Vitamin D status and intermediate vascular and bone outcomes in chronic kidney disease: a secondary post hoc analysis of IMPROVE-CKD.

BACKGROUND AND AIMS: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and has been associated with abnormalities of mineral metabolism and vascular calcification. Vitamin D influences parathyroid hormone values and calcium and phosphate metabolism, and may play a role in vascular function and bone health. We aimed to test our hypothesis that vitamin D deficiency is associated with arterial stiffness, aortic calcification and lower bone mineral density (BMD) in patients with CKD. METHODS: A cross-sectional analysis was performed using baseline data from the IMpact of Phosphate Reduction On Vascular Endpoints in CKD (IMPROVE-CKD) study cohort. Clinical and laboratory parameters were compared between those with and without vitamin D deficiency, defined as 25-hydroxyvitamin D (25(OH)D) <50 nmol/L. Univariable and multivariable linear regression analyses were performed to assess associations between serum 25(OH)D levels and pulse wave velocity (PWV), augmentation index (AIx), abdominal aortic calcification (measured by the Agatston score) and lumbar spine BMD. RESULTS: Baseline 25(OHD) values were available in 208 out of 278 IMPROVE-CKD study participants, with a mean value of 70.1 ± 30.7 nmol/L. Of these, 57 (27%) patients had vitamin D deficiency. Those with 25(OH)D deficiency were more likely to have diabetes (56% vs 38%), cardiovascular disease (54% vs 36%) and lower serum calcium (2.29 ± 0.13 vs 2.34 ± 0.13 mmol/L). On univariable and multivariable regression analyses, baseline 25(OH)D values were not associated with PWV, the AIx, Agatston score or BMD. CONCLUSION: Baseline 25(OH)D levels were not associated with intermediate markers of vascular function and BMD in patients with CKD stages 3b and 4.

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.

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.

Relationship Between Dietary Phosphate Intake and Biomarkers of Bone and Mineral Metabolism in Australian Adults With Chronic Kidney Disease.

OBJECTIVE: Higher serum phosphate is associated with increased adverse outcomes including cardiovascular disease. Abnormalities of bone and mineral metabolism in chronic kidney disease (CKD), including higher serum phosphate, are important risk factors for increased cardiovascular disease. Associations between dietary phosphate intake and biochemical and cardiovascular parameters in non-dialysis CKD patients, however, have not been adequately studied. This study aimed to explore associations between phosphate intake and biomarkers of bone and mineral metabolism and intermediate cardiovascular markers in adults with stage 3-4 CKD. DESIGN AND METHODS: One hundred thirty-two participants enrolled in the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease trial were invited to participate in this sub-study. At baseline, dietary phosphate intake and its source (animal, plant, or a mixture of animal and plant) were determined using a 7-day self-administered diet food record, and measurements were made of serum and urinary phosphate, serum calcium, parathyroid hormone, fibroblast growth factor-23, and the intermediate cardiovascular markers pulse wave velocity (PWV) and abdominal aortic calcification. The relationships between dietary phosphate intake and these bone metabolism and cardiovascular markers were explored using Pearson's correlation and linear regression. The effect of source of phosphate intake was analyzed using compositional data analysis. RESULTS: Ninety participants (age 64 ± 12 years, 68% male, estimated glomerular filtration rate 26.6 ± 7.6 mL/min/1.73 m2, daily phosphate intake 1,544 ± 347 mg) completed the study. Correlations among dietary phosphate intake and biochemical measures, PWV, and abdominal aortic calcification ranged from r = -0.13 to r = +0.13. Linear regression showed no association between dietary phosphate measurements and biochemical or cardiovascular parameters. Source of phosphate intake was associated with PWV (P = .01), but not with other biomarkers of bone and mineral metabolism. Higher PWV values were associated with higher intake of plant-based relative to animal-based phosphate (1.058 [1.020-1.098], P = .003). CONCLUSION: Levels of total dietary phosphate intake measured by dietary food record show no statistically significant relationship with biochemical markers of bone and mineral metabolism or intermediate cardiovascular markers. Higher PWV levels associated with higher intake of plant-based relative to animal-based phosphate intake were an unexpected finding and further research is needed in this area.

The Australian Calciphylaxis Registry: reporting clinical features and outcomes of patients with calciphylaxis.

