Pro: Should phosphate binders be used in chronic kidney disease stage 3 4?

Transcription

1 Nephrol Dial Transplant (2016) 31: doi: /ndt/gfv405 Advance Access publication 17 December 2015 Polar Views in Nephrology Pro: Should phosphate binders be used in chronic kidney disease stage 3 4? Antonio Bellasi 1,2 1 Division of Nephrology, Sant Anna Hospital, Como, CO, Italy and 2 Department of Health Sciences, University of Milan, Milan, Italy Correspondence and offprint requests to: Antonio Bellasi; antoniobellasi@gmail.com ABSTRACT Convincing epidemiological data have repeatedly shown that increased phosphate levels as well as generous phosphate intakes are associated with unfavourable outcome both in normal and chronically impaired kidney disease (CKD) individuals. Indeed, evidence suggest that impaired phosphate metabolism is associated with markers of cardiovascular damage such as left ventricular hypertrophy, arterial stiffness or vascular calcification as well as mortality. Although current guidelines suggest phosphate control in CKD, evidence on the impact of different approaches to minimize phosphate burden on clinically meaningful outcome are still lacking. How to manipulate, when to start in the course of CKD and to what extent to control phosphate metabolism still remain to be addressed by properly designed clinical studies. Treatment decisions should be based on a risk benefit assessment to avoid unnecessary exposure to potentially harmful side effects of available compounds. The focus and the ambition of this review are to summarize current evidence and to provide a point of care suggestion on the use of phosphate binders in CKD stage 3 and 4 patients. Keywords: chronic kidney disease, outcome, phosphate, phosphate binders, phosphate metabolism Phosphorus is essential for life and is involved in several key biological systems. It is involved in adenosine triphosphate (ATP) and energy metabolism, is a deoxyribonucleic acid (DNA) as well as a cell membrane constituent and is a substrate for various kinases involved in numerous signal transduction pathways [4]. Phosphorus exists in humans as phosphate (PO 4 3 ), and is mainly located in the intracellular or the interstitial compartment (99% of the total body pool) and largely stored in bones [2]. Only less than 1% of the body pool is dissolved in serum. Due to its essential role and to preserve its peculiar distribution in the body, phosphate homeostasis is maintained by a complicated interplay of various factors that balance intestinal absorption with urinary excretion [2]. Phosphate and/or factors involved in phosphate homeostasis may account for (i) the link between phosphate metabolism and other key metabolic pathways in CKD [5], (ii) a poor correlation of serum levels with phosphate balance, (iii) a poor correlation of serum phosphate levels with the risk of unfavourable outcome at the individual level and (iv) help understating the results of recent randomized clinical trials that have investigated the impact of phosphate binders in CKD patients. The aim of the current review is to provide the reader with a personal point of care view on the phosphate binder use in non-dialysis dependent CKD patients (NDD-CKD). INTRODUCTION As renal function declines numerous metabolic abnormalities ensue [1]. Among others, phosphate retention and hyperphosphataemia are prevalent complications of late stages of chronic kidney disease (CKD) [2]. A large body of evidence supports the notion that phosphate is linked to increased risk of death, cardiovascular (CV) events and CKD progression [3]. PHOSPHORUS OR PHOSPHATE BALANCE: AN UNANSWERED CONUNDRUM Although the mechanism(s) is not completely clarified, in vitro and animal studies document that PO 4 3 stimulates parathyroid gland parathyroid hormone (PTH) secretion and growth, endothelial reactive oxygen species production and apoptosis [6] as well as soft tissue and vascular calcification [7]. Numerous albeit not all epidemiological and clinical observations further The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 184

2 corroborate these findings [3]. Serum levels of phosphorus, even within the range of normality, are associated with endothelial dysfunction [8], carotid artery intima media thickness [9], vascular calcification [10] and arterial stiffness [11], as well as hard outcomes such as accelerated CKD progression [12 15] and increased risk of death [16 19] in different populations with various degrees of renal impairment. Notably, the reported relationship between phosphataemia and the risk of death in NDD-CKD is almost linear and significant for levels within the range of normality, at least from a statistical point of view. Hence, it is uncertain what is the optimal range of serum phosphate. Demographic and comorbid conditions such as age, sex hormones, diabetes and residual renal function may influence phosphate balance and serum levels [12, 20]. Whether we should define and implement age-, sex- or diseasespecific laboratory references is unclear at the current