Association of Sevelamer Initiation with Gastrointestinal Bleeding Hospitalization in Individuals Requiring Hemodialysis.

INTRODUCTION: Case reports have suggested a causative role between sevelamer use and subsequent gastrointestinal bleeding (GIB), but no large observational studies have evaluated this association. METHODS: Using the United States Renal Data System database from 2015 to 2019, we examined the association between initiation of sevelamer (vs. non-sevelamer containing phosphate binders) and GIB hospitalization as well as all-cause mortality among individuals on hemodialysis. We emulated a target trial using Cox regression models and inverse probability of treatment weights to estimate the adjusted hazard ratios (HR) across outcomes and subgroups. RESULTS: Among 21,354 new users of phosphate binders (11,276 sevelamer and 10,078 non-sevelamer) with baseline lab data (calcium, phosphorus, hemoglobin, and albumin), there were 2,811 GIB hospitalizations and 5,920 deaths after a median follow-up of 1.3 years. Compared with the initiation of non-sevelamer binders, sevelamer was not associated with an increased risk of GIB hospitalization (89 vs. 90 events per 1,000 person-years; IPTW-HR: 0.98, 95% CI: 0.91-1.06) or all-cause mortality (220 vs. 224 events per 1,000 person-years; IPTW-HR: 0.98, 95% CI: 0.93-1.03). Subgroup analyses (such as diabetes and anti-coagulation use) were generally consistent, and there was no association between sevelamer dose and GIB hospitalization. CONCLUSION: Among patients requiring hemodialysis, sevelamer (vs. non-sevelamer) containing phosphate binders was not associated with increased risk of GIB hospitalization.

Calcium-based phosphate binders and bone mineral density in patients undergoing hemodialysis: a retrospective cohort study.

BACKGROUND: Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients. METHODS: Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4 years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated. RESULTS: The femoral neck's BMD decreased from 0.836 g/cm2 (0.702-0.952) to 0.764 g/cm2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4 years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833 g/cm2 (0.736-0.965) to 0.824 g/cm2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [ß-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [ß-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]. CONCLUSION: CBPB administration may be associated with BMD maintenance.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

Effect of lanthanum carbonate on serum calciprotein particles in patients with stage 3-4 CKD-results from a placebo-controlled randomized trial.

BACKGROUND: Calciprotein particles (CPP) are colloidal aggregates of calcium phosphate and the mineral-binding protein fetuin-A, and are potential mediators of cardiovascular disease in chronic kidney disease (CKD). Emerging evidence suggests non-calcium-containing phosphate binders may reduce serum CPP in patients with kidney failure who require dialysis; however, it is unclear whether similar interventions are effective in patients with earlier stages of CKD. METHODS: The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) was a multi-centre, placebo-controlled, randomized trial of lanthanum carbonate on cardiovascular markers in 278 participants with stage 3b/4 CKD. In this pre-specified exploratory analysis, primary (CPP-I) and secondary CPP (CPP-II) were measured in a sub-cohort of participants over 96 weeks. Treatment groups were compared using linear mixed-effects models and the relationship between serum CPP and pulse wave velocity (PWV) and abdominal aortic calcification (AAC) was examined. RESULTS: A total of 253 participants had CPP data for baseline and at least one follow-up timepoint and were included in this analysis. The mean age was 62.4 ± 12.6 years, 32.0% were female and the mean estimated glomerular filtration rate (eGFR) was 26.6 ± 8.3 mL/min/1.73 m2. Baseline median serum CPP-I was 14.9 × 104 particles/mL [interquartile range (IQR) 4.6-49.3] and median CPP-II was 3.3 × 103 particles/mL (IQR 1.4-5.4). There was no significant difference between treatment groups at 96 weeks in CPP-I [22.8% (95% confidence interval -39.2, 36.4), P = 0.65] or CPP-II [-18.3% (95% confidence interval -40.0, 11.2), P = 0.20] compared with a placebo. Serum CPP were not correlated with baseline PWV or AAC, or with the progression of either marker. CONCLUSIONS: Lanthanum carbonate was not associated with a reduction of CPP at 96 weeks when compared with a placebo in a CKD cohort.

Interventions To Attenuate Vascular Calcification Progression in Chronic Kidney Disease: A Systematic Review of Clinical Trials.

