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.

Chronic kidney disease-related sarcopenia as a prognostic indicator in elderly haemodialysis patients.

BACKGROUND: The mortality of dialysis patients greatly exceeds that of the general population and identifying predictive factors for mortality may provide opportunities for earlier intervention. This study assessed the influence of sarcopenia on mortality in patients on haemodialysis. METHODS: This prospective, observational study enrolled 77 haemodialysis patients aged 60 years and over, of whom 33 (43%) were female, from two community dialysis centres. Baseline demographic and laboratory data were collected, and sarcopenia was diagnosed using grip strength, muscle mass by bioimpedance analysis (BIA) and muscle function by timed up-and-go according to European Working Group on Sarcopenia in Older People criteria. Nutritional status was assessed using a subjective nutritional assessment score, comprising functional changes in weight, appetite, gastrointestinal symptoms and energy.. A comorbidity score (maximum 7 points) was derived from the presence or absence of hypertension, ischaemic heart disease, vascular disease (cerebrovascular disease, peripheral vascular disease, and abdominal aortic aneurysm), diabetes mellitus, respiratory disease, a history of malignancy and psychiatric disease. Outcomes over six years were linked to the Australian and New Zealand Dialysis and Transplant Registry. RESULTS: The median participant age was 71 years (range 60-87). Probable and confirmed sarcopenia was present in 55.9% and severe sarcopenia with reduced functional testing in 11.7%. Over 6 years, overall mortality was 50 of the 77 patients (65%), principally from cardiovascular events, dialysis withdrawal and infection. There were no significant survival differences between patients with no, probable, confirmed, or severe sarcopenia, or between tertiles of the nutritional assessment score. After adjustment for age, dialysis vintage, mean arterial pressure (MAP) and the total comorbidity score, no sarcopenia category predicted mortality. However, the total comorbidity score [Hazard Ratio (HR) 1.27, Confidence Intervals (CI) 1.02, 1.58, p = 0.03] and MAP (HR 0.96, CI 0.94, 0.99, P = < 0.01) predicted mortality. CONCLUSION: Sarcopenia is highly prevalent in elderly haemodialysis patients but is not an independent predictor of mortality. Haemodialysis patients have multiple competing risks for mortality which, in this study, was predicted by a lower MAP and a higher total comorbidity score. TRIAL REGISTRATION: Recruitment commenced December 2011. The study was registered 10.01.2012 with the Australian New Zealand Clinical Trials Registry (ACTRN12612000048886).

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.

Importance of bone turnover for therapeutic decisions in patients with CKD-MBD.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) frequently have low bone formation rates. A recent review suggested that adynamic bone disease is not always associated with negative outcomes and therefore antiresorptive medications could be used more often. However, there is currently no evidence to support an improvement in fracture risk or mortality in patients with CKD-MBD and low bone turnover who are treated with antiresorptive medication. There is reasonable pathophysiological evidence suggesting that it may even be harmful.

Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have higher fracture rates and post-fracture mortality than the general population, but bone mineral density by dual-energy X-ray absorptiometry (DXA) is less predictive of fracture in this patient group. Bone biopsy and high-resolution imaging indicate that cortical thickness (CT) is reduced and cortical porosity is increased in ESKD. The aim of this study was to assess cortical parameters using DXA in patients with ESKD. It was hypothesized that these parameters would show deterioration and be associated with fracture. METHODS: Using advanced hip analysis, normal age-related ranges were determined from 752 female and 861 male femur scans and were compared with scans of 226 patients with ESKD at the time of transplantation. RESULTS: Compared with controls, female patients had lower mean±SD CT (mms) at the femoral neck (FN) (2.59 ± 1.42 versus 5.23 ± 1.85), calcar (3.46 ± 1.07 versus 5.09 ± 1.30) and shaft (4.42 ± 1.21 versus 7.44 ± 2.07; P < 0.001 for each), and buckling ratios were higher (8.21 ± 4.6 versus 3.63 ± 1.42; P < 0.001), indicating greater FN instability. All findings were similar for men. Prevalent fracture was documented in 28.8% of patients; 12.4% vertebral only, 8.4% non-vertebral only and 8% vertebral plus non-vertebral. In adjusted models, each 1 SD reduction in FN CT and increase in the buckling ratio was associated with a respective 1.73 (1.22-2.46)- and 1.82 (1.49-2.86)-fold increase in the risk of prevalent vertebral fracture. CONCLUSIONS: In patients with ESKD, DXA-derived cortical parameters are markedly abnormal compared with age- and sex-matched controls. These parameters should be assessed for incident fracture prediction and targeting treatment.