time. The circadian fluctuations [21] in serum and the lack of standardization of phosphate assessment further complicate the use of phosphataemia as a surrogate marker in clinics, at least when serum PO 4 3 is within the laboratory range of normality. Although data are far from being conclusive on the causal role of serum phosphorus in organ damages, hyperphosphataemia may represent the epiphenomenon of a metabolic complication that arises in the course of CKD and a maker of uncompensated renal failure (Figure 1). Indeed, chronically elevated serum levels of phosphate are likely expression of a prolonged exposure to a positive phosphate balance (i.e. diet intake and intestinal absorption greater than intestinal and renal excretion). Serum PO 4 3 is determined by diet intake and bone metabolism as well as kidney and intestinal excretion [2, 3]. Animal and clinical data suggest a linear correlation between dietary phosphate intake and urinary output [22, 23], indicating that no effective inhibitory mechanism of intestinal absorption exists and renal excretion is the major determinant of phosphate balance. In other words, the excessive dietary intake is counterbalanced by an increase in the amount of PO 4 3 excreted per single nephron. Prolonged exposure to oral phosphate overload and/or a reduction in nephron mass increase the workload of the proximal convoluted tubules, where renal phosphate handling occurs. In turn, the increased workload may be responsible for the tubulointerstitial lesions observed in an animal model of uni- or partially nephrectomized rats exposed to diets with different amount of phosphorus [22]. Interestingly, only few rats developed hyperphosphataemia and phosphataemia did not correlate with the severity of the histological lesions, corroborating the notion that phosphate balance rather than serum levels is clinically relevant [22]. As glomerular filtration rate (GFR) declines in CKD, phosphaturic factors such as fibroblast growth factor-23 (FGF23) or PTH are secreted to prevent a positive phosphate balance and hyperphosphataemia at the cost of an increase in tubular workload and phosphaturia [24, 25]. Indeed, recent data [26] suggest that a neutral phosphate balance is maintained until late stages of CKD, contradicting the hypothesis that as renal function POLAR VIEWS IN NEPHROLOGY FIGURE 1: Two different phases in the course of CKD can be distinguished: phase 1 characterized by substantially preserved renal excretory capacity and normal serum phosphate levels and phase 2 characterized by insufficient excretory capacity (generally when the GFR drops below 30 ml/min/1.73 m 2 ) and hyperphosphataemia. While normal serum levels of phosphate cannot discriminate neutral versus positive and potentially harmful phosphate balance, hyperphosphataemia should be regarded as a sign of phosphate metabolism imbalance and a potential target for interventions. P, phosphate. Phosphate binders in renal failure 185

3 POLAR VIEWS IN NEPHROLOGY declines a progressive expansion of the total phosphate body pool occurs. Whether and to what extent phosphaturia and/or phosphaturic factors mediate organ damage is unclear, although it is likely that both phosphate and phosphaturic mechanisms maybe harmful [27, 28]. This hypothesis is supported by a recent report by Dominguez et al. [29]. As reported in numerous observational studies, FGF23 predicted the occurrence of any fatal as well as major CV events [29] among the 872 individuals recruited in the Heart and Soul Cohort. However, high fractional excretion of phosphate (FePi) substantially mitigated the risk associated with FGF23 (highly significant interaction test) [29], suggesting that an adequate phosphaturic response to FGF23 reduces the risk associated with positive phosphate balance. Notably, all study subjects had normal to mild renal function impairment and normal serum phosphorus levels at study inception. These findings corroborate the notion that FGF23 is an adaptive phosphaturic system to prevent hyperphosphataemia that in some circumstances, such as renal function decline, may turn into a maladaptive mechanism that likely contributes to the organ damage. As documented by Isakova et al., two different phases in the course of CKD can be distinguished: phase 1 characterized by substantially preserved renal excretory capacity and normal serum phosphate levels and phase 2 characterized by insufficient excretory capacity (generally when the GFR drops below 30 ml/min/1.73 m 2 ) and hyperphosphataemia [24] (Figure 1). Hence, while normal serum levels of phosphate cannot discriminate neutral versus positive and potentially harmful phosphate balance, hyperphosphataemia should be regarded as a sign of phosphate metabolism imbalance and a potential target for interventions (Figure 1). CLINICAL TRIALS ON PHOSPHATE BINDER USE IN CKD PATIENTS WITH OR WITHOUT HYPERPHSOPHATAEMIA Recent randomized clinical trials (RCTs) on phosphate management in CKD patients apparently yielded conflicting results [23, 30 32]. However, the