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The slow transformation of new research findings into clinical guidelines is a barrier to providing evidence-based care. The Caring for Australians and New Zealanders with Kidney Impairment (CARI) guidelines are developing models to improve guideline production, one methodology involves more functional concordance between trial groups, such as the Australian Kidney Trials Network (AKTN) and CARI. The objective of this project was to rapidly produce an evidence-based guideline on urate-lowering therapy in patients with chronic kidney disease (CKD), in response to new clinical trial publications on the topic by the AKTN.To produce a guideline as rapidly as possible, an existing systematic review was utilized as the evidence base, and then updated with the inclusion of clinical trials that had been published subsequently. A Work Group was convened to review the evidence and compose an appropriate guideline using CARI/GRADE methodology. The group met 3 times over 45 days to formulate the guideline.The result was a strong recommendation against the use urate-lowering therapies in individuals with CKD (not receiving dialysis) and asymptomatic hyperuricemia. The process of identifying an appropriate existing systematic review, updating the literature search, and synthesizing the evidence, was done by 2 individuals over 15 days. The Work Group was formulated and composed the guideline over 45 days. In all, a new guideline incorporating the most up-to-date evidence was formulated in 60 days.This method of guideline development represents a potentially new way of releasing guidelines that encapsulates all available evidence in a time-efficient manner.

Background Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro. Methods This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays. Results In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {−62% [95% confidence interval (CI) −76 to −44], P Conclusions High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.

High dietary phosphate intake may lead to adverse outcomes including cardiovascular disease (CVD). Urinary phosphate excretion, a marker of intestinal phosphate absorption, may be a more reliable marker of phosphate homeostasis in steady state than serum phosphate. Studies report good agreement between urine phosphate-to-creatinine ratio (uPiCr) and 24-hour urinary phosphate; however, whether uPiCr is associated with increased risk of CVD or mortality remains uncertain. This study aimed to assess the relationship between uPiCr and all-cause and CVD mortality.This is an observational longitudinal cohort study using data from the population-based national Australian Diabetes, Obesity and Lifestyle study (n = 10,014 participants). Non-linear association between uPiCr and all-cause and CVD mortality was assessed using fractional polynomial transformations. Cox proportional hazards regression models were used to estimate adjusted hazard ratios for all-cause and CVD mortality.Median age [interquartile range] was 50 [41-62] years, and 46% were male. Median uPiCr was 1.38 [1.02-1.79] mmol/mmol. Median follow-up time was 16.9 years with 1,735 deaths. uPiCr was associated with all-cause and CVD mortality in univariate models and when adjusted for age and gender. However, associations were not significant in multivariate models. Sensitivity analyses excluding participants with chronic kidney disease (CKD) revealed a significant J-shaped association between uPiCr and all-cause mortality. Urine phosphate alone showed an association with increased all-cause mortality in a similar J-shape relationship.Although no association between uPiCr and all-cause and CVD mortality was observed in multivariate analyses in the whole cohort, a significant relationship between uPiCr and mortality in those without CKD suggests that uPiCr may have predictive validity for future adverse outcomes in people with no CKD.

Previous studies report an association between longer haemodialysis treatment sessions and improved survival. Worldwide, there is a trend to increasing age among prevalent patients receiving haemodialysis. This analysis aimed to determine whether the mortality benefit of longer haemodialysis treatment sessions diminishes with increasing age.This was a retrospective cohort study of people who first commenced thrice-weekly haemodialysis aged ≥65 years, reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry from 2005 to 2015, included from 90 days after dialysis start. The primary outcome was all-cause mortality. Cox regression analysis was performed with haemodialysis session duration the exposure of interest.Of 8224 people who commenced haemodialysis as their first treatment for kidney failure aged ≥65 years during this period, 4727 patients died. Longer dialysis hours per session was associated with a decreased risk of death in unadjusted analyses [hazard ratio, HR, for ≥5 h versus 4 to4.5 h: 0.81 (0.75-0.88, p .001)]. Patients having longer dialysis sessions were younger but had greater co-morbidity. In an adjusted model including age and other variables, the survival benefit of longer hours was only partially attenuated [HR for previous comparison: 0.75 (0.69-0.82, p .001)], and no interaction between age and hours was demonstrated (p = .89).The apparent survival benefit associated with longer haemodialysis session length appears to be preserved in patients 65 years or older. In practice, the benefit of longer dialysis hours should be carefully weighed against other factors in this patient group.

