6Lowering and maintaining phosphorus levels is accepted as an important therapeutic goal to improve outcomes of CKD MBD in CKD patientsUnresolved questionsActive 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 ?
7Treatment Target Ranges for Phosphate StageTarget PO43KDIGO: Maintain NormalKDOQI: mg/dL4-55DKDIGO: Towards NormalKDOQI: mg/dLLe Linee Guida KDIGO suggeriscono per gli stadi 3-4 dell’Insufficienza renale Cronica di mantenere i livelli di Fosforemia nel range di normalità (grado di evidenza 2C).Le linee guida KDIGO sottolineano l’importanza di uno stretto controllo del bilancio fosforico sin dalle prime fasi dell’IRC, pur con i limiti delle attuali conoscenze sui target terapeutici nella sindrome CKD-MBD.KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003(suppl 3)KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003(suppl 3)7
8How treating Phosphate Retention in CKD? Diet ?Binders ?Or Both ?
9Protein 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
10How treating Phosphate Retention in CKD? Diet ?Binders ?Or Both ?
12Mean 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/dSevelamer carbonate 6.3 g/d
14This 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.
15Caution 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.
16CAC calcification (p=0.02) 1,25 dihydroxyvitamin D levels Ca AcetatoCAC calcification (p=0.02)Non Calcium basedbinders=FGF-23 (p= 0.02)1,25 dihydroxyvitamin D levels(P =0.004)=PTH(P =0.0002)= oAlthough the studywas not powered to detect differences among individualsubgroups randomly assigned to differenttypes of phosphate binder, patients randomly assignedto lanthanum carbonate or sevelamer carbon-ate did not have significant increases in coronaryartery calcification, whereas those who receivedcalcium acetate experienced statistically significantincreases in intact FGF-23 levels (P 0.02), reductionsin 1,25 dihydroxyvitamin D levels (P0.0002), and progression of coronary artery calcification(P 0.02) versus placebo-treated patients.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.
17Hyperphosphataemia in chronic kidney disease Calcium based phosphate binders:a case for changeABOUT THIS PRESENTATION:This presentation has been developed to support education and learning about the NICE clinical guideline ‘Hyperphosphataemia in chronic kidney disease’. It is intended for secondary care healthcare professionals with a specialism in adult renal services who care for adults (18 years and older) with stage 4 and 5 chronic kidney disease (CKD), including those with stage 5 CKD who are on dialysis.The aim of this presentation is to present the case for offering calcium based phosphate binders as the first-line phosphate binder to control serum phosphate. This presentation will provide the information and rationale for the case for change and will set the phosphate binder recommendations in the context of the clinical guideline including details of recommendations about dietary management and sequencing of phosphate binders. In addition, this presentation can also provide a helpful briefing for use before undertaking the clinical case scenarios which are available to support education and learning for this guideline.In the presentation, the page number of the guideline from which the information was taken is given, for example [pg 84], to refer to for more information.The guideline is available in a range of formats (from including a NICE Pathway (http://pathways.nice.org.uk/pathways/hyperphosphataemia-in-chronic-kidney- disease). You may want to print copies of the NICE pathway (select ‘save and print’) for the audience to refer to.You can add your own organisation’s logo alongside the NICE logo.DISCLAIMERThis slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself.PROMOTING EQUALITYImplementation of the guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in the guidance should be interpreted in a way which would be inconsistent with compliance with those duties.March 2013NICE clinical guideline 15717
19First-line phosphate binders: recommendations For both people ‘on’ and ‘not on’ dialysisFor 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]NOTES FOR PRESENTERS:Recommendations in full:Recommendations [1.1.8] and [1.1.9] in full on the slideKey points to raise:Early intervention to prevent or manage high phosphate levels was considered key to preventing downstream complications resulting from the poor management of serum calcium and PTH. The Guideline Development Group (GDG) therefore emphasised the importance of starting phosphate binder therapy early, and stressed that this should be with concurrent dietary management of serum phosphate. [pg 103]The Guideline Development Group (GDG) felt it would be inappropriate to use the limited evidence available about the use of phosphate binders in people not on dialysis, to recommend a different phosphate binder for pre-dialysis patients than that recommended for those on dialysis, which was supported by a more substantial evidence base. The GDG also believed that continuity of care was important.For patients on dialysis, a cost–utility model was built based on effectiveness data from network meta-analyses comparing various phosphate binders. The model suggests that calcium acetate is likely to be the preferred first-line option. It provides appreciable benefit, when compared with calcium carbonate, at a relatively modest additional cost. While the use of non‑calcium-based binders may be associated with some extension of quality-adjusted life expectation compared with first-line calcium acetate, this gain is insufficient to justify the additional costs of the proprietary binders, when judged according to conventional standards (ICERs around £90,000 per QALY gained or greater were estimated). [Pg 218]Additional informationDo your local protocols for initiation of first line phosphate binders to control serum phosphate reflect this recommendation?19