rationale summarized in Figure 1 may be useful in interpreting these findings. Studies have looked into the impact of phosphate binders in two different populations: normophosphataemic and hyperphosphataemic CKD patients. Two recent studies [26, 33] investigated the impact of calcium carbonate supplementation (as phosphate lowering intervention) on phosphate and calcium balance in NDD-CKD. Of interest, calcium administration did not affect phosphate but significantly increased calcium balance [26, 33]. A reduction in urine phosphate for the duration of calcium carbonate administration is likely responsible for maintaining phosphataemia within the range of normality as well as a neutral phosphate balance [26]. Overall these results corroborate the notion that phosphataemia is not an accurate marker of phosphate balance and question the need for phosphate management in patients with residual renal function and normophosphataemia. However, in consideration of the potential effect of calcium on FGF23 secretion [34] as well as FGF23 toxicity [27, 35], they should also prompt further studies to assess whether calcium-containing or calcium-free phosphate binder administration is safe in CKD patients. In a small RCT of 149 CKD patients (estimated GFR of ml/min/1.73 m 2 ) with normal serum phosphorus at study inception (mean serum phosphate: 4.2 mg/dl), investigators tested the effects of maximal dosage of different phosphate binders (sevelamer carbonate, lanthanum carbonate and calcium acetate) or placebo on parameters of mineral metabolism [30]. Albeit statistically significant, authors reported a modest reduction in serum phosphate (from 4.2 to 3.9 mg/dl) after 9 months of active treatment [30]. As expected, a larger effect of phosphate binders was detected in urine phosphate excretion ( phosphate binders reduced mean 24-h urine phosphorus by 22%) [30]. Although largely influenced by calcium acetate, the use of phosphate binders was associated with a significant increase in coronary and abdominal aorta vascular calcification. Overall, these results suggest some caution in the use of phosphate binders in patients with normophosphataemia and residual renal function [30]. Another RCT [31] tested the impact of 9 months of treatment with sevelamer carbonate versus placebo on left ventricular mass (LVM) and pulse wave velocity (PWV). As per the inclusion and exclusion criteria, all the 109 CKD stage 3 subjects recruited had normal serum phosphorus levels (mean serum phosphate, 3.1 mg/dl) and no signs of chronic kidney disease mineral bone disorder (CKD-MBD) at study inception [31]. Despite the fact that this study did not raise any safety concern [31], it failed to show any impact of sevelamer carbonate on LVM or PWV. In line with previous studies, no change in phosphataemia was detected. However, in consideration of the low levels of FGF23 and the normal LVM of the study cohort at study inception [31], it is likely that only patients in neutral phosphate balance and at low CV risk were randomized. Similar conclusions were reached in another small study of 38 CKD stage 3 (creatinine clearance 47 ml/min) patients with normal serum phosphate levels (3.5 mg/dl) [36]. Twelve months administration of lanthanum carbonate had no effects on serum phosphorus or makers of CV disease such as PWV, carotid intima media thickness and vascular calcification [36]. These results lend credibility to the hypothesis that overall normophosphataemic subjects may not benefit from phosphate management interventions and the use of phosphate binders in this population should be discouraged. However, the use of an unreliable marker of phosphate balance (i.e. phosphataemia), the relatively short follow-up, the use of surrogate markers as well as the lack of a clear demonstration of the effects of phosphorus balance manipulation (i.e. RCT that compares an active treatment versus placebo on hard outcomes) preclude any definitive conclusion and more studies are needed in this domain. In the recent past, few RCTs have looked into the potential impact on hard and surrogate outcomes of calcium-free versus calcium-containing phosphate binder regimens in patients with hyperphosphataemia. Although these studies do not include a comparison with placebo, they shed some light on the potential of phosphate balance modulation in a subgroup of CKD patients with a clear sign of phosphate imbalance (i.e. hyperphosphataemia). In a recent study of 100 CKD stage 186 A. Bellasi