BACKGROUND: Calciphylaxis is a rare disease, predominantly affecting patients with chronic kidney disease (CKD) and associated with significant morbidity and mortality due to progressive cutaneous calcification, necrotic ulceration and infection. Clinical registries have been established to better understand the risk factors, optimal treatments and disease outcomes of calciphylaxis. METHODS: We established a prospective, Internet-based clinical registry for the online notification of calciphylaxis cases in Australia. Seven institutions participated, with data recorded on patient characteristics, biochemical parameters, treatments and disease outcomes. RESULTS: Between 2014 and 2019, 47 cases of calciphylaxis were registered. The mean patient age was 66 ± 11 years and body mass index was 35 ± 9 kg/m2, with a higher proportion of females (51%). Eighty-seven percent of patients had end-stage kidney disease (ESKD), with 61% on hemodialysis or hemodiafiltration, with a median dialysis vintage of 4.8 [interquartile range (IQR) 1.7-7.4)] years. Five patients had CKD not requiring dialysis and two were kidney transplant recipients. Diabetes was present in 76% of patients and the cause of ESKD in 60%; 34% received vitamin K antagonists (VKAs) before diagnosis. The median parathyroid hormone level at diagnosis was 32 (IQR 14-50) pmol/L. The most common site of calciphylaxis was the lower limbs (63%), with 19% of patients having more than one area involved. Ten patients (22%) had a resolution of calciphylaxis and 25 died, with 50% mortality at a median of 1.6 (IQR 0.2-2.5) years from diagnosis. CONCLUSIONS: The Australian Calciphylaxis Registry highlights risk factors for calciphylaxis, including diabetes, obesity and VKA use. Resolution of calciphylaxis is uncommon despite multimodal therapy and mortality from calciphylaxis in the first year following diagnosis remains high.

Serum phosphate and mortality in incident dialysis patients in Australia and New Zealand.

AIM: Hyperphosphataemia is associated with increased adverse outcomes, including mortality. Re-examining this association using up-to-date data reflecting current and real-world practices, across different global regions and in both haemodialysis and peritoneal dialysis patients, is important. METHODS: We describe the association between serum phosphate and all-cause and cardiovascular mortality in incident dialysis patients between 2008 and 2018 using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Time-dependent Cox proportionate hazards models were used. Models were adjusted for available covariates and fitted for the overall cohort, and also each dialysis modality. RESULTS: 31 989 patients were followed over 97 122 person-years at risk (mean age at first dialysis 61 years, 38% female, 67% haemodialysis). We observed a U-shaped association between serum phosphate and all-cause mortality. In the fully adjusted model, categories of serum phosphate above and below 1.25-1.99 mmol/L were associated with progressively higher risk, reaching a hazard ratio of 2.13 (95% CI 1.93-2.36, p < .001) for serum phosphate ≥2.75 mmol/L, and 1.56 (95% CI 1.44-1.69, p < .001) for serum phosphate <1.00 mmol/L. Low and high levels of serum phosphate were also associated with increased risk of cardiovascular mortality, however the association with high serum phosphate was more pronounced ("J-shaped relationship"). The associations were consistent across sub-analyses of patients receiving haemodialysis and peritoneal dialysis treatment. CONCLUSION: In this large contemporary dialysis cohort, both high and low levels of serum phosphate were independently associated with increased risk of mortality. Future studies are required to determine whether treatment of abnormal serum phosphate levels improves mortality.

Dietary Phosphate Consumption in Australians With Stages 3b and 4 Chronic Kidney Disease.

OBJECTIVE: Dietary phosphate modification is a common therapy to treat hyperphosphatemia in individuals with chronic kidney disease (CKD). However, current dietary intake and common food sources of phosphate typically consumed by individuals with CKD are not well characterized. This study examined a cohort of CKD patients to determine total dietary intake and common food sources of phosphate, including phosphate additives. DESIGN AND METHODS: Participants with CKD stages 3b and 4 recruited to a substudy of the "IMPROVE-CKD (IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease) Study" completed a 7-day self-administered diet record at baseline. Diet histories were analyzed and daily phosphate intakes determined using FoodWorks V.9 (Xyris). The proportion of phosphate contributed by each food group was determined using the AUSNUT 2011-2013 Food Classification System. Ingredient lists of packaged food items consumed were reviewed to determine frequency of phosphate-based additives. RESULTS: Ninety participants (mean eGFR 26.5 mL/min/1.73 m2) completed this substudy. Mean phosphate intake of participants was 1544 ± 347 mg/day, with 96% of individuals exceeding the recommended daily intake of phosphate (1000 mg/day). The highest sources of dietary phosphate were milk-based products (25%) and meat and poultry products/dishes (25%). Phosphate-based food additives were identified in 39% (n = 331/845) of packaged foods consumed by participants. CONCLUSION: Dietary phosphate intakes of Australians with CKD are high and come from a variety of sources. Managing dietary phosphate intake requires a patient-centered, tailored approach with an emphasis on maintaining nutritional adequacy and awareness of phosphate additives.

