Phosphate Management in Patients with End-Stage Kidney Disease

Introduction

Achieving adequate control of serum phosphate (P) is one of the most difficult challenges facing clinicians caring for patients with end-stage kidney disease. Despite the global acceptance of the consequences of elevated P and despite a large number of therapeutic options targeting this mineral disorder, almost no discernible progress has been made toward routinely achieving the international recommendation of a P level of < 4.6 mg/dL. More than 80% of patients on dialysis receive phosphate binders, leading to a tremendous pill burden estimated at nearly 11 pills per patient per day, and yet, the proportion of patients achieving a serum P < 5.5 mg/dL has decreased over the last decade, and nearly 80% of patients do not maintain a serum P < 5.5 mg/dL over a 6-month period. Elevations of P are a key component of what is now commonly referred to as CKD-MBD (chronic kidney disease–mineral and bone disorder), a systemic disorder affecting the skeleton and vasculature and is consistently associated with an increased risk of all-cause mortality, cardiovascular (CV) mortality, and vascular calcification. A recent analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) demonstrated that globally, fewer than 17% of patients achieve a P < 4.6 mg/dL over a 6-month period. In this analysis, a time-averaged P of between 5.5 and 6.5 mg/dL was associated with a 40% increase in CV mortality, and a time-averaged P ≥ 6.5 mg/dL was associated with a doubling of CV mortality. Effective P control requires thoughtful attention to all aspects of phosphate homeostasis, including diet, dialysis prescription, control of secondary hyperparathyroidism (sHPT), and individualized prescription of medication to reduce intestinal phosphate absorption.

Phosphate Physiology

Phosphorus is the second most abundant element in the human body after calcium. Approximately 85% of phosphorus is located in bones and teeth, 14% is intracellular, and only 1% is extracellular. In normal adults, the fasting plasma phosphate concentration ranges from 2.5 to 4.5 mg/dL (0.80–1.45 mmol/L); however, the majority of healthy individuals have serum phosphate < 4.0 mg/dL. This represents the net balance of daily dietary intake, intestinal absorption, skeletal influx/efflux, cellular redistribution, and urinary phosphate excretion. There is substantial diurnal variation in serum P even in patients on dialysis, with > 1 mg/dL differences between nadir (8 a.m.–12 noon) and peak (3–5 a.m.). The recommended dietary allowance of phosphorus is 700 mg/day, whereas the average dietary intake according to nutritional database information ranges from 1000 to 1800 mg (18–36 mmol) per day. These estimates, however, substantially underestimate actual phosphorus intake by 35%–100% because they reflect only natural sources of phosphate and do not account for the routine use of phosphate additives in food processing. Substantial quantities of phosphate in the form of additives are found in commonly prescribed medications and common beverages. Foods high in phosphate are typically those also high in protein and include dairy products, meats, eggs, and cereal; however, the bioavailability of meat-based phosphate far exceeds that of plant-based phosphate because of the lack of naturally occurring phytase in the human gastrointestinal (GI) tract. Phosphate contained in food additives is essentially 100% absorbed, a fact that underlies the recommendation to encourage fresh and homemade foods for patients with CKD. Given the importance of maintaining adequate total protein intake (1.2 g/kg/day) in patients on dialysis, we concur with recommendations to go beyond the superficial assessment of total P content to evaluate both the bioavailability and P density (mg P/gram protein)—foods previously recommended to “avoid,” such as nuts and legumes, have far less bioavailability and may be a part of an appropriate plant-based diet. Intestinal absorption of phosphate is greatest in the jejunum and ileum and occurs passively via a paracellular route and actively via a phosphate sodium-dependent cotransporter (NaPi-2b). Basal phosphate absorption is a linear, nonsaturable function of oral intake that is normally approximately 70% of ingested. Despite a reduction in circulating levels of 1,25(OH)-D3, intestinal P absorption is not reduced in CKD, suggesting that passive, paracellular P transport is the primary route of phosphate absorption. Phosphate-lowering therapy generally affects only the passive, nonregulated component of phosphate absorption, a finding likely underlying the unusual observation that all current phosphate-lowering therapies have similar clinical efficacy. Renal handling of phosphate occurs primarily by the regulation of proximal tubule expression of type II-a and type II-c sodium phosphate cotransporter (NaPi-2a/c). The daily filtered load of phosphate is approximately 4–8 g, and under normal conditions, only 5%– 20% of the filtered phosphate is excreted. Parathyroid hormone (PTH), 1,25(OH)D3, and fibroblast growth factor 23 (FGF-23) are key regulators of NaPi-2a/c expression and, thus, phosphate reabsorption in the renal proximal tubule. FGF-23 levels are extraordinarily elevated in patients receiving dialysis (10-1000X ULN), and FGF-23 has emerged as one of several plausible causative links between CKD-MBD and CV disease. Elevated serum FGF-23 levels consistently associate with adverse CV outcomes, particularly those related to incident congestive heart failure, sudden death, and more recently recognized infectious events. These adverse effects are complementary yet distinct from those seen with elevations in serum phosphate, which is universally recognized to accelerate the development of vascular calcification and subsequent arterial stiffening. It is of clinical relevance that dietary P load, serum calcium, calcium load, active vitamin D administration, and iron deficiency all stimulate production of FGF-23.

Phosphate-Lowering Therapy

There is a consistent body of literature to support the biologic plausibility of attempting to reduce serum P. Elevated phosphate levels are consistently associated with a variety of adverse outcomes in multivariable-adjusted analyses in patients with CKD-G5D, including all-cause mortality, CV mortality, and CV hospitalization. In the prospective observational COSMOS study of hemodialysis (HD) patients, optimal patient survival was observed at a P of 4.4 mg/dL. Recently, a novel approach to evaluating serum P control over time demonstrated that the time spent and the extent of elevation above a serum P ≥ 4.5 mg/dL were strongly associated with CV mortality. There are three methods to reduce phosphate exposure: dietary phosphate restriction, use of phosphate-lowering medication, and dialytic removal of P.

Dietary Phosphate Restriction

Dietary P restriction has traditionally been a mainstay of therapy; however, clinical trial data to support its efficacy in reducing serum P are limited. Intensive dietary counseling has been shown to reduce serum P over 6 months; however, a Cochrane analysis found limited overall support for the effect of dietary intervention on patient-level outcomes. Moe et al. have reported that despite equivalent total phosphorus content, significantly lower P exposure over 24 hours is observed with plant-based versus meat-based diets in patients with CKD. Current dietary recommendations emphasize the importance of the source of P (animal, plant, natural, or processed) rather than the total P content and in educating patients how to read food labels to identify phosphate additives. While not germane to its efficacy in patients requiring dialysis, the utility of dietary intervention is further confounded by recent data establishing that the historical “gold standard” of P intake and absorption, 24-hour urinary P, fails to reflect P absorption in patients with CKD and is rather a reflection of P retention. An interesting new line of research points to the potential role of gut dysbiosis in CKD as a potential modifier of MBD.

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