS: Pre dialysis serum P was 4.7±1.7 mg/dl. Reduction rate of serum P was 47.4 ± 14.3 and 45.1 ± 10.8% in 1- and 4-hour of HD, respectively (p=0.322). P removal was 194 (145, 242) mg in 1-hour (p<0.0001), which represents 25.0 ± 0.2% of the total removed during the entire HD. Patients with pre dialysis P ≥ 5.5mg/dl had higher P removal during HD than those with P < 5.5mg/dl [975 (587, 1354) vs. 776 (580, 784) mg, p=0.025], although the percentage of removal in 1 hour was not different from those with P < 5.5mg/d (24.9 ± 0.3 vs. 25.0 ± 0.1%, p=0.918). P removal during dialysis correlated with pre dialysis serum P (r=0.455, p=0.001), parathormone (r=0.264, p=0.037) and ultrafiltration volume (r=0.343, p=0.019). CONCLUSION: despite the P serum concentration normalizing in the first hour of hemodialysis, the removal in the same period reaches only 25% of the entire session.

Hyperphosphatemic tumoral calcinosis caused by FGF23 compound heterozygous mutations: what are the therapeutic options for a better control of phosphatemia?

BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels. CASE-DIAGNOSIS/TREATMENT: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery. CONCLUSIONS: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.

Impact of using two dialyzers in parallel on phosphate clearance in hemodialysis patients: a randomized trial.

BACKGROUND: Dietary restriction and phosphate binders are the main interventions used to manage hyperphosphatemia in people on hemodialysis, but have limited efficacy. Modifying conventional dialysis regimens to enhance phosphate clearance as an alternative approach remains relatively unstudied. METHODS: This was a 10-week, 2-arm, randomized crossover study. Participants were prevalent dialysis patients ( n = 32) with consecutive serum phosphate levels >1.6 mmol/L and on stable doses of a phosphate binder. Following a 2-week run-in period, participants were randomized to initiate dialysis using two high flux dialyzers in parallel (blood flow ≥350 mL/min, dialysate flow 800 mL/min) or standard dialysis using one high flux dialyzer (blood flow ≥350 mL/min, dialysate flow of 800 mL/min). Each regimen was 3 weeks in duration. After a 2-week washout period, participants received the alternate regimen. The primary outcome was the mean difference in phosphate clearance by dialyzer strategy. Secondary outcomes were phosphate removal and pre-dialysis serum phosphate. RESULTS: Phosphate clearance for the double dialyzer strategy did not differ significantly from the single dialyzer strategy [mean difference 7.5 mL/min (95% confidence interval, 95% CI, -6.1, 21.0), P = 0.28]. There was no difference in total phosphate removal and pre-dialysis phosphate between the double and single dialyzer strategies [total phosphate removal mean difference -0.2 mmol (95% CI -4.1, 3.7), P = 0.93; pre-dialysis mean difference 0.01 mmol/L (95% CI -0.18, 0.21), P = 0.88]. There was no difference in the proportion of participants who experienced at least one episode of intradialytic hypotension (32 versus 47%, P = 0.13). A limitation of the study was frequent protocol deviations in the dialysis prescription. CONCLUSIONS: In this study, the use of two dialyzers in parallel did not increase phosphate clearance, phosphate removal or pre-dialysis serum phosphorus when compared with a standard dialysis treatment strategy. Future studies should continue to evaluate novel methods of phosphate removal using conventional hemodialysis.

Analysis of Hypo- and Hyperphosphatemia in an Intensive Care Unit Cohort.

BACKGROUND: Blood phosphate levels are vulnerable to fluctuations and changes in phosphate levels are often neglected. The aim of this study was to evaluate whether deviations in phosphate levels correlate to higher 180-day overall mortality or morbidity. METHODS: Four thousand six hundred fifty-six patients with 19,467 phosphate values treated at the adult intensive care unit at Skåne University Hospital, Lund, Sweden during 2006-2014 were retrospectively divided into a control group and 3 study groups: hypophosphatemia, hyperphosphatemia, and a mixed group showing both hypo/hyperphosphatemia. Sex, age, disease severity represented by maximal organ system Sequential Organ Failure Assessment score, renal Sequential Organ Failure Assessment score, lowest ionized calcium value, and diagnoses classes were included in a Cox hazard model to adjust for confounding factors, with time to death in the first 180 days from the intensive care unit (ICU) admission as outcome. RESULTS: When compared to normophosphatemic controls, the hyperphosphatemic study group was associated with higher risk of death with a hazard ratio of 1.2 (98.3% confidence interval 1.0-1.5, P = .0089). Mortality in the hypophosphatemic or mixed study group did not differ from controls. The mixed group showed markedly longer ventilator times and ICU stays compared to all other groups. CONCLUSIONS: Phosphate alterations in ICU patients are common and associated with worse morbidity and mortality. Many underlying pathophysiologic mechanisms may play a role. A rapidly changing phosphate level or isolated hypo or hyperphosphatemia should be urgently corrected.

Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder.