20Sequencing of phosphate binders for patients not on dialysis: recommendations Adults with stage 4 or 5 CKD not on dialysisand taking a calcium-based binderCalcium‑based phosphate binders are not toleratedHypercalcaemia develops (account for other causes of raised calcium) orSerum PTH hormone levels are lowNOTES FOR PRESENTERS:Recommendation in full:For adults with stage 4 or 5 chronic kidney disease (CKD) who are not on dialysis and who are taking a calcium-based binder:consider switching to a non-calcium-based binder if calcium‑based phosphate binders are not toleratedconsider either combining with, or switching to, a non‑calcium‑based binder if hypercalcaemia develops (having taken into account other causes of raised calcium), or if serum parathyroid hormone levels are low. [1.1.10]Additional informationIf considering the use of non-calcium-based binders because of high serum calcium levels in patients on calcium-based binders, it is important to review possible causes of high calcium, such as dialysate calcium content, vitamin D, calcium supplements, dietary calcium or certain over-the-counter preparations, such as indigestion remedies, before making any changes to the choice of binder. In some cases, it might be easier to make small changes to these sources of elemental calcium than changing (and ensuring adherence to) the phosphate binder regimen. For example, it may be the case that a patient is on a high dose of vitamin D, and a reduction in this may be the most appropriate course of action. [pg 217]The choice of which non-calcium-based binder to use in these scenarios for people not on dialysis, should be determined through clinical judgement and patient preference. Metabolites and toxins are less likely to accumulate in patients not on dialysis; therefore, aluminium hydroxide and magnesium (Magnesium carbonate is only licensed as a combination with calcium acetate; therefore, it cannot currently be used as monotherapy in the UK.) are included as non-calcium-based options alongside sevelamer hydrochloride and lanthanum carbonate. Some GDG members felt that regular monitoring of serum aluminium may be beneficial in those receiving aluminium hydroxide. [pg 104]For further information about the evidence reviewed by the GDG to develop the recommendations about phosphate binder use in patients not on dialysis, see pages 101–104 of the full guideline.Consider either combining with, or switching to, a non‑calcium‑based binderConsider switching to a non-calcium-based binder20
21First-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 carbonateChanging 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.NOTES FOR PRESENTERS:Key points to raise:NICE anticipate that depending upon current practice locally, in some organisations, prescription of calcium acetate as the first line phosphate binder is likely to reduce the number of people being prescribed sevelamer hydrochloride and lanthanum carbonate. NICE estimate that the potential savings per person arising due to this change in prescribing are: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.It could be suggested that these savings could be used to offset the additional costs anticipated with the increase in number of people receiving dietary assessment with a specialist renal dietician (slide 7).The NICE costing report advises commissioners and services leads to check current practice in their local area and use the local costing template to ascertain the resource impact for their population.21
22The 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.
23The 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-calcium-based 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.
24Final remarksOur 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.
25Mosaico Cattedrale Pesaro - VI sec d.c. Grazie per l’attenzione !!!
26A randomized multicenter , non –blinded, pilot study to compare the impact of sevelamer vs. calcium carbonate on hard outcomes such as mortality, progression to end-stage renal disease (ESRD) and CAC progression in 212 patients with mild to moderate CKD (creatinine clearance 30 ml/min).patients allocated to sevelamer experienceda significantly lower risk of CAC progression orde novo onset of CAC (12.8% in sevelamer-treated patientsand 81.8% in calcium carbonate–treated patients) after24 months of treatment (Clin J Am Soc Nephrol. 2012;7(3):
27significant reduction in the risk of all-cause mortality (hazard ratio [HR] = 0.36; 95%confidence interval [95% CI], ) and a trend towarda reduction of the risk of dialysis inception (HR = 0.77; 95%CI, ) (42) in patients treated with sevelamer.The all-cause mortality in our pilot study was not related to any parameter of mineral metabolism. the survival benefit in the sevelamer group could be related to the several pleiotropic effects of the binder beyond its hypophosphatemic effects.The major limitation of this study is the sample size, no specific target of serum phosphorus to be reached and urinary phosphorus excretion or serum FGF-23 levels not measured.
28Final remarksThe use of phosphate binder in CKD 3-5 is based on observational rather than clinical trial data.The few studies available suggest a limited effect of phosphate binders, at least when used in normophosphatemic patients and not in combination with diet .Nevertheless, considering the several limitations of the few available studies and the many unanswered questions, more clinical trials of adequate power and follow-up should investigate the impact of phosphorus metabolism management (nutritional interventions and phosphate binder use) on hard outcomes at different levels of phosphatemia and renal function impairment.Randomized controlled trials (RCTs) comparing effective phosphorus-lowering interventions (i.e., diet and phosphate binders) vs. placebo could shed light on this cogent question and 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.