BACKGROUND: Vascular calcification is associated with cardiovascular morbidity and mortality in people with CKD. Evidence-based interventions that may attenuate its progression in CKD remain uncertain. METHODS: We conducted a systematic review of prospective clinical trials of interventions to attenuate vascular calcification in people with CKD, compared with placebo, another comparator, or standard of care. We included prospective clinical trials (randomized and nonrandomized) involving participants with stage 3-5D CKD or kidney transplant recipients; the outcome was vascular calcification measured using radiologic methods. Quality of evidence was determined by the Cochrane risk of bias assessment tool and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method. RESULTS: There were 77 trials (63 randomized) involving 6898 participants eligible for inclusion (median sample size, 50; median duration, 12 months); 58 involved participants on dialysis, 15 involved individuals with nondialysis CKD, and 4 involved kidney transplant recipients. Risk of bias was moderate over all. Trials involving magnesium and sodium thiosulfate consistently showed attenuation of vascular calcification. Trials involving intestinal phosphate binders, alterations in dialysate calcium concentration, vitamin K therapy, calcimimetics, and antiresorptive agents had conflicting or inconclusive outcomes. Trials involving vitamin D therapy and HMG-CoA reductase inhibitors did not demonstrate attenuation of vascular calcification. Mixed results were reported for single studies of exercise, vitamin E-coated or high-flux hemodialysis membranes, interdialytic sodium bicarbonate, SNF472, spironolactone, sotatercept, nicotinamide, and oral activated charcoal. CONCLUSIONS: Currently, there are insufficient or conflicting data regarding interventions evaluated in clinical trials for mitigation of vascular calcification in people with CKD. Therapy involving magnesium or sodium thiosulfate appears most promising, but evaluable studies were small and of short duration.

Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD.

BACKGROUND: Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD. METHODS: We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. RESULTS: In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant. CONCLUSIONS: Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.

Differences in Phosphate and Parathyroid Hormone Concentrations over the Day among Patients on Hemodialysis.

BACKGROUND: Elevated serum phosphate and parathyroid hormone (PTH) concentrations are associated with cardiovascular events, bone disease, and mortality in patients on maintenance hemodialysis. Although circadian changes are known in people with CKD, it is unknown whether differences occur in these parameters over the course of a day in people receiving hemodialysis. METHODS: We used clinical data from Fresenius Medical Care US dialysis clinics to determine how the time of day when measurements were collected (hemodialysis treatment start time) may be associated with serum phosphate and PTH concentrations. We used harmonic regression to assess these associations while accounting for demographic data and treatment parameters. RESULTS: A total of 96,319 patients receiving maintenance hemodialysis were included in this analysis. Patients had a mean age of 64±14 years, 43% were women, and dialysis start times ranged from 3:00 am to 7:59 pm. The mean serum phosphate concentration was 5.2±1.5 mg/dl, and the median PTH was 351 pg/ml (interquartile range [IQR], 214-547). In fully adjusted models, serum phosphate had a nadir at 11:00 am of 4.97 (IQR, 4.94-5.01) mg/dl and a peak at 7:00 pm of 5.56 (IQR, 5.50-5.62) mg/dl. Serum PTH had a nadir at 9:00 am of 385 (IQR, 375-395) pg/ml and a peak at 7:00 pm of 530 (IQR, 516-547) pg/ml. CONCLUSIONS: Among patients receiving maintenance hemodialysis, concentrations of PTH and phosphate before a dialysis session vary with the time of day that these values are measured. Consideration of whether these values were obtained at peak or nadir times of the day may be important in treatment decisions.

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure.

BACKGROUND: Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. METHODS: We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies. RESULTS: The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress. CONCLUSION: In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Gut Microbiome-Derived Uremic Toxin Levels in Hemodialysis Patients on Different Phosphate Binder Therapies.

INTRODUCTION: Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. METHODS: Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. RESULTS: The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, p < 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5-7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. CONCLUSION: There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.

Impact of phosphate binders on quality of life in dialysis patients: Results from the prospective Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes study.