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.

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.

Radiographic absorptiometry: a step in solving the CKD fracture puzzle.

Patients on dialysis are highly prone to fracture, and radiographic absorptiometry can be used to measure their bone mineral density and assess fracture risk. However, to determine its place in management, radiographic absorptiometry should be compared with dual-energy X-ray absorptiometry, and with fracture risk assessment tools such as FRAX, tests of muscle strength, biomarkers, and newer dual-energy X-ray absorptiometry techniques. The convenience, accessibility, and cost of radiographic absorptiometry may contribute to its utility in a number of clinical settings.

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.

Changes to bone mineral density, the trabecular bone score and hip structural analysis following parathyroidectomy: a case report.

BACKGROUND: Reduction in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) occurs in secondary hyperparathyroidism associated with chronic kidney disease. BMD generally increases following parathyroidectomy, however longitudinal changes to other DXA-derived parameters, the trabecular bone score (TBS) and hip structural analysis (HSA), have not been described. Postoperative calcium requirements and positive calcium balance raise concerns for an increased risk of vascular calcification. This case illustrates the dramatic increase in BMD that can follow parathyroidectomy in a patient on dialysis, and for the first time demonstrates improvements to HSA parameters and to the TBS. CASE PRESENTATION: A 30-year old woman on haemodialysis underwent subtotal parathyroidectomy for secondary hyperparathyroidism. She developed a post-operative 'hungry bone syndrome' requiring substantial calcium and calcitriol supplementation. Six months post-parathyroidectomy, BMD increased by 42% at the lumbar spine, 30% at the femoral neck and 25% at the total proximal femur, with increases sustained over the following 18 months. The TBS increased by 8%. HSA showed a 63% increase in femoral neck cortical thickness and 38% reduction in the buckling ratio, consistent with increased femoral neck stability. The abdominal aortic vascular calcification score (0-24) increased from zero 8-years pre-parathyroidectomy to 2/24 at 18-months post-parathyroidectomy. CONCLUSION: BMD losses incurred by secondary hyperparathyroidism recover rapidly after parathyroidectomy, particularly at sites of trabecular bone. Bone architectural parameters, measured as the TBS and by HSA, also improve. Greater BMD gains may be associated with higher post-operative calcium requirements. While bone is the major reservoir for post-parathyroidectomy calcium supplementation, positive calcium balance may contribute to vascular calcification risk.

Association between Aortic Calcification, Cardiovascular Events, and Mortality in Kidney and Pancreas-Kidney Transplant Recipients.

BACKGROUND: Cardiovascular (CV) disease is the leading cause of death in kidney and simultaneous pancreas-kidney (SPK) transplant recipients. Assessing abdominal aortic calcification (AAC), using lateral spine x-rays and the Kaupilla 24-point AAC (0-24) score, may identify transplant recipients at higher CV risk. METHODS: Between the years 2000 and 2015, 413 kidney and 213 SPK first transplant recipients were scored for AAC at time of transplant and then followed for CV events (coronary heart, cerebrovascular, or peripheral vascular disease), graft-loss, and all-cause mortality. RESULTS: The mean age was 44 ± 12 years (SD) with 275 (44%) having AAC (26% moderate: 1-7 and 18% high: ≥8). After a median of 65 months (IQR 29-107 months), 46 recipients experienced CV events, 59 died, and 80 suffered graft loss. For each point increase in AAC, the unadjusted hazard ratios (HR) for CV events and mortality were 1.11 (95% CI 1.07-1.15) and 1.11 (1.08-1.15). These were similar after adjusting for age, gender, smoking, transplant type, dialysis vintage, and diabetes: aHR 1.07 (95% CI 1.02-1.12) and 1.09 (1.04-1.13). For recipients with high versus no AAC, the unadjusted and fully-adjusted HRs for CV events were 5.90 (2.90-12.02) and 3.51 (1.54-8.00), for deaths 5.39 (3.00-9.68) and 3.38 (1.71-6.70), and for graft loss 1.30 (0.75-2.28) and 1.94 (1.04-3.27) in age and smoking history-adjusted analyses. CONCLUSION: Kidney and SPK transplant recipients with high AAC have 3-fold higher CV and mortality risk and poorer graft outcomes than recipients without AAC. AAC scoring may be useful in assessing and targeted risk-lowering strategies.