4 4 patients (estimated GFR 22 ml/min/1.73 m 2 )withhyperphosphataemia (>6.0 mg/dl at study inception) [8], it was shown that a short course of 8 weeks treatment with sevelamer HCl but not calcium acetate was associated with FGF23 reduction and endothelial dysfunction improvement [8]. Although a different phosphate control among sevelamer-treated patients was noted ( phosphorus at baseline and study completion: and mg/dl in the sevelamer and calcium acetate study arm, respectively), these results lend support the notion that phosphate binder use improves endothelial dysfunction. However, calcium may contribute to FGF23 release [34] and preclude flow-mediated dilatation restoration [8]. Di Iorio et al. [32] studied the impact of sevelamer HCl and calcium carbonate on hard outcome (i.e. all-cause mortality and dialysis inception) as well as coronary artery calcification progression in a sample of 212 CKD stage 3 4 patients (mean creatinine clearance 32 ml/min) and hyperphosphataemia (mean serum phosphate 4.8 mg/dl) [32]. Over the 36 months of follow-up, a lower risk of the composite endpoint of all-cause mortality and dialysis inception were observed among patients allocated to sevelamer HCl treatment (fully adjusted hazard ratio 0.62; 95% confidence interval ) [32]. At study completion, however, a significantly better versus unchanged phosphate control was noted among patients allocated to sevelamer versus calcium carbonate ( phosphorus at baseline and study completion: and mg/dl in the sevelamer and calcium carbonate study arm, respectively). Although the lack of a placebo group precludes any consideration about the potential benefit associated with phosphate lowering or calcium harm, these results are corroborated by two other RCTs that have explored the effects of these two phosphate binder regimens in hyperphosphataemic patients incident to dialysis [37, 38]. A recent meta-analysis [39] of studies that have compared the effects on mortality of different calcium-free versus calcium containing phosphate binders suggests that these results may be extended to all calcium-free phosphate binders, although this hypothesis warrants further confirmation. Overall, it seems that phosphate control in hyperphosphataemic patients may be beneficial. However, it remains to be elucidated whether this is secondary to the correction of phosphate or other factors responsible for phosphate homeostasis (i.e. FGF23). CONCLUSIONS AND TAKE-HOME MESSAGES How to reconcile available evidence? A large and expanding body of evidence suggests that phosphorus imbalance portends poor prognosis in CKD patients. Although definitive clinical evidence on the causal role of phosphate on organ damage is still missing and future efforts are needed to disentangle the potential toxicity associated with phosphate and the mechanisms responsible for maintaining phosphate homeostasis (for example, FGF23), it is plausible that a positive phosphate balance is a sign of uncompensated CKD. In this regard, phosphate binder administration and phosphorus metabolism manipulation may be beneficial. However, serum phosphate is not an accurate marker of phosphate balance and it is likely useless for risk stratification in patients with normophosphataemia. Indeed, an articulated interplay of factors may maintain serum levels of phosphate within the range of normality even in the setting of positive phosphate balance. Future studies need to validate the prognostic role of a marker(s) of phosphate balance and test whether the use of these markers can guide phosphorus metabolism manipulation and improve survival of CKD patients. Until further evidence becomes available, RCT results suggest that phosphate binder administration in patients with normal levels of serum phosphate may be useless or even unsafe, particularly if coupled with calcium loading. However, hyperphosphataemia, as a sign of phosphate imbalance, may identify a high-risk subgroup of patients suitable for interventions. In this regard, when low-phosphate diet fails, it seems reasonable to use phosphate binders (possibly without increasing calcium loading) to correct hyperphosphataemia, as suggested by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the management of CKD-MBD [40]. Nevertheless, in consideration of the limited resources available for CKD management, the real cost-effectiveness of these compounds still warrants proper pharmacoeconomic evaluations. CONFLICT OF INTEREST STATEMENT Dr Bellasi has received honoraria from Sanofi, Amgen, Keryx, Shire, Sanifit. (See related article by Kestenbaum. Con: Phosphate binders in chronic kidney disease. Nephrol Dial Transplant 2016; 31: ; See related article by Zoccali and Mallamaci. Moderator s view: Phosphate binders in chronic kidney disease patients: a clear No at the moment, but stay tuned. Nephrol Dial Transplant 2016; 31: ) REFERENCES 1. Moranne O, Froissart M, Rossert J et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol 2009; 20: Bellasi A, Galassi A, Cozzolino M et al. The evolving world of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). Eur Med J Nephrol 2013; 1: Bellasi A, Cozzolino M, Adragao T et al. Phosphate binders in moderate chronic kidney disease: where do we stand? J Nephrol 2013; 26: Kuro-o M. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol 2013; 9: Cozzolino M, Gentile G, Mazzaferro S et al. Blood pressure, proteinuria, and phosphate as risk factors for progressive kidney disease: a hypothesis. Am J Kidney Dis 2013; 62: Abbasian N, Burton JO, Herbert KE et al. Hyperphosphatemia, phosphoprotein phosphatases, and microparticle release in vascular endothelial cells. J Am Soc Nephrol 2015; 26: Jono S, McKee MD, Murry CE et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000; 87: E10 E17 8. Yilmaz MI, Sonmez A, Saglam M et al. Comparison of calcium acetate and sevelamer on vascular function and fibroblast growth factor 23 in CKD patients: a randomized clinical trial. Am J Kidney Dis 2012; 59: Onufrak SJ, Bellasi A, Shaw LJ et al. Phosphorus levels are associated with subclinical atherosclerosis in the general population. Atherosclerosis 2008; 199: Russo D, Palmiero G, De Blasio AP et al. Coronary artery calcification in patients with CRF not undergoing dialysis. Am J Kidney Dis 2004; 44: POLAR VIEWS IN NEPHROLOGY Phosphate binders in renal failure 187

