Dietary Phosphorus and FGF23

Patients with ESKD undergoing hemodialysis are at high risk for cardiovascular events, which have been associated with abnormal phosphate homeostasis. Hyperphosphatemia and elevated serum fibroblast growth factor 23 (FGF23) cause vascular calcifications and left ventricular hypertrophy, respectively, and are associated with increased all-cause and cardiovascular mortality (1). Dietary phosphorus restriction is recommended as a mainstay in clinical management of bone and mineral disease in patients with ESKD who are on dialysis (2,3). However, there are few controlled feeding intervention studies to empirically support the effectiveness of dietary phosphorus restriction on bone and mineral outcomes, or to inform what specific intake levels or features of these diets might be most beneficial.

In this issue of CJASN, Tsai et al. (4) report on the effects of a very-low-phosphorus diet (8 mg/g phosphorus-to-protein ratio) compared with a low-phosphorus diet (10 mg/g phosphorus-to-protein ratio) on serum intact fibroblast growth factor 23 (iFGF23) in n=35 Taiwanese adults with ESKD undergoing thrice-weekly hemodialysis. This was a randomized, active-control, crossover study in which patients consumed each diet regimen in random order for 2 days, with the two diets separated by a 5-day washout. The primary outcome was the difference in change from baseline in iFGF23 between the two diets, and secondary outcomes were differences in change from baseline in serum phosphate, intact parathyroid hormone, and C-terminal FGF23. The investigators found no benefit in restricting dietary phosphorus-to-protein ratio to 8 mg/g compared with 10 mg/g on the primary outcome of iFGF23. However, there was a significantly greater reduction from baseline in serum phosphate in the 8 mg/g diet compared with the 10 mg/g diet. The authors suggest that this greater reduction of serum phosphate with the 8 mg/g diet might support the recommendation for use of this more restrictive phosphorus intake in patients with hyperphosphatemia who are receiving hemodialysis. However, as also noted by the authors, longer-term data are needed to support this conclusion. At the heart of this study is the question of how restrictive dietary phosphorus recommendations should be for patients on hemodialysis, both to manage hyperphosphatemia and disordered phosphate metabolism, and with mindfulness toward maintaining protein intake and overall nutritional status.

Despite the null finding for the primary outcome between the two dietary interventions, this study is evidence of the strong potential effect of dietary interventions to manage disordered mineral metabolism. However, this study was designed as an active comparator study, and not to evaluate effects on phosphate metabolism within each diet. With this design limitation in mind for the following interpretation, both diets (8 and 10 mg/g) appeared to lower iFGF23 and serum phosphate from baseline in a very short time frame. Mean serum iFGF23 was approximately 1000 pg/ml lower (a decrease of 18%–19%) in each diet group after only 2 days. This is especially remarkable given the already low habitual dietary phosphorus intake of the patients assessed by 3-day food records before the interventions. Baseline dietary phosphorus intake in these patients was approximately 700 mg/d (approximately 12–13 mg/g phosphorus-to-protein ratio), which already meets the Kidney Disease Outcomes Quality Initiative (KDOQI) dietary phosphorus intake recommendations (2). In contrast, typical phosphorus intakes in the general population of the United States are estimated at around twice this amount (5). The study diets, by design, further lowered phosphorus intake to 557 and 663 mg/d in the 8 mg/g diet and 10 mg/g diet, respectively. This is only a decrease of 172 mg/d from the average estimated baseline phosphorus level in the 8 mg/g diet, and only 41 mg/d lower from the average estimated baseline of the 10 mg/g diet. It is surprising that these small decreases in daily phosphorus intake elicited the apparent effects on phosphate metabolism that they did. One may argue that the baseline diets may have been underestimated by inaccuracies of food composition tables, as has been shown numerous times in the literature (6). However, Tsai et al. (7) showed in another recent publication that food composition table estimates of phosphorus content of natural foods, free from phosphate additives, may not be marred by the same underestimation as foods with additives. In fact, their estimates of phosphorus content from food composition tables closely matched the chemically analyzed values (7). Thus, there is no strong reason to suspect the baseline values for phosphorus intake were underestimated drastically in this study.

