title: Derangements in phosphate metabolism in chronic kidney diseases/endstage renal disease: therapeutic considerations.
abstract: The changes in phosphate (PO(4)) metabolism across the spectrum of chronic kidney disease (CKD) and specific strategies to address these abnormalities by reducing PO(4) loads are discussed in this review. This review also addresses briefly the evidence for specific PO(4) serum targets in CKD and endstage renal disease (ESRD) and the potential for other biomarkers such as fibroblast growth factor-23 (FGF-23) to define disease and monitor the effectiveness of therapy. As renal function declines, single nephron excretion of PO(4) must increase to maintain PO(4) balance. Abnormalities in PO(4) metabolism occur early in CKD. Compensatory changes in renal PO(4) handling are sufficient to maintain a normal serum PO(4) level in early stages of CKD, but in more advanced CKD, these processes no longer suffice and overt hyperphosphatemia develops. The resulting increased PO(4) burden contributes directly to development of secondary hyperparathyroidism. The FGF-23 increases early in CKD, likely in response to abnormal PO(4) metabolism, and mediates processes that help restore serum PO(4) levels to normal in CKD stage 3 and in early stage 4. The increased PO(4) burden and subsequent overt hyperphosphatemia are associated with increased mortality and morbidity. Dietary PO(4) restriction, modification of dialysis prescriptions, and administration of oral PO(4) binders can restore PO(4) balance. As CKD progresses, population-based studies demonstrate that diet alone is typically not able to prevent or treat hyperphosphatemia. Dialysis modalities that are currently used often fail to remove sufficient PO(4) to prevent hyperphosphatemia in patients with an inadequately controlled dietary PO(4) load. This is particularly likely among patients without significant residual renal function. Thus, in the majority of ESRD patients, PO(4) binders remain the mainstay of therapy for hyperphosphatemia. All currently available PO(4) binders can restore serum PO(4) to the required level when administered appropriately and in conjunction with dietary PO(4) restrictions. PO(4) binders differ regarding their potential side-effects and impact on long-term patient-centered outcomes. Which of the PO(4) binders might result in the most favorable survival and cardiovascular morbidity profiles and which remain uncertain, remains a subject of considerable clinical investigation. Compelling observational and more limited randomized controlled trial (RCT) evidence support the view that PO(4) binders might differ in their effects on mortality and/or morbidity. The limited evidence from RCTs is mostly congruent with the findings from large observational studies. In particular, evidences from both epidemiologic and RCT support the view that excess calcium administration may independently increase the risk of cardiovascular disease in individuals with normal renal function and in patients with CKD and ESRD. Additional RCT evidence might help determine the degree at which any increased risk from oral calcium exposure can be mitigated with the use of noncalcium-based PO(4) binders. Judicious control of PO(4) early in CKD, possibly monitored by measures of FGF-23, could potentially reduce the risk of development of renal secondary hyperparathyroidism and all of the adverse clinical consequences of poorly controlled CKD-mineral and bone disorder. The mainstays of therapy are likely to include a balance of dietary restriction and PO(4) binders to reduce PO(4) input, and in ESRD patients, dialysis modalities to augment PO(4) output.
authors.affiliation: Division of Renal Diseases and Hypertension, Center for Clinical Research and Evidence-Based Medicine, University of Texas Houston, Medical School, USA. donald.a.molony@uth.tmc.edu
authors.forename: Donald A
authors.initials: DA
authors.lastname: Molony
authors.forename: Brett W
authors.initials: BW
authors.lastname: Stephens
mesh_terms: D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000628:therapy; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000378:metabolism / Q000628:therapy; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D054559:Hyperphosphatemia / Q000628:therapy; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy; D028044:Phosphate-Binding Proteins / Q000627:therapeutic use; D010710:Phosphates / Q000378:metabolism*; D016226:Phosphorus, Dietary / Q000378:metabolism; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000628:therapy*; D013577:Syndrome
chemical_list: C000717427:FGF23 protein, human; D028044:Phosphate-Binding Proteins; D010710:Phosphates; D016226:Phosphorus, Dietary; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23