N Lioufas1,2,3, E Pascoe4, C Hawley4,5,6,G Elder7,8,9,13, S Badve4,10,11, G Block12, D Johnson4,5,6, N Toussaint1,2
1Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia, 2Department of Medicine (RMH), The University of Melbourne, Parkville, Australia, 3Western Health, St Albans, Australia, 4Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia, 5Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia, 6Translational Research Institute, Brisbane, Australia, 7The University of Notre Dame, Sydney, Australia, 8Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, Australia, 9Department of Nephrology, Westmead Hospital, Sydney, Australia, 10Department of Nephrology, St George Hospital, Sydney, Australia, 11Renal and Metabolic Division, The George Institute for Global Health, University of New South Wales, Sydney, Australia, 12Reata Pharmaceuticals, Plano, United States of America, 13University of Sydney, Sydney, Australia
Aim: To summarize evidence from randomized controlled trials (RCTs) regarding the effects of non-calcium-based phosphate-lowering treatment in patients with non-dialysis chronic kidney disease (CKD).
Background: Benefits of phosphate-lowering interventions are unclear in the non-dialysis CKD population. Systematic reviews have predominantly involved dialysis patients, who have more advanced cardiovascular remodelling and calcification.
Methods: A systematic review and meta-analysis was conducted involving searches in Ovid, MEDLINE, EMBASE and CENTRAL, reviews of guidelines and pre-existing meta-analyses. Abstract review was conducted for eligible studies >3 months duration, involving adult patients with CKD not on dialysis and without a kidney transplant. Outcomes included biomarkers of mineral metabolism, cardiovascular parameters and adverse events at final follow-up. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Quality of evidence was determined by Cochrane risk of bias tools and GRADE assessment.
Results: Twenty trials involving 2,498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Compared with placebo, non-calcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.48, 95%CI -0.71,-0.25 mg/dL, moderate certainty evidence) and urinary phosphate excretion (8 trials, standardised mean difference [SMD] -0.54 95%CI -0.85,-0.22, low certainty evidence) but resulted in increased constipation (9 trials, odds ratio 0.93, 95%CI 0.02,1.84, moderate certainty evidence) and greater vascular calcification score (3 trials, SMD 0.45 95%CI 0.15,0.74, very low certainty evidence). There was little data for effects on cardiovascular events and death.
Conclusions: Non-calcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion but had unclear effect on clinical outcomes and surrogate cardiovascular end-points. Further well-designed randomised trials of phosphate-lowering therapy targeting hard clinical outcomes are needed.
Dr Lioufas is a consultant nephrologist at Western Health, undertaking her PhD in CKD-MBD and the effect of phosphate on cardiovascular disease in patients with chronic kidney disease at the Royal Melbourne Hospital.