There is increasing global incidence of acute kidney injury (AKI) and significant short- and long-term impacts on patients.To determine incidence and outcomes of community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI) among inpatients in the Australian healthcare setting using modern health information systems.A retrospective cohort study of adult patients admitted to a quaternary hospital in Melbourne, Australia, between 1 January 2018 and 31 December 2019 utilising an electronic data warehouse. Participants included adult patients admitted for24 h who had more than one serum creatinine level recorded during admission. Kidney transplant and maintenance dialysis patients were excluded. Main outcomes measured included AKI, as classified by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, hospital length of stay and 30-day mortality.A total of 6477 AKI episodes was identified across 43 791 admissions. Of all AKI episodes, 77% (n = 5011), 15% (n = 947) and 8% (n = 519) were KDIGO stage 1, 2 and 3 respectively. HA-AKI accounted for 55.9% episodes. Patients required intensive care unit admission in 22.7% (n = 1100) of CA-AKI and 19.3% (n = 935) of HA-AKI, compared with 7.5% (n = 2815) of patients with no AKI (P = 0.001). Patients with AKI were older with more co-morbidities, particularly chronic kidney disease (CKD). Length of stay was longer in CA-AKI (8.8 days) and HA-AKI (11.8 days) compared with admissions without AKI (4.9 days; P 0.001). Thirty-day mortality was increased with CA-AKI (10.2%) and HA-AKI (12.8%) compared with no AKI (3.7%; P 0.001).The incidence of AKI detected by the electronic data warehouse was higher than previously reported. Patients who experienced AKI had greater morbidity and mortality. CKD was an important risk factor for AKI in hospitalised patients.

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

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.

Introduction Measurement of bone mineral density (BMD) is recommended in patients with chronic kidney disease (CKD). However, most persons in the community and most patients with CKD have osteopenia, suggesting fracture risk is low. Bone loss compromises bone microarchitecture which increases fragility disproportionate to modest deficits in BMD. We therefore hypothesized that patients with CKD have reduced estimated failure load due to deterioration in microarchitecture irrespective of whether they have normal femoral neck (FN) BMD, osteopenia or osteoporosis. Methods We measured distal tibial and distal radial microarchitecture in 128 patients with CKD and 275 age- and sex-matched controls using high resolution peripheral quantitative computed tomography, FN-BMD using bone densitometry and estimated failure load at the distal appendicular sites using finite element analysis. Results Patients versus controls respectively had: lower tibial cortical area 219 (40.7) vs. 237 (35.3) mm2, p = 0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm3 due to higher porosity 69.6 (6.19) vs. 61.9 (6.48)% and lower matrix mineral density 64.2 (0.62) vs. 65.1 (1.28)%, lower trabecular vBMD 92.2 (41.1) vs. 149 (43.0) mgHA/cm3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm2 and reduced estimated failure load 3825 (1152) vs. 5778 (1467) N, all p < 0.001. Deterioration in microarchitecture and estimated failure load was most severe in patients and controls with osteoporosis. Patients with CKD with osteopenia and normal FN-BMD had more deteriorated tibial microarchitecture and estimated failure load than controls with BMD in the same category. In univariate analyses, microarchitecture and FN-BMD were both associated with estimated failure load. In multivariable analyses, only microarchitecture was independently associated with estimated failure load and accounted for 87% of the variance. Conclusions Bone fragility is likely to be present in patients with CKD despite them having osteopenia or normal BMD. Measuring microarchitecture may assist in targeting therapy to those at risk of fracture.

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.

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 1.73m(2); 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.

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.

