Prevention and treatment of hyperphosphatemia in chronic kidney disease

Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field. Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field. Abnormal phosphate metabolism is one of the key disturbances in chronic kidney disease (CKD). It is now recognized that overt hyperphosphatemia occurs rather late in the process of CKD progression, usually at stage 4 and onward.1Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (817) Google Scholar However, adaptive mechanisms, particularly high concentrations of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), antedate the development of overt hyperphosphatemia, promoting kidney phosphate excretion.2Isakova T. Wolf M.S. FGF23 or PTH: which comes first in CKD?.Kidney Int. 2010; 78: 947-949Google Scholar Because these adaptive mechanisms may be directly involved in uremia-associated pathologies, it is difficult to untangle assumed phosphate toxicity from pathogenetic effects of these adaptive responses. Moreover, a reduction of phosphate exposure by dietary intervention or inhibition of intestinal phosphate absorption does not normalize elevated concentrations of PTH and FGF23. Other factors such as vitamin D deficiency, inflammation, and autonomous overproduction of these hormones may explain the limited effects of phosphate-targeted intervention on their circulating levels. Maintaining normal phosphate balance is of crucial importance for many physiological processes including bone mineralization. Phosphate homeostasis is determined by modulation of intestinal uptake of dietary phosphate, renal phosphate reabsorption of ultrafiltered phosphate, and the shift of intracellular phosphate between extracellular and bone storage pools (Figure 1).3Marks J. Debnam E.S. Unwin R.J. Phosphate homeostasis and the renal-gastrointestinal axis.Am J Physiol Renal Physiol. 2010; 299: F285-296Crossref PubMed Scopus (0) Google Scholar, 4Hruska K.A. Mathew S. Lund R. Qiu P. Pratt R. Hyperphosphatemia of chronic kidney disease.Kidney Int. 2008; 74: 148-157Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar It is well established that phosphate is one of the major factors in the maintenance of bone health and that phosphate deficiency results in bone pathology, as seen in patients with specific monogenic diseases, leading to isolated renal phosphate wasting syndromes.5Alizadeh Naderi A.S. Reilly R.F. Hereditary disorders of renal phosphate wasting.Nat Rev Nephrol. 2010; 6: 657-665Crossref PubMed Scopus (35) Google Scholar Hyperphosphatemia per se usually is asymptomatic. Morbidity associated with hyperphosphatemia is the consequence of acquired structural or functional6Six I. Maizel J. Barreto F.C. et al.Effects of phosphate on vascular function under normal conditions and influence of the uraemic state.Cardiovasc Res. 2012; 96: 130-139Crossref PubMed Scopus (0) Google Scholar abnormalities, including vascular calcification, which has been recently summarized7Vervloet M.G. Sezer S. Massy Z.A. et al.The role of phosphate in kidney disease.Nat Rev Nephrol. 2016; 13: 27-38Crossref PubMed Scopus (2) Google Scholar but is beyond the scope of the current review. This is important because the justification for treating hyperphosphatemia is based on the assumption that associated abnormalities are caused by abnormal phosphate homeostasis. The second assumption is that a reduction in phosphate concentration over time toward the normal range is accompanied by a parallel decline in morbidities and death. Comparable assumptions formed the base to restore hemoglobin concentration in renal anemia to near normal levels by epoetin, aiming to improve clinical outcome, but proved untrue.8Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1426) Google Scholar The assumptions described above are based on numerous observational studies that generally reported on the risk for mortality or cardiovascular disease of higher serum phosphate concentrations across the entire spectrum of CKD, ranging from normal or slightly decreased kidney function to dialysis-dependent end-stage kidney disease. Large studies in non-CKD populations, collectively encompassing over 39,000 subjects all found an association between phosphate, even in the normal range, and all-cause mortality,9Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Crossref PubMed Scopus (515) Google Scholar, 10Foley R.N. Collins A.J. Ishani A. Kalra P.A. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) study.Am Heart J. 2008; 156: 556-563Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar cardiovascular events,11Dhingra R. Sullivan L.M. Fox C.S. et al.Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Arch Intern Med. 2007; 167: 879-885Crossref PubMed Scopus (479) Google Scholar or cardiovascular mortality.12Vart P. Nigatu Y.T. Jaglan A. van Zon S.K. Shafique K. Joint effect of hypertension and elevated serum phosphorus on the risk of mortality in national health and nutrition examination survey-III.J Am Heart Assoc. 