Marina Di Luca A.O.Osp.Riuniti Marche Nord Presidio San Salvatore AGENDA Phosphorus and outcome: serum phosphorus links with a poor prognosis Causative role ? OR Epiphenomenon ? numerous epidemiological studies, but data are far from being conclusive Lowering and maintaining phosphorus levels is accepted as an important therapeutic goal to improve outcomes of CKD MBD in CKD patients Unresolved questions Active measures should be taken in early stages of CKD when serum phosphorus is still in the normal or near normal range? What serum phosphorus levels should be targeted or maintained in CKD stage 3-4 ? When to Start Treating Phosphate Retention in CKD? Which binder is more appropriate in CKD ? Treatment Target Ranges for Phosphate Stage 3 Target PO4 KDIGO: Maintain Normal KDOQI: 2.7-4.6 mg/dL 4-5 KDIGO: Maintain Normal KDOQI: 2.7-4.6 mg/dL 5D KDIGO: Towards Normal KDOQI: 3.5-5.5 mg/dL KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003(suppl 3) How treating Phosphate Retention in CKD? Diet ? Binders ? Or Both ? Protein restriction is effective in reducing urinary phosphate levels, reducing FGF 23 and is associated with a very modest decrease in serum phosphate levels. Britt Newsome How treating Phosphate Retention in CKD? Diet ? Binders ? Or Both ? Mean serum phosphorus declined from 4.2 to 3.9 mg/dl in pts treated. Daily urine phosphorus was reduced by 22% in pts treated. Median duration of follow-up: 249 days. Mean doses of study medication: Ca acetate 5.9 g/d (1.5 g elementalcalcium) Lanthanum carbonate 2.7 g/d Sevelamer carbonate 6.3 g/d This randomized placebo-controlled pilot clinical trial shows that the use of phosphate binders in patients with nondialysis requiring CKD reduces urinary phosphorus excretion (a surrogate of intestinal phosphate absorption) and attenuates progressive secondary hyperparathyroidism. The effect on serum phosphorus, although statistically significant, was modest, despite relatively high-dose therapy and a significant effect on urinary phosphorus excretion. Active therapy resulted in progression of vascular calcification, particularly among patients randomized to calcium acetate. Caution regarding the type of statistical analysis selected by the authors. The choice to compare all treatment groups together (90 patients) with only one placebo group(58 patients) constitutes in our view a major problem. The three phosphate binders considered together greatly differ from each other in several aspects. The assessment of changes in arterial calcium scores in the study by Block et al. was possible only in a subset of 90 patients (60 active and 36 placebo) and was effectively performed only in those with non-zero calcium scores at baseline (n 81; 55% of the original cohort). Moreover, the baseline characteristics of this subgroup of 81 patients have not been reported separately in the manuscript, and lack of perfect matching between active treatment and placebo groups therefore remains possible; insufficient sample size, with large standard deviations. Clearly, additional RCTs in larger CKD patient cohorts both before and after the initiation of dialysis therapy are required to answer the question of whether phosphate binders should be given early. Ca Acetato CAC calcification (p=0.02) = Non Calcium based binders FGF-23 (p= 0.02) 1,25 dihydroxyvitamin D levels (P =0.004) = PTH (P =0.0002) =o These data, in concert with calcium and phosphate balance study,from Hill et al ., argue against the nearly universal practice of providing calcium-containing phosphate binders to patients with CKD. Hyperphosphataemia in chronic kidney disease Calcium based phosphate binders: a case for change March 2013 NICE clinical guideline 157 First-line phosphate binders: recommendations For both people ‘on’ and ‘not on’ dialysis •For adults, offer calcium acetate as the first-line phosphate binder to control serum phosphate in addition to dietary management. [1.1.8] •For adults, consider calcium carbonate if calcium acetate is not tolerated or patients find it unpalatable. [1.1.9] Sequencing of phosphate binders for patients not on dialysis: recommendations Adults with stage 4 or 5 CKD not on dialysis and taking a calcium-based binder Calcium-based phosphate binders are not tolerated • Hypercalcaemia develops (account for other causes of raised calcium) or • Serum PTH hormone levels are low Consider switching to a non-calcium-based binder Consider either combining with, or switching to, a non-calcium-based binder First-line phosphate binders: the savings Depending upon practice locally, prescription of calcium acetate as first line phosphate binder is likely to reduce the number of people prescribed sevelamer hydrochloride and lanthanum carbonate • Changing from sevelamer hydrochloride to either calcium carbonate or calcium acetate will result in savings of £2186 or £2096 per person respectively. • Changing from lanthanum carbonate to either calcium carbonate or calcium acetate will result in savings of £1806 or £1716 per person respectively. The primary outcome, all-cause mortality, was based on the 11 randomised trials that reported an outcome of mortality, and consisted of 4622 patients with 936 deaths.Patients randomly assigned to non-calcium-based phosphate binders had a statistically significant 22% reduction in all-cause mortality compared with those randomly assigned to calcium-based phosphate binders. The reduction in vascular calcification in patients assigned to non-calcium- based phosphate binders vs those assigned to calcium binders was statistically significant when we analysed data from the longest follow-up point for each study (mean diff erence in Agatston score −95·26, 95% CI −146·68 to −43·84) We suggest that the first-line therapy for phosphate lowering should be non-calciumbased binders — specifically sevelamer or lanthanum. One potential explanation for the decrease in mortality associated with the use of non-calcium-based binders might be related to slowing of vascular calcifi cation. Final remarks Our current approaches to treatment, which are focused on dietary restriction and the prescription of intestinal binders to prevent phosphate absorption, are based on principles and assumptions that need to be examined more rigorously. Recent clinical trials involving phosphate binders have failed to show the expected impact on serum phosphate levels. Future clinical studies comparing effective phosphorus-lowering interventions (i.e., diet and phosphate binders) vs. placebo should provide some definitive evidence on when in the course of CKD these should be used and how low serum phosphorus should be kept in chronic renal failure. Uncertainty remains as to whether the clinical benefits of targeting phosphate homeostasis require a change in serum phosphate level or whether modification of intestinal phosphate load is sufficient : a decrease in urine phosphate excretion might represent a useful treatment target?? It is likely that as our understanding of phosphate metabolism in early CKD advances, our therapeutic approaches will change, our therapies will be more appropriate. Mosaico Cattedrale Pesaro - VI sec d.c. Grazie per l’attenzione !!!