Background Acute kidney injury (AKI) survivors are at increased risk of major adverse kidney events (MAKEs), including chronic kidney disease (CKD), end-stage kidney disease (ESKD) and death. High-risk AKI patients may benefit from specialist follow-up, but factors associated with increased risk have not been reported. Methods We conducted a retrospective study of AKI patients admitted to a single centre between 2012 and 2016 who had a baseline estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 and were alive and independent of renal replacement therapy (RRT) at 30 days following discharge. AKI was identified using International Classification of Diseases, Tenth Revision codes and staged according to the Kidney Disease: Improving Global Outcomes criteria. Patients were excluded if they were kidney transplant recipients or if AKI was attributed to intrinsic kidney disease. We performed Cox regression models to examine MAKEs in the first year, defined as the composite of CKD (sustained 25% drop in eGFR), ESKD (requirement for chronic RRT or sustained eGFR Results We studied 2101 patients (mean ± SD age 69 ± 15 years, baseline eGFR 72 ± 23 mL/min/1.73 m2). Of these, 767 patients (37%) developed at least one MAKE (429 patients developed CKD, 21 patients developed ESKD, 375 patients died). MAKEs occurred more frequently with older age [hazard ratio (HR) 1.16 per decade, 95% confidence interval (CI) 1.10–1.24], greater severity of AKI (Stage 2 HR 1.38, 95% CI 1.16–1.64; Stage 3 HR 1.62, 95% CI 1.31–2.01), higher serum creatinine at discharge (HR 1.04 per 10 µmol/L, 95% CI 1.03–1.06), chronic heart failure (HR 1.41, 95% CI 1.19–1.67), liver disease (HR 1.68, 95% CI 1.39–2.03) and malignancy (non-metastatic HR 1.44, 95% CI 1.14–1.82; metastatic HR 2.26, 95% CI 1.80–2.83). Traditional risk factors (e.g. diabetes and cardiovascular disease) had limited predictive value. Conclusions More than a third of AKI patients develop MAKEs within the first year. Clinical variables available at the time of discharge can help identify patients at increased risk of such events.

Background. The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. Methods. Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. Results. Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88–2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01–1.06), female sex (HR 2.49, CI 1.70–3.65), previous fracture (HR 2.30, CI 1.58–3.34), Asian race (HR 1.74, CI 1.09–2.78), vitamin D therapy requirement (HR 2.05, CI 1.31–3.21), HbA1c (HR 1.14, CI 1.00–1.32), prior cardiovascular event (HR 1.60, CI 1.10–2.33), and serum albumin (HR 0.41, CI 0.23–0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92–1849.51, SBC range 1875.60–1948.04). Conclusion. Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors.

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.

Excess sodium is a major modifiable contributor to hypertension and cardiovascular risk. Knowledge of sodium storage and metabolism has derived mainly from indirect measurements of dietary sodium intake and urinary sodium excretion, however both attempt to measure body sodium and fluid in a two-compartment model of intracellular and extracellular spaces. Our understanding of total body sodium has recently included a storage pool in tissues. In the last two decades, sodium-23 magnetic resonance imaging (23 Na MRI) has allowed dynamic quantification of tissue sodium in vivo. Tissue sodium is independently associated with cardiovascular dysfunction and inflammation. This review explores (i) The revolution of our understanding of sodium physiology, (ii) The development and potential clinical adoption of 23 Na MRI to provide improved measurement of total body sodium in CKD and (iii) How we can better understand mechanistic and clinical implications of tissue sodium in hypertension, cardiovascular disease and immune dysregulation, especially in the CKD population.

Excess sodium intake is a leading but modifiable risk factor for mortality, with implications on hypertension, inflammation, cardiovascular disease, and chronic kidney disease (CKD). This review will focus mainly on the limitations of current measurement methods of sodium balance particularly in patients with CKD who have complex sodium physiology. The suboptimal accuracy of sodium intake and excretion measurement is seemingly more marked with the evolving understanding of tissue (skin and muscle) sodium. Tissue sodium represents an extrarenal influence on sodium homeostasis with demonstrated clinical associations of hypertension and inflammation. Measurement of tissue sodium has been largely unexplored in patients with CKD. Development and adoption of more comprehensive and dynamic assessment of body sodium balance is needed to better understand sodium physiology in the human body and explore therapeutic strategies to improve the clinical outcomes in the CKD population.