5 POLAR VIEWS IN NEPHROLOGY 11. Ix JH, De Boer IH, Peralta CA et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol 2009; 4: Bellasi A, Mandreoli M, Baldrati L et al. Chronic kidney disease progression and outcome according to serum phosphorus in mild-to-moderate kidney dysfunction. Clin J Am Soc Nephrol 2011; 6: Kovesdy CP, Ahmadzadeh S, Anderson JE et al. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int 2008; 73: Schwarz S, Trivedi BK, Kalantar-Zadeh K et al. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006; 1: Zoccali C, Ruggenenti P, Perna A et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. J Am Soc Nephrol 2011; 22: Voormolen N, Noordzij M, Grootendorst DC et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant 2007; 22: De Nicola L, Chiodini P, Zoccali C et al. Prognosis of CKD patients receiving outpatient nephrology care in Italy. Clin J Am Soc Nephrol 2011; 6: Kestenbaum B, Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16: Eddington H, Hoefield R, Sinha S et al. Serum phosphate and mortality in patients with chronic kidney disease. Clin J Am Soc Nephrol 2010; 5: Onufrak SJ, Bellasi A, Cardarelli F et al. Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause mortality. Am J Epidemiol 2009; 169: Ix JH, Anderson CA, Smits G et al. Effect of dietary phosphate intake on the circadian rhythm of serum phosphate concentrations in chronic kidney disease: a crossover study. Am J Clin Nutr 2014; 100: Haut LL, Alfrey AC, Guggenheim S et al. Renal toxicity of phosphate in rats. Kidney Int 1980; 17: Di Iorio BR, Bellizzi V, Bellasi A et al. Phosphate attenuates the antiproteinuric effect of very low-protein diet in CKD patients. Nephrol Dial Transplant 2013; 28: Isakova T, Wahl P, Vargas GS et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79: Craver L, Marco MP, Martinez I et al. Mineral metabolism parameters throughout chronic kidney disease stages 1-5 achievement of K/DOQI target ranges. Nephrol Dial Transplant 2007; 22: Nephrol Dial Transplant (2016) 31: doi: /ndt/gfv405a 26. Hill KM, Martin BR, Wastney ME et al. Oral calcium carbonate affects calcium but not phosphorus balance in stage 3 4 chronic kidney disease. Kidney Int 2013; 83: Faul C, Amaral AP, Oskouei B et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: Scialla JJ, Lau WL, Reilly MP et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013; 83: Dominguez JR, Shlipak MG, Whooley MA et al. Fractional excretion of phosphorus modifies the association between fibroblast growth factor-23 and outcomes. J Am Soc Nephrol 2013; 24: Block GA, Wheeler DC, Persky MS et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol 2012; 23: Chue CD, Townend JN, Moody WE et al. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol 2013; 24: Di Iorio B, Bellasi A, Russo D. Mortality in kidney disease patients treated with phosphate binders: a randomized study. Clin J Am Soc Nephrol 2012; 7: Spiegel DM, Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets. Kidney Int 2012; 81: Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR et al. Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 2012; 23: Isakova T, Xie H, Yang W et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305: Seifert ME, de las Fuentes L, Rothstein M et al. Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. Am J Nephrol 2013; 38: Di Iorio B, Molony D, Bell C et al. Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am J Kidney Dis 2013; 62: Block GA, Raggi P, Bellasi A et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71: Jamal SA, Vandermeer B, Raggi P et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009: S1 130 Opponent s comments Bryan Kestenbaum Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Harborview Medical Center, Seattle, WA, USA Correspondence and offprint requests to: Bryan Kestenbaum; brk@u.washington.edu In his review, Bellasi expertly points out the central importance of phosphate balance in stage 3 4 chronic kidney disease (CKD) patients. As kidney function progressively declines, key phosphaturic hormones fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH) increase to maintain phosphate homeostasis by enhancing renal phosphate excretion. The Author Published by Oxford University Press on behalf of Downloaded from ERA-EDTA. All rights reserved. 188