BACKGROUND: Phosphate binders cause high pill burden for dialysis patients, complicate medication regimens, and have unpleasant taste and large size which may affect patients' quality of life. This study explores the association between phosphate binder pill burden and health-related quality of life (HRQoL) in dialysis patients. METHODS: We conducted a cross-sectional multi-centre cohort study in 21 Dutch dialysis centres. Phosphate binder pill burden was extracted from electronic patient records. Primary outcome was HRQoL measured with the Short Form 12 physical and mental component summary scores (PCS and MCS). Secondary endpoints were severity of gastro-intestinal symptoms, itching, dry mouth, and mental health symptoms, measured with the Dialysis Symptom Index. RESULTS: Of 388 included patients, aged 62 ± 16 years, 77% underwent haemodialysis. PCS scores were comparable for patients with and without phosphate binders. Patients using 1-3 pills reported lower scores for decreased appetite (ß -0.5; 95%CI -0.9 to -0.2), implying better appetite, than patients without phosphate binders. Patients using 4-6 pills also reported lower scores for decreased appetite (ß -0.5; 95%CI -0.8 to -0.1) and for itching (ß -0.5; 95%CI -0.9 to -0.1). Patients using >6 pills reported lower MCS (ß -2.9; 95%CI -6.2-0.4) and higher scores for feeling nervous (ß 0.6; 95%CI 0.1-1.1) and feeling sad (ß 0.4; 95%CI 0.0-0.9). CONCLUSION: Phosphate binder pill burden is not associated with physical quality of life. A higher pill burden is associated with better appetite and less itching. Patients using >6 pills per day report lower mental quality of life and felt nervous and sad more often.

Effects of phosphate binders on bone biomarkers and bone density in haemodialysis patients.

AIM: The incidences of osteoporosis, fracture and vascular calcification increase concordantly with the progression of chronic kidney disease (CKD). CKD-mineral bone disease (CKD-MBD) induced by hyperphosphatemia is a major pathophysiologic mechanism. The effects of phosphate binders on bone turnover biomarkers and bone mineral density (BMD) in haemodialysis patients are still inconclusive. Our aim is to demonstrate the effects of these phosphate binders on different aspects of CKD-MBD. METHODS: We conducted a prospective cohort of 65 haemodialysis patients to investigate the effect of 12-month monotherapy of phosphate binders composing calcium-based phosphate binders (CPB) or non-calcium-based phosphate binders (NCPB), including sevelamer and lanthanum, on bone turnover biomarkers and BMD changes. The performance of bone turnover biomarkers to predict low BMD was attentively determined. RESULTS: When compared with CPB, NCPB use was associated with higher levels of bone turnover biomarkers. NCPB was also associated with lower BMD at lumbar and distal radius. Total procollagen type 1N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase 5b (TRAP5b) provided the best performance for diagnosing low BMD in haemodialysis patients. CONCLUSION: Switching from CPB to NCPB might increase bone biomarkers and prevent the development of adynamic bone disease. On the contrary, NCPB should be cautiously used in haemodialysis patients who already had low BMD. P1NP, BALP and TRAP5b could be used to guide the appropriate management, including anti-resorptive and anabolic medications, and predict low BMD in haemodialysis patients treated with phosphate binders.

Optimal Phosphate Control Related to Coronary Artery Calcification in Dialysis Patients.

BACKGROUND: In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges. METHODS: We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment. RESULTS: The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1; P=0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants (P value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores. CONCLUSIONS: Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.

A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY).

BACKGROUND: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis. METHODS: This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. RESULTS: Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, P<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. CONCLUSIONS: A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: AMPLIFY, NCT03824587.

Effect of Neighborhood Food Environment and Socioeconomic Status on Serum Phosphorus Level for Patients on Chronic Dialysis.

BACKGROUND: Elevated blood phosphorus levels are common and associated with a greater risk of death for patients receiving chronic dialysis. Phosphorus-rich foods are prevalent in the American diet, and low-phosphorus foods, including fruits and vegetables, are often less available in areas with more poverty. The relative contributions of neighborhood food availability and socioeconomic status to phosphorus control in patients receiving dialysis are unknown. METHODS: Using longitudinal data from a national dialysis provider, we constructed hierarchical, linear mixed-effects models to evaluate the relationships between neighborhood food environment or socioeconomic status and serum phosphorus level among patients receiving incident dialysis. RESULTS: Our cohort included 258,510 patients receiving chronic hemodialysis in 2005-2013. Median age at dialysis initiation was 64 years, 45% were female, 32% were Black, and 15% were Hispanic. Within their residential zip code, patients had a median of 25 "less-healthy" food outlets (interquartile range, 11-40) available to them compared with a median of four "healthy" food outlets (interquartile range, 2-6). Living in a neighborhood with better availability of healthy food was not associated with a lower phosphorus level. Neighborhood income also was not associated with differences in phosphorus. Patient age, race, cause of ESKD, and mean monthly dialysis duration were most closely associated with phosphorus level. CONCLUSIONS: Neither neighborhood availability of healthy food options nor neighborhood income was associated with phosphorus levels in patients receiving chronic dialysis. Modifying factors, such as nutrition literacy, individual-level financial resources, and adherence to diet restrictions and medications, may be more powerful contributors than food environment to elevated phosphorus.