Surgical parathyroidectomy may be required for severe and refractory secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Parathyroidectomy is associated with long-term survival benefit despite an increase in short-term morbidity and mortality. Global variation in practice exists, with limited Australian data on outcomes following parathyroidectomy.To evaluate clinical outcomes of patients with chronic kidney disease undergoing surgical parathyroidectomy for secondary hyperparathyroidism.We conducted a retrospective study of patients who underwent parathyroidectomy for SHPT between January 2010 and December 2019 at a single tertiary referral centre in Melbourne, Australia. Biochemical markers and medications were assessed 12 months pre- and post-surgery. Clinical outcomes, including hospital readmission, cardiovascular events and mortality were assessed following surgery.During the 10-year study period, 129 patients underwent parathyroidectomy for SHPT (mean age 50.7 ± 15 years; 109 (85%) on dialysis). Significant immediate post-operative complications were seen in eight (6%) patients, requiring admission to the intensive care unit (n = 6) or return to theatre (n = 2). Within the first 6 months, 24 (19%) patients required hospital readmission. Within 12 months post-parathyroidectomy, 100 (78%) and 103 (80%) patients experienced at least one episode of hypercalcaemia (corrected calcium2.6 mmol/L) or hypocalcaemia (corrected calcium2.1 mmol/L) respectively. Over a 12-month period, there were six (5%) deaths and eight (6%) patients experienced a major cardiovascular event.Significant fluctuations in serum calcium levels are common post-parathyroidectomy; however, long-term morbidity and mortality in our cohort were lower than previously reported, highlighting that parathyroidectomy in a carefully selected cohort is safe for severe SHPT refractory to medical treatment.

Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral‐binding protein fetuin‐A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP‐I], and secondary CPP [CPP‐II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP‐I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non‐responders at week 8. This was accompanied by reductions in CPM (β = −6.5 × 103 AU [95% CI −11.1, −1.8], p = 0.006) and CPP‐I (β = −23.4 × 104 particles/mL [95% CI −34.8, −11.9], p

Background and Aims Calcification propensity of serum can be measured with the so-called T50-test, which integrates the complex biological interplay of promoters and inhibitors of calciprotein particle formation in blood into a single readout. Calcification propensity is associated with the risk for cardiovascular events and death in dialysis patients. As we have recently demonstrated in a randomized, controlled, cross-over study in 39 chronic hemodialysis patients with hyperphosphatemia, lowering serum phosphate with high-dose phosphate-binder therapy with 2000 mg/d of sucroferric oxyhydroxide (SO) over two weeks reduces calcification propensity as determined by the T50-test compared to a two-week wash-out phase. Based on these results, we hypothesized that SO would influence endogenous calciprotein particle (CPP) formation and crystallization, i.e. conversion from primary to secondary CPP. Method To test this hypothesis, we conducted post-hoc analyses of the previously reported RCT (74% men, mean age 63±27 years, median dialysis vintage 24, IQR 16-36 months). Native serum CPP levels were measured by a fluorescent probe-based flow cytometric assay. Moreover, hydrodynamic radii (Rh) of secondary CPP formed after enrichment with exogenous calcium and phosphate was assessed by three-dimensional cross-correlation dynamic light scattering. Results Phosphate-binder therapy with SO lead to a reduction in serum phosphate levels from 2.28±0.5 mmol/l to 1.63±0.43 mmol/l (p Conclusion In chronic hemodialysis patients, lowering serum phosphate with SO is associated with a reduction in the load of primary and secondary CPP and a smaller size of secondary CPP.