2015; 4: e001706https://doi.org/10.1161/JAHA.114.001706Crossref PubMed Scopus (2) Google Scholar Also in patients with CKD, an association between phosphate and adverse events exists. In an analysis of 1203 patients, Eddington et al. found a stepwise positive association of serum phosphate concentration and mortality in CKD stages 3 and 4 but not stage 5.13Eddington H. Hoefield R. Sinha S. et al.Serum phosphate and mortality in patients with chronic kidney disease.Clin J Am Soc Nephrol. 2010; 5: 2251-2257Crossref PubMed Scopus (0) Google Scholar Voormolen et al.,14Voormolen N. Noordzij M. Grootendorst D.C. et al.High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients.Nephrology Transplant. 2007; 22: 2909-2916Crossref PubMed Scopus (0) Google Scholar however, analyzing patients with stage 5 (nondialysis) CKD did find an increased relative risk for mortality of 1.62 for patients with an average eGFR of 13 (±5.4) ml/min per 1.73 m2 and serum phosphate concentration of 4.71 (±1.16) mg/dl.14Voormolen N. Noordzij M. Grootendorst D.C. et al.High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients.Nephrology Transplant. 2007; 22: 2909-2916Crossref PubMed Scopus (0) Google Scholar Although an analysis of the Modification of Diet in Renal Disease (MDRD) study (n = 840) could not confirm this association,15Menon V. Greene T. Pereira A.A. et al.Relationship of phosphorus and calcium-phosphorus product with mortality in CKD.Am J Kidney Dis. 2005; 46: 455-463Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar the largest study to date, from the Veterans Affairs Medical Centers (n = 3490) by Kestenbaum et al.16Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (703) Google Scholar found a linearly increasing mortality risk for patients with CKD, above a threshold serum phosphate concentration of 3.5 mg/dl (1.13 mmol/l).16Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (703) Google Scholar Finally, in patients undergoing dialysis, numerous studies have consistently reported the independent association between hyperphosphatemia and mortality risk.17Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Google Scholar, 18Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (276) Google Scholar, 19Naves-Diaz M. Passlick-Deetjen J. Guinsburg A. et al.Calcium, phosphorus, PTH and death rates in a large sample of dialysis patients from Latin America. The CORES study.Nephrology Transplant. 2011; 26: 1938-1947Crossref PubMed Scopus (0) Google Scholar, 20Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2005; 67: 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 21Ganesh S.K. Stack A.G. Levin N.W. Hulbert-Shearon T. Port F.K. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Google Scholar, 22Floege J. Kim J. Ireland E. et al.Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.Nephrology Transplant. 2011; 26: 1948-1955Crossref PubMed Scopus (0) Google Scholar, 23Kalantar–Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Generally, hyperphosphatemia is considered indicative for overall phosphate burden. However, routine clinical observations demonstrate that this view is an oversimplification, as hyperphosphatemia is widely prevalent in CKD, even in individuals with low bone mass, in which the tissue contains approximately 85% of total body phosphate. In fact, phosphate resides in different compartments, of which plasma and interstitial fluids represent very small fractions (Figure 2).24Osuka S. Razzaque M.S. Can features of phosphate toxicity appear in normophosphatemia?.J Bone Miner Metab. 2012; 30: 10-18Crossref PubMed Scopus (0) Google Scholar Among these compartments, a rather rapid exchangeable pool must exist, which is responsible for the rebound of serum phosphate after dialysis, which is both rapid and high, reaching a 40% increase within 60 minutes after its hemodialysis-induced nadir.25Agar B.U. Akonur A. Lo Y.C. Cheung A.K. Leypoldt J.K. Kinetic model of phosphorus mobilization during and after short and conventional hemodialysis.Clin J Am Soc Nephrol. 2011; 6: 2854-2860Crossref PubMed Scopus (0) Google Scholar This phosphate pool of unknown residence, which is responsible for the rebound, can probably be depleted by intensified hemodialysis therapy, especially by extended duration dialysis schedules.26Pierratos A. Ouwendyk M. Francoeur R. et al.Nocturnal hemodialysis: three-year experience.J Am Soc Nephrol. 1998; 9: 859-868PubMed Google Scholar, 27Cornelis T. van der Sande F.M. Eloot S. et al.Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study.Am J Kidney Dis. 2014; 64: 247-256Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Importantly, the magnitude of this phosphate pool is difficult to estimate, and therefore, no report has been able to demonstrate an association between serum phosphate concentration and the amount of phosphate in this or other phosphate reservoirs. The implication is that phosphate may accumulate in CKD, initially without causing hyperphosphatemia. Remarkable observations for instance from the Framingham offspring cohort, as described above, indicate that serum phosphate even within the normal range is associated with increased risk for cardiovascular events.9Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Crossref PubMed Scopus (515) Google Scholar, 11Dhingra R. Sullivan L.M. Fox C.S. et al.Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Arch Intern Med. 2007; 167: 879-885Crossref PubMed Scopus (479) Google Scholar This may be explained by the assumption that differences in the amount of stored phosphate in pools is much larger than suggested by corresponding serum concentrations. Based on these observations, authors have speculated about the potential of phosphate toxicity in the absence of overt hyperphosphatemia.24Osuka S. Razzaque M.S. Can features of phosphate toxicity appear in normophosphatemia?.J Bone Miner Metab. 2012; 30: 10-18Crossref PubMed Scopus (0) Google Scholar, 28Kuro O.M. A phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease (2011).Kidney Int Suppl. 2013; 3: 420-426Abstract Full Text Full Text PDF Scopus (30) Google Scholar It is possible that serum phosphate concentration is just an unreliable reflection of phosphate stores and that these stores are the true "phosphate culprit" causing cardiovascular disease (Figure 3, left side). This hypothesis is supported by the observation in the third National Health and Nutrition Examination Survey (NHANES) cohort that observed that fasted phosphate concentrations, which may better reflect phosphate stores, were associated with mortality, while the higher non-fasted values were not.29Chang A.R. Grams M.E. Serum phosphorus and mortality in the Third National Health and Nutrition Examination Survey (NHANES III): effect modification by fasting.Am J Kidney Dis. 2014; 64: 567-573Abstract Full Text Full Text PDF PubMed Google Scholar These valid, yet unproven, considerations form the evidence-base to consider clinical interventions in the absence of hyperphosphatemia, as discussed below.Figure 3Pathways of phosphate toxicity. Conceptual models of phosphate toxicity: as an example, the effects of phosphate on vascular smooth muscle cells are shown. As detailed in the text, exposure to phosphate, even with similar serum concentration, may induce pathology. The therapeutic intervention, indicated on top, would be to limit phosphate exposure (left-sided scenario). Currently, observational clinical studies are consistently demonstrating associations between overt hyperphosphatemia and dismal outcomes. The intervention, therefore, that follows, as suggested for instance by the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, is to treat hyperphosphatemia (center scenario). Phosphate toxicity is importantly modified by other factors, like α-klotho status, pH, calcium concentration, inflammation, and possibly others as well. Targeting phosphate toxicity would be to optimize these factors, besides controlling phosphate itself (right-sided scenario).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Phosphate toxicity at a given concentration may differ in severity under different microenvironmental conditions (Figure 3, right side). Changes in systemic and local pH, for instance, modify transmembrane phosphate transport. In acid–base physiology, it is well recognized that phosphate is a relevant buffer in the extracellular fluid. In this regard, it is noteworthy that trivalent phosphate (PO43− ) does not exist under physiological conditions, nor does the element phosphorus (P) itself. At a pH of 7.4 the predominant phosphate species are HPO42− and H2PO4−. Because the pKa at body temperature of this phosphate buffer is 6.8, approximately 80% of total phosphate consists of the bivalent version HPO42–. This is of relevance for phosphate transport across cellular membranes but is frequently neglected. Sodium-phosphate cotransporters (NaPi) are specific for either monovalent or divalent phosphate.30Virkki L.V. Biber J. Murer H. Forster I.C. Phosphate transporters: a tale of two solute carrier families.Am J Physiol Renal Physiol. 2007; 293 (F643–564)Crossref PubMed Scopus (144) Google Scholar Phosphate transport into vascular smooth muscle cells (VSMC) across the inorganic sodium phosphate co-transporter NaPi-III (SLC20 subfamily member Pit-1) is considered to be among the earliest triggers in the development of arterial wall calcification.31Li X. Yang H.Y. Giachelli C.M. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification.Circ Res. 2006; 98: 905-912Crossref PubMed Scopus (257) Google Scholar Interestingly, Pit-1 transports only monovalent phosphate (H2PO4−).30Virkki L.V. Biber J. Murer H. Forster I.C. Phosphate transporters: a tale of two solute carrier families.Am J Physiol Renal Physiol. 2007; 293 (F643–564)Crossref PubMed Scopus (144) Google Scholar At a given systemic serum concentration of phosphate, the local tissue pH dictates the availability of this phosphate species to enter VSMC, as the ratio of monovalent over bivalent phosphate changes with pH, meaning that more substrate for Pit-1 becomes available at lower pH. In advanced stages of CKD, acidosis is prevalent,32Kraut J.A. Madias N.E. Metabolic Acidosis of CKD: An Update.Am J Kidney Dis. 2016; 67: 307-317Abstract Full Text Full Text PDF PubMed Google Scholar, 33Kovesdy C.P. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?.Nephrology Transplant. 2012; 27: 3056-3062Crossref PubMed Scopus (0) Google Scholar and the lower pH may directly promote phosphate transport into VSMCs. However, because the systemic pH is generally maintained in the normal range, the local pH of the arterial vessel wall is likely to be more important than systemic acidemia. Hypermetabolism or inflammation in the vessel wall increases local CO2 production,34Bernelot Moens S.J. Verweij S.L. van der Valk F.M. et al.Arterial and Cellular Inflammation in Patients with CKD.J Am Soc Nephrol. 2016; PubMed Google Scholar comparable to the Bohr effect on hemoglobin. Moreover, VSMCs can regulate local pH at the micro-level and increase acidity in its proximity.35Hordijk P.L. Intracellular pH steers vascular wall remodelling.Cardiovasc Res. 2016; 111: 165-166Crossref PubMed Scopus (0) Google Scholar Besides pH, other conditions also influence local phosphate toxicity. In vitro studies have clearly shown that α-klotho inhibits phosphate entrance into VSMCs in a concentration- dependent manner.36Hu M.C. Shi M. Zhang J. et al.Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol. 2011; 22: 124-136Crossref PubMed Scopus (398) Google Scholar Therefore phosphate toxicity may be more pronounced in settings of α-klotho deficiency such as CKD. This was recently confirmed in a mouse CKD model with α-klotho deficiency, which demonstrated that restoring α-klotho by delivery through adeno-associated viral vector attenuated aortic calcification.37Hum J.M. O'Bryan L.M. Tatiparthi A.K. et al.Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho.J Am Soc Nephrol. 2017; 28: 1162-1174Crossref PubMed Google Scholar In support of this concept, upregulation of endogenous α-klotho by treatment with an activator of peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear factor that upregulates α-klotho, led to an inhibition of VSMC calcification in vitro.38Cheng L. Zhang L. Yang J. Hao L. Activation of peroxisome proliferator-activated receptor gamma inhibits vascular calcification by upregulating Klotho.Exp Ther Med. 2017; 13: 467-474Crossref PubMed Scopus (1) Google Scholar These studies indicated that phosphate-induced vascular pathology may differ depending on the α-klotho status. A final example of the relevance of the biochemical context in which phosphate may or may not exert toxic effects on the vasculature is the modifying role of calcium.39Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Higher concentration of systemic or local calcium (from VSMC apoptosis or matrix vesicles) may act synergistically with phosphate to induce and propagate vascular calcification.40Shanahan C.M. Crouthamel M.H. Kapustin A. Giachelli C.M. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate.Circ Res. 2011; 109: 697-711Crossref PubMed Scopus (296) Google Scholar Some proximal aspects of the process of vascular calcification are dependent on concentration of calcium even at high concentrations of phosphate.41Reynolds J.L. Joannides A.J. Skepper J.N. et al.Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.J Am Soc Nephrol. 2004; 15: 2857-2867Crossref PubMed Scopus (527) Google Scholar, 42Shroff R.C. McNair R. Skepper J.N. et al.Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification.J Am Soc Nephrol. 2010; 21: 103-112Crossref PubMed Scopus (149) Google Scholar Apart from phenotypic changes induced by entrance of phosphate into VSMSs, spontaneously formed calcium-phosphate crystals, if the concentration of the minerals exceed their saturation product, may induce part of the pathological effects on VSMCs as well.43Sage A.P. Lu J. Tintut Y. Demer L.L. Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro.Kidney Int. 2011; 79: 414-422Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Because inhibition of this crystal formation, and not lowering phosphate concentration per se, has protective properties against soft tissue calcification as shown in experimental studies,44Villa-Bellosta R. Sorribas V. Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition.Arterioscler Thromb Vasc Biol. 2009; 29: 761-766Crossref PubMed Scopus (59) Google Scholar it is conceivable that targeting calcification propensity (a novel circulating biomarker for calcification)45Smith E.R. Ford M.L. Tomlinson L.A. et al.Serum calcification propensity predicts all–cause mortality in predialysis CKD.J Am Soc Nephrol. 2014; 25: 339-348Crossref PubMed Scopus (0) Google Scholar or specific features of calciprotein particles,46Smith E.R. Ford M.L. Tomlinson L.A. Rajkumar C. McMahon L.P. Holt S.G. Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with predialysis CKD.Nephrology Transplant. 2012; 27: 1957-1966Crossref PubMed Google Scholar is a more effective approach than solely focusing on phosphate concentrations. None of the above-mentioned aspects of potential mechanisms of phosphate-related pathology and subsequent morbidity have been thoroughly studied in clinical trials. Despite decades of research dedicated to controlling phosphate overload in CKD, it is disappointing to conclude that an unequivocal proof of benefit of phosphate lowering strategies is still lacking. As outlined previously, the paradigm of exclusively targeting hyperphosphatemia may have to change to target phosphate-induced toxicity, an approach that encompasses more than just restricting phosphate exposure by diet or phosphate binders. With these considerations in mind, a balanced view of potential benefits and harms of current dietary and pharmacological interventions for phosphate exposure in CKD is presented as either a preventive measure or a treatment modality for established hyperphosphatemia. The first phosphate restriction studies were conducted in animals decades ago. Multiple animal models (rat, dog, and cat) demonstrated a dose-response relationship between diets with increasing phosphate content and renal toxicity, as reflected by renal tubular necrosis, nephrocalcinosis, inflammation, and albuminuria, or by the development of hyperparathyroidism.47Haut L.L. Alfrey A.C. Guggenheim S. Buddington B. Schrier N. Renal toxicity of phosphate in rats.Kidney Int. 1980; 17: 722-731Abstract Full Text PDF PubMed Google Scholar, 48Brown S.A. Crowell W.A. Barsanti J.A. White J.V. Finco D.R. Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass.J Am Soc Nephrol. 1991; 1: 1169-1179Crossref PubMed Google Scholar, 49Finco D.R. Brown S.A. Crowell W.A. Groves C.A. Duncan J.R. Barsanti J.A. Effects of phosphorus/calcium-restricted and phosphorus/calcium-replete 32% protein diets in dogs with chronic renal failure.Am J Vet Res. 1992; 53: 157-163PubMed Google Scholar, 50Ross L.A. Finco D.R. Crowell W.A. Effect of dietary phosphorus restriction on the kidneys of cats with reduced renal mass.Am J Vet Res. 1982; 43: 1023-1026PubMed Google Scholar, 51Slatopolsky E. Caglar S. Pennell J.P. et al.On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog.J Clin Invest. 1971; 50: 492-499Crossref PubMed Google Scholar In subtotally nephrectomized animal models, restriction of phosphate intake can prevent proteinuria, kidney calcification, proximal tubular injury, and premature death.52Finch J.L. Lee D.H. Liapis H. et al.Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification.Kidney Int. 2013; 84: 1145-1153Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 53Ibels L.S. Alfrey A.C. Haut L. Huffer W.E. Preservation of function in experimental renal disease by dietary restriction of phosphate.N Engl J Med. 1978; 298: 122-126Crossref PubMed Google Scholar, 54Lumlertgul D. Burke T.J. Gillum D.M. et al.Phosphate depletion arrests progression of chronic renal failure independent of protein intake.Kidney Int. 1986; 29: 658-666Abstract Full Text PDF PubMed Google Scholar, 55Bauer K.D. Griminger P. Long-term effects of activity and of calcium and phosphorus intake on bones and kidneys of female rats.J Nutr. 1983; 113: 2011-2021Crossref PubMed Google Scholar These studies demonstrated a direct relationship between phosphate load per nephron, kidney calcification, and proximal tubular injury. Human metabolic studies performed decades ago indicate that high intake of phosphate additives could lead to a positive phosphate balance.56Farquharson R.F. Tibbetts D.M. Studies of calcium and phosphorus metabolism: XVIII. On temporary fluctuations in the level of calcium and inorganic phosphorus in blood serum of normal individuals.J Clin Invest. 1931; 10: 271-286Crossref PubMed Google Scholar, 57Spencer H. Menczel J. Lewin I. Samachson J. Effect of high phosphorus intake on calcium and phosphorus metabolism in man.J Nutr. 1965; 86: 125-132Crossref PubMed Scopus (32) Google Scholar It is, however, still unclear what the clinical implication of this positive balance will be, and if ultimately a novel steady state will be reached, for instance, through an increase of FGF23 and PTH synthesis, both of which promote phosphaturia.58Gutierrez O.M. Luzuriaga-McPherson A. L