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

BACKGROUND: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. METHODS: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. RESULTS: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. CONCLUSIONS: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Australian Clinical Trials Registry, ACTRN12610000650099.

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

BACKGROUND: Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown. METHODS: We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. RESULTS: Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. CONCLUSION: Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

Magnesium but not nicotinamide prevents vascular calcification in experimental uraemia.

BACKGROUND: Optimal phosphate control is an unmet need in chronic kidney disease (CKD). High serum phosphate increases calcification burden and is associated with mortality and cardiovascular disease in CKD. Nicotinamide (NA) alone or in combination with calcium-free phosphate binders might be a strategy to reduce phosphate levels and calcification and thus impact cardiovascular disease in CKD. METHODS: We studied the effect of NA alone and in combination with magnesium carbonate (MgCO3) as a potential novel treatment strategy. CKD was induced in dilute brown non-agouti/2 mice by subtotal nephrectomy followed by a high-phosphate diet (HP) and 7 weeks of treatment with NA, MgCO3 or their combination. Control mice underwent subtotal nephrectomy and received an HP or underwent sham surgery and received standard chow plus NA. RESULTS: CKD mice showed increased serum fibroblast growth factor 23 and calcium-phosphate product that was normalized by all treatment regimes. NA alone increased soft tissue and vascular calcification, whereas any treatment with MgCO3 significantly reduced calcification severity in CKD. While MgCO3 supplementation alone resulted in decreased calcification severity, it resulted in increased intestinal expression of the phosphate transporters type II sodium-dependent phosphate transporter 1 (Pit-1). Combined therapy of MgCO3 and NA reduced tissue calcification and normalized expression levels of intestinal phosphate transporter proteins. CONCLUSIONS: In conclusion, the data indicate that NA increases while MgCO3 reduces ectopic calcification severity. Augmented expression of intestinal phosphate transporters by MgCO3 treatment was abolished by the addition of NA. However, the clinical relevance of the latter remains to be explored. Importantly, the data suggest no benefit of NA regarding treatment of calcification in addition to MgCO3.

Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients.

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by -3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by -17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was -7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by -13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Controversies in the Management of Secondary Hyperparathyroidism in Chronic Kidney Disease.

Secondary hyperparathyroidism is a frequent complication of chronic kidney disease that begins early in the course of renal insufficiency as an adaptive response to maintain mineral homeostasis. This complex disorder affects the bone, leading to an increase in fracture risk and is associated with increased risks of vascular calcification and mortality. PURPOSE OF REVIEW: In this review, we examine the different strategies available to manage secondary hyperparathyroidism. Particularly, we focus on the adequate control of serum phosphorus by restricting intake and the use of phosphate binders, correction of hypocalcemia while minimizing calcium burden, and reduction in PTH levels through the use of vitamin D sterols and calcimimetics. RECENT FINDINGS: It was observed that although numerous agents directed at the correction of these abnormalities have demonstrated effectiveness on biochemical markers, there is still a relative scarcity of studies demonstrating treatment effectiveness as measured by hard clinical outcomes. In addition, most agents have side effects that may limit their use, even in patients in which the treatment has demonstrated efficacy in controlling these parameters. There is still controversy as to what therapeutic regimens to choose for a particular patient and what parameter should be used to follow their effects, including outcomes, side effects, pill burden, and costs, among others. In the present article, we analyze controversial aspects of the different therapeutic agents available. Although many tools and regimens are available, no one by itself is enough for an adequate management of the patient. But rather, combined therapy and individualization of approaches are recommended for better results. We suggest that new studies analyzing the effectiveness of therapeutic approaches to the management of secondary hyperparathyroidism should be directed not only to controlling parathyroid hormone levels but also to the evaluation of long-term outcomes, based on modification of morbidity, mortality, and end organ impact, while reducing side effects and controlling costs, among others.

The Importance of Adherence in the Treatment of Secondary Hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) is a frequent condition in the presence of chronic kidney disease (CKD). In CKD patients, SHPT is reported to increase both morbidity and mortality, especially cardiovascular. The difficulty in the treatment of SHPT in clinical practice is frequently encountered from a not always adequate conduct of the clinicians and a common non-compliance to the therapy of CKD patients. In this review, the greatest difficulties from clinicians and CKD-patients' point of view in the treatment of SHPT will be addressed, with particular attention to those related to dialysis features, nutritional habits, and medical therapy.