Background Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) is a significant cause of morbidity among haemodialysis patients and is associated with pathological changes in phosphate, calcium and parathyroid hormone (PTH). In the ACTIVE Dialysis study, extended hours dialysis reduced serum phosphate but did not cause important changes in PTH or serum calcium. This secondary analysis aimed to determine if changes in associated therapies may have influenced these findings and to identify differences between patient subgroups. Methods The ACTIVE Dialysis study randomised 200 participants to extended hours haemodialysis (≥24 h/week) or conventional haemodialysis (≤18 h/week) for 12 months. Mean differences between treatment arms in serum phosphate, calcium and PTH; and among key subgroups (high vs. low baseline phosphate/PTH, region, time on dialysis, dialysis setting and frequency) were examined using mixed linear regression. Results Phosphate binder use was reduced with extended hours (− 0.83 tablets per day [95% CI -1.61, − 0.04; p = 0.04]), but no differences in type of phosphate binder, use of vitamin D, dose of cinacalcet or dialysate calcium were observed. In adjusted analysis, extended hours were associated with lower phosphate (− 0.219 mmol/L [− 0.314, − 0.124; P

There is a paucity of epidemiological data in Australia on fracture rates in patients with chronic kidney disease (CKD). Using data from the Victorian Admitted Episodes Dataset, we assessed the incidence of hip fractures requiring hospitalisation between 2006 and 2015, comparing those coded with and without the co-morbidity CKD. ICD-9 and ICD-10 codes were used to determine hip fractures and comorbidities. Overall, 7.4% of 77 076 Victorian hospital admissions for hip fractures had CKD as a co-morbidity, with an increasing proportion over the study period. Mortality was significantly higher in the CKD cohort compared to no CKD, perhaps in part due to increased associated comorbidities of diabetes and ischaemic heart disease.

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.

Reliable estimates of the long-term outcomes of acute kidney injury (AKI) are needed to inform clinical practice and guide allocation of health care resources. This systematic review and meta-analysis aimed to quantify the association between AKI and chronic kidney disease (CKD), end-stage kidney disease (ESKD), and death. Systematic searches were performed through EMBASE, MEDLINE, and grey literature sources to identify cohort studies in hospitalized adults that used standardized definitions for AKI, included a non-exposed comparator, and followed patients for at least 1 year. Risk of bias was assessed by the Newcastle-Ottawa Scale. Random effects meta-analyses were performed to pool risk estimates; subgroup, sensitivity, and meta-regression analyses were used to investigate heterogeneity. Of 4973 citations, 82 studies (comprising 2,017,437 participants) were eligible for inclusion. Common sources of bias included incomplete reporting of outcome data, missing biochemical values, and inadequate adjustment for confounders. Individuals with AKI were at increased risk of new or progressive CKD (HR 2.67, 95% CI 1.99-3.58; 17.76 versus 7.59 cases per 100 person-years), ESKD (HR 4.81, 95% CI 3.04-7.62; 0.47 versus 0.08 cases per 100 person-years), and death (HR 1.80, 95% CI 1.61-2.02; 13.19 versus 7.26 deaths per 100 person-years). A gradient of risk across increasing AKI stages was demonstrated for all outcomes. For mortality, the magnitude of risk was also modified by clinical setting, baseline kidney function, diabetes, and coronary heart disease. These findings establish the poor long-term outcomes of AKI while highlighting the importance of injury severity and clinical setting in the estimation of risk.

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. 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: 228 patients were 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. Seven 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 (IQR 27‐90) pmol/L to 85 (IQR 41‐139) pmol/L (p

