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Marina Di Luca A.O.Osp.Riuniti Marche Nord Presidio San Salvatore
Phosphorus and outcome: serum phosphorus links with a poor prognosis Causative role ?Epiphenomenon ? OR numerous epidemiological studies, but data are far from being conclusive
Unresolved questions Active measures should be taken in early stages of CKD when serum phosphorus is still in the normal or near normal range? Lowering and maintaining phosphorus levels is accepted as an important therapeutic goal to improve outcomes of CKD MBD in CKD patients 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 ?
StageTarget PO 4 3 KDIGO: Maintain Normal KDOQI: mg/dL 4-5 KDIGO: Maintain Normal KDOQI: mg/dL 5D KDIGO: Towards Normal KDOQI: mg/dL Treatment Target Ranges for Phosphate 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)
Diet ? Binders ? Or Both ? How treating Phosphate Retention in CKD?
Britt Newsome Protein restriction is effective in reducing urinary phosphate levels, reducing FGF 23 and is associated with a very modest decrease in serum phosphate levels.
Diet ? Binders ? Or Both ? How treating Phosphate Retention in CKD?
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 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.
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.
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. Ca Acetato Non Calcium based binders CAC calcification (p=0.02) FGF-23 (p= 0.02) 1,25 dihydroxyvitamin D levels (P =0.004) PTH (P =0.0002) = o = =
Hyperphosphataemia in chronic kidney disease Calcium based phosphate binders: a case for change March 2013 NICE clinical guideline 157
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] First-line phosphate binders: recommendations
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 Consider switching to a non-calcium-based binder Consider either combining with, or switching to, a non ‑ calcium ‑ based binder Hypercalcaemia develops (account for other causes of raised calcium) or Serum PTH hormone levels are low
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. First-line phosphate binders: the savings
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-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.
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. 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. 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??
Grazie per l’attenzione !!! Mosaico Cattedrale Pesaro - VI sec d.c.
Clin J Am Soc Nephrol. 2012;7(3): 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).
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.
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. Final remarks
Stadio 3 Stadio 4 0 Stadio 5 - D GFR P mg/dl dieta dieta chelanti (Ca, Al, Mg) dieta chelantiLantanio, Sevelamer 5.5 IPTH pg/ml VDRA CalcitrioloAnaloghi ? ? P P P P P P P P P P P P P P P P Vit D 25 OH Vit D ng/ml 30 colecalciferolo - calcifediolo
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). 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). 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?
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.
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.
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.
“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”. 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. 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.
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. 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.
Calcium kinetics demonstrated positive net bone balance (259 mg ) with Calcium but less than overall calcium balance (508 mg ), suggesting soft-tissue deposition.
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.