Outcomes of cinacalcet withdrawal in Australian dialysis patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) in chronic kidney disease is associated with cardiovascular and bone pathology. Measures to achieve parathyroid hormone (PTH) target values and control biochemical abnormalities associated with SHPT require complex therapies, and severe SHPT often requires parathyroidectomy or the calcimimetic cinacalcet. In Australia, cinacalcet was publicly funded for dialysis patients from 2009 to 2015 when funding was withdrawn following publication of the EVOLVE study, which resulted in most patients on cinacalcet ceasing therapy. We examined the clinical and biochemical outcomes associated with this change at Australian renal centres. AIM: To assess changes to biochemical and clinical outcomes in dialysis patients following cessation of cinacalcet. METHODS: We conducted a retrospective study of dialysis patients who ceased cinacalcet after August 2015 in 11 Australian units. Clinical outcomes and changes in biochemical parameters were assessed over a 24- and 12-month period, respectively, from cessation of cinacalcet. RESULTS: A total of 228 patients was included (17.7% of all dialysis patients from the units). Patients were aged 63 ± 15 years with 182 patients on haemodialysis and 46 on peritoneal dialysis. Over 24 months following cessation of cinacalcet, we observed 26 parathyroidectomies, 3 episodes of calciphylaxis, 8 fractures and 50 deaths. Eight patients recommenced cinacalcet, meeting criteria under a special access scheme. Biochemical changes from baseline to 12 months after cessation included increased levels of serum PTH from 54 (interquartile range 27-90) pmol/L to 85 (interquartile range 41-139) pmol/L (P < 0.0001), serum calcium from 2.3 ± 0.2 mmol/L to 2.5 ± 0.1 mmol/L (P < 0.0001) and alkaline phosphatase from 123 (92-176) IU/L to 143 (102-197) IU/L (P < 0.0001). CONCLUSION: Significant increases in serum PTH, calcium and alkaline phosphatase occurred over a 12-month period following withdrawal of cinacalcet. Longer-term follow up will determine if these biochemical and therapeutic changes are associated with altered rates of parathyroidectomies and cardiovascular mortality and morbidity.

Health-related quality of life following kidney and simultaneous pancreas kidney transplantation.

INTRODUCTION: Kidney and simultaneous pancreas kidney (SPK) transplant recipients are younger and fitter than most other dialysis patients, but are also more vulnerable in areas of social, emotional and physical interaction. Few studies have tracked their post-transplant health-related quality of life (HRQoL). AIM: To assess HRQoL following kidney and SPK transplantation, with comparison to dialysis patients, people with multiple co-morbidities and general population data. METHODS: Patients completed the Kidney Disease Quality of Life Short Form (KDQOL-SF™) 1.3 to assess their pre-transplant HRQoL within 4 weeks of transplantation and 12 months later. Demographic and laboratory data were collected on participating patients and on non-participating patients at both time-points. RESULTS: Of 118 patients who completed the baseline KDQOL-SF™, 75 (57 kidney and 18 SPK) completed the 1 year survey. Compared to baseline, 12 months HRQoL scores improved in all domains except for work status, exceeded those of patients on dialysis and, except for emotional wellbeing and mental health, exceeded the scores of people with multiple co-morbidities. For female transplant recipients, 12 months HRQoL scores were not statistically different from similarly aged women in the general population. Male transplant recipients had similar scores for bodily pain and energy/fatigue, but lower scores in other domains. Compared to kidney-only transplant recipients, SPK recipients achieved higher scores in work and sleep domains. CONCLUSION: Improvements in most HRQoL domains occur within 1 year of kidney or SPK transplantation, and women achieve similar HRQoL to women in the general population. These data are encouraging for patients contemplating transplant listing.

Sex hormone-binding globulin is a biomarker associated with nonvertebral fracture in men on dialysis therapy.