Differences in early graft function between kidney transplant recipients previously managed with either haemodialysis (HD) or peritoneal dialysis are well described. However, only two single-centre studies have compared graft and patient outcomes between extended hour and conventional HD patients, with conflicting results. This study compared the outcomes of all extended hour (≥24 hours/week) and conventional HD patients transplanted in Australia and New Zealand between 2000 and 2014. The primary outcome was delayed graft function (DGF), defined in an ordinal manner as either a spontaneous fall in serum creatinine of less than 10% within 24 hours, or the need for dialysis within 72 hours following transplantation. Secondary outcomes included the requirement for dialysis within 72 hours post-transplant, acute rejection, estimated glomerular filtration rate at 12 months, death-censored graft failure, all-cause and cardiovascular mortality, and a composite of graft failure and mortality. A total of 4,935 HD patients (378 extended hour HD, 4,557 conventional HD) received a kidney transplant during the study period. Extended hour HD was associated with an increased likelihood of DGF compared with conventional HD (adjusted proportional odds ratio 1.33; 95% confidence interval 1.06-1.67). There was no significant difference between extended hour and conventional HD in terms of any of the secondary outcomes. Compared to conventional HD, extended hour HD was associated with DGF, although long-term graft and patient outcomes were not different.

Introduction: Hemodialysis (HD) with medium cut-off (MCO) dialyzers may expand molecular clearance, predominantly larger middle molecules (molecular weight 25–60 kDa). However, the impact of MCO dialyzers on long-term clearance of various other components of the uremic milieu is unknown. The tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) provided an opportunity to assess the effect of MCO dialyzers on protein-bound uremic toxins and novel markers of mineral metabolism. Methods: This exploratory sub-study of REMOVAL-HD evaluated changes in protein-bound solutes (total and free indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) and mineral metabolism markers (intact fibroblast growth factor-23 [iFGF23], fetuin-A and endogenous calciprotein particles [CPP-1 and CPP-2]). Mid-week, pre-HD serum samples were collected at baseline and after 12 and 24 weeks of MCO use in stable adult patients. Change from baseline to Week 12 and 24 was estimated using linear mixed effects models. Findings: Eighty-nine participants were studied (mean age 67 ± 15 years, 38% female, 51% diabetic, median urine output 200 ml/24 h). Serum iFGF23 was reduced at Week 12 compared to baseline (−26.8% [95%CI −39.7, −11.1], p = 0.001), which was sustained at Week 24 (−21.7% [95%CI -35.7, −4.5], p = 0.012). There was no significant change in serum IS, PCS, fetuin-A, CPP-1, or CPP-2. Discussion: The use of a MCO dialyzer over 24 weeks was associated with a sustained reduction in FGF23, while other measured components of the uremic milieu were not significantly altered. Further studies are required to determine whether FGF23 reduction is associated with improved patient outcomes.

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.

Introduction: Acute kidney diseases and disorders (AKD) encompass acute kidney injury (AKI) and subacute or persistent alterations in kidney function that occur after an initiating event. Unlike AKI, accurate estimates of the incidence and prognosis of AKD are not available and its clinical significance is uncertain. Methods: We studied the epidemiology and long-term outcome of AKD (as defined by the KDIGO criteria), with or without AKI, in a retrospective cohort of adults hospitalized at a single centre for >24 h between 2012 and 2016 who had a baseline eGFR ≥60 mL/min/1.73 m2 and were alive at 30 days. In patients for whom follow-up data were available, the risks of major adverse kidney events (MAKEs), CKD, kidney failure, and death were examined by Cox and competing risk regression analyses. Results: Among 62,977 patients, 906 (1%) had AKD with AKI and 485 (1%) had AKD without AKI. Follow-up data were available for 36,118 patients. In this cohort, compared to no kidney disease, AKD with AKI was associated with a higher risk of MAKEs (40.25 per 100 person-years; hazard ratio [HR] 2.51, 95% confidence interval [CI] 2.16–2.91), CKD (27.84 per 100 person-years); subhazard ratio [SHR] 3.18, 95% CI 2.60–3.89), kidney failure (0.56 per 100 person-years; SHR 24.84, 95% CI 5.93–104.03), and death (14.86 per 100 person-years; HR 1.52, 95% CI 1.20–1.92). Patients who had AKD without AKI also had a higher risk of MAKEs (36.21 per 100 person-years; HR 2.26, 95% CI 1.89–2.70), CKD (22.94 per 100 person-years; SHR 2.69, 95% CI 2.11–3.43), kidney failure (0.28 per 100 person-years; SHR 12.63, 95% CI 1.48–107.64), and death (14.86 per 100 person-years; HR 1.57, 95% CI 1.19–2.07). MAKEs after AKD were driven by CKD, especially in the first 3 months. Conclusions: These findings establish the burden and poor prognosis of AKD and support prioritisation of clinical initiatives and research strategies to mitigate such risk.