PURPOSE OF REVIEW: In this paper, we review the pathogenesis and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD), especially as it relates to pediatric CKD patients. RECENT FINDINGS: Disordered regulation of bone and mineral metabolism in CKD may result in fractures, skeletal deformities, and poor growth, which is especially relevant for pediatric CKD patients. Moreover, CKD-MBD may result in extra-skeletal calcification and cardiovascular morbidity. Early increases in fibroblast growth factor 23 (FGF23) levels play a key, primary role in CKD-MBD pathogenesis. Therapeutic approaches in pediatric CKD-MBD aim to minimize complications to the growing skeleton and prevent extra-skeletal calcifications, mainly by addressing hyperphosphatemia and secondary hyperparathyroidism. Ongoing clinical trials are focused on assessing the benefit of FGF23 reduction in CKD. CKD-MBD is a systemic disorder that has significant clinical implications. Treatment of CKD-MBD in children requires special consideration in order to maximize growth, optimize skeletal health, and prevent cardiovascular disease.

Management of phosphorus load in CKD patients.

Disturbances in mineral and bone metabolism play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). The term "renal osteodystrophy" has recently been replaced with "CKD-mineral and bone disorder (CKD-MBD)", which includes vascular calcification as well as bone abnormalities. In Japan, proportions of the aged and long-term dialysis patients are increasing which makes management of vascular calcification and parathyroid function increasingly more important. There are three main strategies to manage phosphate load: phosphorus dietary restriction, administration of phosphate binder and to ensure in the CKD 5D setting, an adequate dialysis.

Phosphate-a poison for humans?

Maintenance of phosphate balance is essential for life, and mammals have developed a sophisticated system to regulate phosphate homeostasis over the course of evolution. However, due to the dependence of phosphate elimination on the kidney, humans with decreased kidney function are likely to be in a positive phosphate balance. Phosphate excess has been well recognized as a critical factor in the pathogenesis of mineral and bone disorders associated with chronic kidney disease, but recent investigations have also uncovered toxic effects of phosphate on the cardiovascular system and the aging process. Compelling evidence also suggests that increased fibroblastic growth factor 23 and parathyroid hormone levels in response to a positive phosphate balance contribute to adverse clinical outcomes. These insights support the current practice of managing serum phosphate in patients with advanced chronic kidney disease, although definitive evidence of these effects is lacking. Given the potential toxicity of excess phosphate, the general population may also be viewed as a target for phosphate management. However, the widespread implementation of dietary phosphate intervention in the general population may not be warranted due to the limited impact of increased phosphate intake on mineral metabolism and clinical outcomes. Nonetheless, the increasing incidence of kidney disease or injury in our aging society emphasizes the potential importance of this issue. Further work is needed to more completely characterize phosphate toxicity and to establish the optimal therapeutic strategy for managing phosphate in patients with chronic kidney disease and in the general population.

Optimal management of bone mineral disorders in chronic kidney disease and end stage renal disease.

PURPOSE OF REVIEW: The review summarizes recent studies on chronic kidney disease-mineral bone disorders, with a focus on new developments in disease management. RECENT FINDINGS: The term chronic kidney disease-mineral bone disorder has come to describe an increasingly complex network of alterations in minerals and skeletal disorders that contribute to the significant cardiovascular morbidity and mortality seen in patients with chronic kidney disease and end stage renal disease. Clinical studies continue to suggest associations with clinical outcomes, yet current clinical trials have failed to support causality. Variability in practice exists as current guidelines for management of mineral bone disorders are often based on weak evidence. Recent studies implicate novel pathways for therapeutic intervention in clinical trials. SUMMARY: Mineral bone disorders in chronic kidney disease arise from alterations in a number of molecules in an increasingly complex physiological network interconnecting bone and the cardiovascular system. Despite extensive associations with improved outcomes in a number of molecules, clinical trials have yet to prove causality and there is an absence of new therapies available to improve patient outcomes. Additional clinical trials that can incorporate the complexity of mineral bone disorders, and with the ability to intervene on more than one pathway, are needed to advance patient care.

Long-Term Evaluation of Colestilan in Chronic Kidney Disease Stage 5 Dialysis Patients with Hyperphosphataemia.

BACKGROUND: This study investigated in a North American patient population the longer-term treatment effects of the phosphate binder, colestilan, in patients with CKD Stage 5D and hyperphosphataemia. METHODS: One hundred and sixteen CKD Stage 5D patients with hyperphosphataemia were entered into a multi-centre, open-label study where they received flexible dose colestilan (6-15 g/day) to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl. The primary endpoint was safety, assessed by treatment-emergent adverse events. Efficacy was assessed by changes in serum phosphorus, mineral metabolism, lipids, HbA1c, uric acid and bone markers. RESULTS: Serum phosphorus was significantly reduced by 1.18 mg/dl (p < 0.001), from 6.99 mg/dl at baseline to 5.80 mg/dl at week 52. LDL-cholesterol was also significantly reduced as well as uric acid. Significant change was observed only for one bone marker - PINP. Most adverse events were of mild or moderate intensity. Nausea (22.4%), vomiting (21.6%), and diarrhoea (19.8%) were most commonly reported. CONCLUSIONS: Long-term flexible dosing with colestilan reduces serum phosphorus and demonstrates an acceptable safety and tolerability profile.