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A.O.Osp.Riuniti Marche Nord Presidio San Salvatore

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1 A.O.Osp.Riuniti Marche Nord Presidio San Salvatore
Marina Di Luca A.O.Osp.Riuniti Marche Nord Presidio San Salvatore

2 AGENDA

3 Phosphorus and outcome: serum phosphorus links with a poor prognosis
Causative role ? Epiphenomenon ? OR numerous epidemiological studies, but data are far from being conclusive

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6 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 ?

7 Treatment Target Ranges for Phosphate
Stage Target PO4 3 KDIGO: Maintain Normal KDOQI: mg/dL 4-5 5D KDIGO: Towards Normal KDOQI: mg/dL Le 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-S130 K/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-S130 K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003(suppl 3) 7

8 How treating Phosphate Retention in CKD?
Diet ? Binders ? Or Both ?

9 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

10 How treating Phosphate Retention in CKD?
Diet ? Binders ? Or Both ?

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12 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

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14 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.

15 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.

16 CAC calcification (p=0.02) 1,25 dihydroxyvitamin D levels
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 Although the study was not powered to detect differences among individual subgroups randomly assigned to different types of phosphate binder, patients randomly assigned to lanthanum carbonate or sevelamer carbon-ate did not have significant increases in coronary artery calcification, whereas those who received calcium acetate experienced statistically significant increases in intact FGF-23 levels (P 0.02), reductions in 1,25 dihydroxyvitamin D levels (P 0.0002), 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.

17 Hyperphosphataemia in chronic kidney disease
Calcium based phosphate binders: a case for change ABOUT 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. DISCLAIMER This 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 EQUALITY Implementation 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 2013 NICE clinical guideline 157 17

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19 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] NOTES FOR PRESENTERS: Recommendations in full: Recommendations [1.1.8] and [1.1.9] in full on the slide Key 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 information Do your local protocols for initiation of first line phosphate binders to control serum phosphate reflect this recommendation? 19

20 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 NOTES 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 tolerated consider 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 information If 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 binder Consider switching to a non-calcium-based binder 20

21 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. 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

22 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.

23 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-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.

24 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.

25 Mosaico Cattedrale Pesaro - VI sec d.c. Grazie per l’attenzione !!!

26 A 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 experienced a significantly lower risk of CAC progression or de novo onset of CAC (12.8% in sevelamer-treated patients and 81.8% in calcium carbonate–treated patients) after 24 months of treatment ( Clin J Am Soc Nephrol. 2012;7(3):

27 significant reduction in
the risk of all-cause mortality (hazard ratio [HR] = 0.36; 95% confidence interval [95% CI], ) and a trend toward a 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.

28 Final remarks The 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.

29 CKD stage 3 La 1000 mg x 3

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31 ? ? P Vit D Calcitriolo Analoghi P mg/dl VDRA IPTH pg/ml
5.5 dieta chelanti (Ca, Al, Mg) chelanti Lantanio, Sevelamer ? P P 4.5 4.5 P mg/dl dieta 2.5 2.5 P Vit D 100 60 30 15 Stadio 3 Stadio 4 Stadio 5 - D GFR VDRA Calcitriolo Analoghi IPTH pg/ml 30 60 90 25 OH Vit D ng/ml 30 colecalciferolo - calcifediolo

32 Study 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), normal serum phosphate levels, and a relatively low phosphaturia, patients presented with an elevated fractional excretion of phosphate and serum PTH levels higher than normal. Mean 25-hydroxy-vitamin D was ng/ml, and all but five patients 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 group In 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 elevation we demonstrate for the first time that the use of phosphate binders in early CKD patients with normal serum phosphate is effective at lowering total urinary phosphate excretion, fractional phosphate excretion, and serum PTH without significant changes in serum calcium or phosphate levels. Thus, these data demonstrate that early phosphate binder use provides additional PTH control beyond that of a phosphate-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).

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34 The high dropout rate (about 28% in the
active group), the overall clinically albeit not statistically meaningful differences in baseline CAC and abdominal and thoracic volume scores (39), the potential for imbalances among patients assigned to different phosphate binders (data not provided), the large standard deviation of reported point estimates and the lack of progression among placebo-treated patients greatly limit the interpretation of these results. Furthermore, as the authors point out, the detrimental effect on vascular calcification seems to have been greater among calcium-treated patients, and it probably would have been interesting to analyze the effect of every single binder separately, though this was not feasible due to the small study cohort.

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36 n°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

37 Subjects 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.

39 The 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.

40 Calcium kinetics demonstrated positive net bone balance (259 mg ) with Calcium but less than overall calcium balance (508 mg ) , suggesting soft-tissue deposition.

41 CONCLUSIONS These 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.


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