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.

Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial.

Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b-4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m2 and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1-202) pg/mL and 221.1 (154.3-334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63-5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.

Use of patient-reported outcome measures and patient-reported experience measures in renal units in Australia and New Zealand: A cross-sectional survey study.

AIM: Patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) are increasingly used in research to quantify how patients feel and function, and their experiences of care, however, knowledge of their utilization in routine nephrology is limited. METHODS: The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) PROMs working group conducted a prospective cross-sectional survey of PROMs/PREMs use among renal 'parent hospitals'. One survey per hospital was completed (August-November 2017). Descriptive statistics reported type and frequency of measures used and purpose of use. RESULTS: Survey response rate was 100%. Fifty-five of 79 hospitals (70%) used at least one PROMs or PREMs for specific patient groups. PROMs were more likely to be collected from patients receiving comprehensive conservative care (45% of hospitals) than dialysis patients (32%, 31% and 28% of hospitals for home haemodialysis, peritoneal dialysis and facility dialysis, respectively). Few renal transplanting hospitals (3%) collected PROMs. The Integrated Palliative Outcome Scale-Renal (IPOS-Renal) (40% of units), and the Euro-Qol (EQ-5D-5 L) (25%), were most frequently used. The main reason for collecting PROMs was to inform clinical care (58%), and for PREMs was to fulfil private dialysis/hospital provider requirements (25%). The most commonly reported reason for not using PROMs in 24 hospitals was insufficient staff resources (79%). Sixty-two hospitals (78%) expressed interest in participating in a registry-based PROMs trial. CONCLUSION: Many renal hospitals in Australia and New Zealand collect PROMs and/or PREMs as part of clinical care with use varying by treatment modality. Resources are a key barrier to PROMs use.

Fatal Dialysis Vascular Access Hemorrhage.

Bleeding from dialysis vascular access (arteriovenous fistulas, arteriovenous grafts, and vascular catheters) is uncommon. Death from these bleeds is rare and likely to be under-reported, with incident rates of fewer than 1 episode for every 1,000 patient-years on dialysis, meaning that dialysis units may experience this catastrophic event only once a decade. There is an opportunity to learn from (and therefore prevent) these bleeding deaths. We reviewed all reported episodes of death due to vascular access bleeding in Australia and New Zealand over a 14-year period together with individual dialysis units' root cause analyses on each event. In this perspective, we provide a clinically useful summary of the evidence and knowledge gained from these rare events. Our conclusion is that death due to dialysis vascular access hemorrhage is an uncommon, catastrophic, but potentially preventable event if the right policies and procedures are put in place.

Durable remission of C3 glomerulonephritis with mycophenolate mofetil.

In C3 glomerulopathy, uncontrolled complement C3 activation via the alternative pathway results in glomerular C3 deposition and, in many cases, progressive renal failure. Despite advances in understanding of C3G pathogenesis over the last few years, there are no proven treatments. We describe a patient in whom C3 glomerulopathy was associated with renal impairment and elevated serum free kappa light chains. An initial response to corticosteroids was followed by relapse once steroids were weaned, prompting use of mycophenolate mofetil to maintain remission. We discuss some of the diagnostic and therapeutic issues surrounding C3G, including in the setting of monoclonal gammopathy.

Plasma levels of enoxaparin oligosaccharides, antifactor-Xa and thrombin generation in patients undergoing haemodialysis.