Gonadal hormones impact bone health and higher values of sex hormone-binding globulin (SHBG) have been independently associated with fracture risk in men without chronic kidney disease. People with chronic kidney disease have a greatly increased fracture risk, and gonadal dysfunction is common in men receiving dialysis treatment. Nevertheless, in these men the effect of gonadal steroids and SHBG on bone mineral density (BMD) and fracture risk is unknown. Here we investigate relationships between gonadal steroids, SHBG, BMD and fracture in men on long-term dialysis therapy, awaiting kidney or simultaneous pancreas kidney transplantation. Results of serum biochemistry, SHBG, gonadal steroids (total testosterone, calculated free testosterone and estradiol), BMD by dual-energy X-ray absorptiometry and thoracolumbar X-rays were obtained. Multivariable regression models were used to examine associations between SHBG, gonadal steroids, BMD and fracture of 321 men with a mean age of 47 years. Diabetes mellitus was present in 45% and their median dialysis vintage was 24 months. Prior fractures occurred in 42%, 18% had vertebral fracture on lateral spine X-ray, 17% had non-vertebral fragility fracture within 10 years and 7% had both. After adjustment for age, body mass index and dialysis vintage, higher SHBG levels were significantly associated with nonvertebral fractures [odds ratio 1.81 (1.30-2.53)] and remained significant after adjustment for BMD. Calculated free testosterone and estradiol values were not associated with fracture. Prevalent fracture rates were high in relatively young men on dialysis awaiting transplantation. Thus, SHBG is a novel biomarker associated with fracture, which warrants investigation in prospective studies.

Deterioration of Cortical Bone Microarchitecture: Critical Component of Renal Osteodystrophy Evaluation.

BACKGROUND: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the "Turnover Mineralization Volume" classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). METHODS: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = -0.56; p = 0.03) by micro-CT and to TbTh (r = -0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. CONCLUSIONS: Deterioration of cortical -microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

Changes in bone microarchitecture following kidney transplantation-Beyond bone mineral density.

Bone disease in kidney transplant recipients (KTRs) is characterized by bone mineral density (BMD) loss but bone microarchitecture changes are poorly defined. In this prospective cohort study, we evaluated bone microarchitecture using non-invasive imaging modalities; high-resolution magnetic resonance imaging (MRI), peripheral quantitative computed tomography (pQCT), dual energy X-ray absorptiometry (DXA), and the trabecular bone score (TBS) following kidney transplantation. Eleven KTRs (48.3 ± 11.2 years) underwent MRI (tibia), pQCT (radius) and DXA at baseline and 12 months post-transplantation. Transiliac bone biopsies, performed at transplantation, showed 70% of patients with high/normal bone turnover. Compared with baseline, 12-month MRI showed deterioration in indices of trabecular network integrity-surface to curve ratio (S/C; -15%, P = 0.03) and erosion index (EI; +19%, P = 0.01). However, cortical area increased (+10.3%, P = 0.04), with a non-significant increase in cortical thickness (CtTh; +7.8%, P = 0.06). At 12 months, parathyroid hormone values (median 10.7 pmol/L) correlated with improved S/C (r = 0.75, P = 0.009) and EI (r = -0.71, P = 0.01) while osteocalcin correlated with CtTh (r = 0.72, P = 0.02) and area (r = 0.70, P = 0.02). TBS decreased from baseline (-5.1%, P = 0.01) with no significant changes in BMD or pQCT. These findings highlight a post-transplant deterioration in trabecular bone quality detected by MRI and TBS, independent of changes in BMD, underlining the potential utility of these modalities in evaluating bone microarchitecture in KTRs.

Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).

BACKGROUND: Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES: The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS: We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS: In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.

Acute hypocalcaemia following denosumab in heart and lung transplant patients with osteoporosis.

BACKGROUND: Osteoporosis is highly prevalent in the heart and lung transplant population. Given high rates of concurrent renal impairment, there is increasing use of denosumab in this population. However, denosumab may be associated with hypocalcaemia, particularly in patients with chronic kidney disease (CKD). AIM: To explore the risk of hypocalcaemia in a heart and lung transplant cohort prescribed denosumab for osteoporosis. METHODS: We performed a retrospective database review of all surviving heart and lung transplant patients who had received denosumab for osteoporosis between January 2012 and November 2015. We assessed the rates of hypocalcaemia in this cohort and collected baseline clinical data to determine associated factors. RESULTS: Ten patients received denosumab and had laboratory results available within 3 months of the dose. Of these, three patients developed severe (grade 4) hypocalcaemia, while two patients developed mild (grade 1) hypocalcaemia. In comparison to the five patients who remained normocalcaemic, patients with hypocalcaemia had significantly lower baseline mean estimated glomerular filtration rate but similar baseline mean corrected serum calcium. Unexpectedly, patients developing hypocalcaemia had non-significantly higher levels of 25-hydroxyvitamin D and lower baseline doses of prednisone. CONCLUSIONS: In heart and lung transplant patients, denosumab should be used judiciously in patients with advanced renal disease due to the risk of hypocalcaemia.