31? ? P Vit D Calcitriolo Analoghi P mg/dl VDRA IPTH pg/ml 5.5dietachelanti (Ca, Al, Mg)chelantiLantanio, Sevelamer?PP4.54.5P mg/dldieta2.52.5PVit D100603015Stadio 3Stadio 4Stadio 5 - DGFRVDRACalcitrioloAnaloghiIPTH pg/ml30609025 OH Vit D ng/ml30colecalciferolo - calcifediolo
32Study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4.Design :40 patients normophosphatemics were randomized to receive over a 6-wk period either calcium acetate (n 19) or sevelamer hydrochloride (n 21).Despite low phosphate ingestion ( mg/d), normalserum phosphate levels, and a relatively low phosphaturia,patients presented with an elevated fractional excretion ofphosphate and serum PTH levels higher than normal. Mean25-hydroxy-vitamin D was ng/ml, and all but fivepatients presented elevated serum FGF23 levels.After treatment with both phosphate binders, there was a progressive decline in serum PTH, urinary phosphate, and fractional excretion of phosphate, but no significant change in serum calcium or serum phosphate in either groupIn study presented here, sevelamer hydrochloride treatment appeared more effective at lowering serum FGF23 levels. These findings cannot be attributed to differential control of serum phosphorus or 1,25-vitamin D3, two known regulators of FGF23. It is possible that sevelamer’s increased ability to reduce FGF23 occurs through an unknown effect.Raise the possibility that increased calcium load may contribute to FGF23 elevationwe demonstrate for the first time that theuse of phosphate binders in early CKD patients with normalserum phosphate is effective at lowering total urinary phosphateexcretion, fractional phosphate excretion, and serumPTH without significant changes in serum calcium or phosphatelevels. Thus, these data demonstrate that early phosphatebinder use provides additional PTH control beyond that of aphosphate-restricted diet.Sevelamer hydrochloride treatment appeared more effective at lowering serum FGF23 levels. These findings cannot be attributed to differential control of serum phosphorus or 1,25-vitamin D3.It is possible that sevelamer’s increased ability to reduce FGF23 occurs through an unknown effect. Possibility that increased calcium load may contribute to FGF23 elevation?60% (n 13) of the sevelamer-treated patients presented an increase in 1,25-vitamin D3 levels, whereas this increase was seen in only 31.6% (n 6) of calcium-treated patients (P 0.07).
34The high dropout rate (about 28% in the active group), the overall clinically albeit not statisticallymeaningful differences in baseline CAC and abdominaland thoracic volume scores (39), the potential for imbalancesamong patients assigned to different phosphatebinders (data not provided), the large standard deviationof reported point estimates and the lack of progressionamong placebo-treated patients greatly limit the interpretationof these results. Furthermore, as the authors pointout, the detrimental effect on vascular calcification seemsto have been greater among calcium-treated patients,and it probably would have been interesting to analyzethe effect of every single binder separately, though thiswas not feasible due to the small study cohort.
36n°6 3-4CKD subjects and n°6 controls We hypothesized that subjects with advanced CKD are in positive calcium balance on high dietary calcium intake, and that this positive balance is not reflected in the serum calcium concentration.n° CKD subjects and n°6 controls
37Subjects with late stage 3 and stage 4 CKD were in slightly negative to neutral calcium balance on a daily intake of 800 mg, but were in marked positive balance on 2000 mg/day.If confirmed in larger balance studies, these findings suggest that elemental calcium intake should be limited to 800–1200 mg in individuals with late stage 3 or stage 4 CKD.
38“Results from Spiegel study implie that calcium supplements and calcium-containing phosphate binders are virtually completely to be avoided in CKD, even in patients not yet on dialysis”.Although it is currently clear that patients with CKD consuming their habitual diet are in neutral or even in slightly negative calcium balance, additional balance studies with adequate equilibration times and long collecting periods are required to teach us whether — and, if so, to what extent — calcium supplementation renders the calcium balance positive. Preferably, these balance studies should be combined with validated isotope techniques to define the destination of the excess calcium: the soft tissues or the bone.Several questions need to be raised and warrant caution.A first question to be asked is whether or not the study participants were in steady state during calcium loading; the 7-day equilibration period in the study by Spiegel and Brady might have been too short.A second question relates to the validity of the balance data obtained during calcium loading: the 24- h calcium losses in stool were calculated rather than directly determined.Phosphorus balance was not determined.
39The purpose of this study was to determine whether calcium carbonate, used as a phosphate binder, altered calcium and phosphorus balance and calcium kinetics in patients with stage 3/4 CKD while on a controlled diet.8 patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36 ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo controlled cross-over design.
40Calcium kinetics demonstrated positive net bone balance (259 mg ) with Calcium but less than overall calcium balance (508 mg ) , suggesting soft-tissue deposition.
41CONCLUSIONSThese results challenge the rationale for using calcium-based phosphate binders in stage 3/4 CKD patients to prevent negative calcium balance, reduce PTH, reduce serum phosphate, and prevent phosphorus retention because:(1)patients were not in negative calcium balance or positive phosphorus balance on placebo and(2)calcium carbonate did not affect serum PTH, serum phosphate, or phosphorus balance.Although it is unknown whether the calcium retained from calcium carbonate is deposited into bone or soft tissue in these patients, it is unlikely that bone could serve as the sole reservoir considering the magnitude of the positive calcium balance and the patients’ age.Therefore, the positive calcium balance produced by calcium carbonate cautions against its use as a phosphate binder in stage 3/4 CKD patients.