: Low molecular weight heparins are used during haemodialysis for thromboprophylaxis of the dialysis circuit, with plasma antifactor-Xa (anti-Xa) activity used as a surrogate measure for effective anticoagulation. However, this pharmacokinetic parameter does not always correlate with pharmacodynamic effects in patients. The aim of this study was to investigate the relationship between actual plasma levels of the low molecular weight heparins enoxaparin, anti-Xa activity, and global coagulation measurement of thrombin generation during haemodialysis. Blood was analysed from 16 adult patients with end-stage kidney disease at 0, 2, 4 h, and at completion of 31 dialysis sessions where single fixed doses of 20 (n = 3), 40 (n = 16), 60 (n = 6), or 80 (n = 6) mg of enoxaparin (equating to 0.23-1.07 mg/kg) were used as thromboprophylaxis. Plasma enoxaparin oligosaccharides [degree of polymerization (dp)6-dp16] were measured by high-performance size exclusion chromatography, anti-Xa activity by colourimetric assay, and thrombin generation by calibrated automated thrombogram. Plasma enoxaparin fragments were undetectable at the beginning of each dialysis, peaked at 2 h to levels that correlated with dose (r = 0.68, P < 0.001) then remained relatively stable. In contrast, therapeutic anti-Xa levels achieved at 2 h in 18 cases (58%) quickly dropped to only six cases (19%) at the end of dialysis, by which time thrombin generation had also recovered in 81% of patients. Statistical modelling revealed a threshold value of anti-Xa at 0.53 IU/ml that supressed thrombin generation to 15.28% of baseline (P < 0.001). Despite loss of anticoagulant activity in the majority of patients, plasma levels of enoxaparin oligosaccharides remained detectable and relatively unchanged throughout dialysis.

Chronic Kidney Disease and Pulse Wave Velocity: A Narrative Review.

Chronic kidney disease (CKD) is associated with excess cardiovascular mortality, resulting from both traditional and nontraditional, CKD-specific, cardiovascular risk factors. Nontraditional risk factors include the entity Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) which is characterised by disorders of bone and mineral metabolism, including biochemical abnormalities of hyperphosphatemia and hyperparathyroidism, renal osteodystrophy, and vascular calcification. Increased arterial stiffness in the CKD population can be attributed amongst other influences to progression of vascular calcification, with significant resultant contribution to the cardiovascular disease burden. Pulse wave velocity (PWV) measured over the carotid-femoral arterial segments is the noninvasive gold-standard technique for measurement of aortic stiffness and has been suggested as a surrogate cardiovascular end-point. A PWV value of 10 m/s or greater has been recommended as a suitable cut-off for an increased risk of cardiovascular mortality. CKD is a risk factor for an excessive rate of increase in aortic stiffness, reflected by increases in PWV, and increased aortic PWV in CKD shows faster progression than for individuals with normal kidney function. Patients with varying stages of CKD, as well as those on dialysis or with a kidney transplant, have different biological milieu which influence aortic stiffness and associated changes in PWV. This review discusses the pathophysiology of arterial stiffness with CKD and outlines the literature on PWV across the spectrum of CKD, highlighting that determination of arterial stiffness using aortic PWV can be a useful diagnostic and prognostic tool for assessing cardiovascular disease in the CKD population.

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.

INTRODUCTION: Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD. METHODS AND ANALYSIS: We outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population-the IM pact of P hosphate R eduction O n V ascular E nd-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels. ETHICS AND DISSEMINATION: Ethical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ACTRN12610000650099.

Nonadherence to Medication Therapy in Haemodialysis Patients: A Systematic Review.

BACKGROUND: End-stage kidney disease (ESKD) patients are often prescribed multiple medications. Together with a demanding weekly schedule of dialysis sessions, increased number of medicines and associated regimen complexity pre-dispose them at high risk of medication nonadherence. This review summarizes existing literature on nonadherence and identifies factors associated with nonadherence to medication therapy in patients undergoing haemodialysis. METHODS: A comprehensive search of PubMed, Embase, CINAHL, PsycInfo, and Cochrane Database of Systematic Reviews covering the period from 1970 through November 2014 was performed following a predefined inclusion and exclusion criteria. Reference lists from relevant materials were reviewed. Data on study characteristics, measures of nonadherence, prevalence rates and factors associated with nonadherence were collected. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was followed in conducting this systematic review. RESULTS: Of 920 relevant publications, 44 were included. The prevalence of medication nonadherence varied from 12.5% to 98.6%, with widespread heterogeneity in measures and definitions employed. Most common patient-related factors significantly associated with nonadherence were younger age, non-Caucasian ethnicity, illness interfering family life, being a smoker, and living single and being divorced or widowed. Similarly, disease-related factors include longevity of haemodialysis, recurrent hospitalization, depressive symptoms and having concomitant illness like diabetes and hypertension. Medication-related factors such as daily tablet count, total pill burden, number of phosphate binders prescribed and complexity of medication regimen were also associated with poor adherence. CONCLUSIONS: A number of patient-, disease-, and medication-related factors are associated with medication nonadherence in haemodialysis patients. Clinicians should be aware of such factors so that adherence to medications can be optimised in haemodialysis patients. Future research should be directed towards well-designed prospective longitudinal studies developing standard definitions and validating available measurement tools, while focusing on the role of additional factors such as psychosocial and behavioural factors in predicting nonadherence to medications.