BACKGROUND: Survivors of acute kidney injury (AKI) are at increased risk of major adverse kidney events and international guidelines recommend individuals be evaluated 3 months following AKI. AIMS: We describe practice patterns and predictors of post-AKI care in an Australian tertiary hospital. METHODS: A retrospective analysis was undertaken of adults with AKI (defined by KDIGO criteria) admitted to a single centre between 2012 and 2016. The primary outcome was outpatient nephrology review at 3 months. Secondary outcomes included inpatient nephrology review, and outpatient serum creatinine and urinary protein measurements. Data were analysed using multivariable logistic and competing risk regression. RESULTS: Only 117 of 2111 patients with AKI (6%) were reviewed by a nephrologist at 3 months. Reviewed patients were more likely to have a higher discharge serum creatinine (OR 1.20 per 10 μmol/L increase, 95% CI 1.16-1.25) or a history of peripheral vascular disease (OR 1.77, 95% CI 1.00-3.14). They were less likely to be older (OR 0.66 per decade, 95% CI 0.57-0.76), or to have a history of liver (OR 0.47, 95% CI 0.26-0.87) or ischaemic heart disease (OR 0.50, 95% CI 0.27-0.94). AKI stage did not predict follow up. The median time from discharge to outpatient serum creatinine testing was 12 days (IQR 4-47) and proteinuria was measured in 538 patients (25%). CONCLUSIONS: A minority of admitted AKI patients receive recommended post-AKI care. Studies in other Australian institutions are required to confirm or refute these concerning findings. This article is protected by copyright. All rights reserved.

Aim Preclinical studies suggest treatment of metabolic acidosis may slow chronic kidney disease (CKD) progression. This systematic review aimed to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of bicarbonate therapy on kidney outcomes. Methods Medline, EMBASE, and Cochrane databases were searched for RCTs with ≥3 months’ follow-up in patients with CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min per 1.73 m2 and/or proteinuria) comparing the effects of sodium bicarbonate with placebo/no study medication on kidney outcomes. The primary outcome was change from baseline to last measurement in kidney function measured as either eGFR or creatinine clearance. Treatment effects were summarized using random-effects meta-analysis. Results Fifteen trials (2445 participants, median follow-up 12 months) were eligible for inclusion. Compared with placebo or no study medication, sodium bicarbonate retarded the decline in kidney function (standardized mean difference [SMD]: 0.26; 95% confidence interval [CI]: 0.13–0.40; I2 = 50%, low certainty evidence), and reduced the risk of end-stage kidney failure (risk ratio [RR]: 0.53; 95% CI 0.32–0.89; I2 = 69%, low certainty evidence). The effect of sodium bicarbonate on proteinuria (SMD: −0.09; 95% CI −0.27 to 0.09; I2 = 28%, very low certainty evidence), systolic blood pressure (weighted mean difference [WMD]: −0.57 mm Hg; 95% CI −2.32 to 1.18; I2 = 0%, low certainty evidence), all-cause death (RR: 0.81; 95% CI: 0.39–1.68; I2 = 30%; very low certainty evidence) and edema (RR: 1.16; 95% CI: 0.90–1.50; I2 = 28%; low certainty evidence) were uncertain. Conclusion Sodium bicarbonate may slow CKD progression. Adequately powered randomized trials are required to evaluate the benefits and risks of sodium bicarbonate in CKD., Graphical abstract

Introduction Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non–calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate–containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects. Methods We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC–treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed. Results Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (–70%, 95% confidence interval [CI] –90% to –15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (–83.4%, 95% CI –95.7% to –36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (–2.0 m/s, 95% CI –2.9 to –1.1; –57%, 95% CI –73% to –30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups. Discussion Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation., Graphical abstract