The KDOQI guidelines recommend a dietary phosphorus intake of 800–1000 mg/d, but acknowledge that adequate protein intake must be ensured for patients undergoing dialysis. The guidelines further state that, “for individuals >80 kg, it is impossible to plan a palatable diet with adequate protein while limiting the phosphate intake to <1000 mg/d,” and therefore recommends using 10–12 mg/g protein to estimate a “reasonable” phosphorus intake level (2). But, when it comes to the effects of dietary phosphorus on phosphorus homeostasis, and particularly iFGF23, is it the phosphorus-to-protein ratio or the absolute milligram phosphorus intake that matters? Will a ratio of 10–12 mg/g or even 8 mg/g be effective in lowering iFGF23 if the absolute intake of phosphorus milligram per day is high? Or does absolute intake need to be below a certain lower threshold, perhaps 700 mg/d or lower, to see effects? In their study population, Tsai et al. (4) were able to achieve protein recommendations of 1.2 g/kg per day with approximately 1600 kcal/d, approximately 66 g/d protein, and only approximately 600 mg/d phosphorus in both the 10 and 8 mg/g ratio diets by using natural foods free of phosphate additives and boiling meats to reduce phosphorus content. However, the average body weight of the patients in this study was 55 kg (approximately 120 lbs) and was limited to the range of 42.5–67.5 kg per the inclusion criteria. If one considers a patient who weighs 80 kg, they would require 96 g of protein at 1.2 g/kg per day, which would bring the 10 mg/g diet to 960 mg/d and the 8 mg/g diet to 768 mg/d phosphorus. These are, of course, still in the KDOQI recommended range of 800–1000 mg/d phosphorus (2) and would likely be an improvement over a typical Western diet, but whether these restrictions would result in any benefit to iFGF23 is not clear. Results from a crossover study of 1-week diet interventions (8) comparing the effects of vegetarian and meat protein sources on phosphorus homeostasis in CKD suggest that iFGF23 can be modestly improved when dietary phosphorus intake is restricted to approximately 800 mg/d (approximately 10 mg/g) in patients with CKD presumably consuming a typical United States diet high in phosphorus before the study. However, source mattered, as this was only true with the vegetarian diet. The meat-based diet—also restricted to 800 mg/d phosphorus—actually increased iFGF23 from baseline in these same patients. Further, these were patients with CKD who were predialysis, with average baseline plasma iFGF23 levels of approximately 70–85 pg/ml, and the improvement with the vegetarian diet only brought the average iFGF23 to approximately 60 pg/ml. It remains unknown whether significant reductions in iFGF23 could be achieved by restricting dietary phosphorus modestly to 800–1000 mg/d in patients on hemodialysis who habitually consume a high-phosphorus diet (such as approximately 1500 mg/d, typical in the United States).

Among the major strengths of the Tsai et al. (4) study are the randomized, crossover design using patients as their own control and stratification on the basis of dialysis shift and intact parathyroid hormone levels before randomization, as well as the quality of the dietary intervention methods. This included rigorous diet design, chemical analysis of the diets for accurate nutrient content, detailed preparation of diets, and actions to promote and assess study diet adherence, as well as assessment of baseline habitual dietary intakes of the subjects using 3-day dietary records. As the authors discuss, limitations of the study include the short duration of only 2-day diet interventions and that the two study diets were not as different as planned for phosphorus-to-protein ratio (approximately 1.5 mg/g difference instead of 2 mg/g difference) because of lower adherence to the very-low-phosphorus diet (61%) compared with the low-phosphorus diet (71%). This equaled only approximately 106 mg/d difference in absolute phosphorus intake between the two study diets. The short study duration and lower adherence with the more restrictive diet of 8 mg/g warrant some caution in overinterpreting the additional benefit of the 8 mg/g diet to decreased serum phosphate. It is likely that adherence to the dietary prescription would be even lower over time and in free-living patients. Thus, further data are needed to determine if the additional benefit to serum phosphate would persist long term and in a clinical practice setting.

So, is more phosphorus restriction better? In the context of the Tsai et al. (4) study, it may well be; but perhaps, although feasible, these conditions may be aspirational in clinical settings long term, i.e., by providing nutritious meals to patients on dialysis (9), achieving adequate protein intake by minimizing the phosphorus-to-protein ratio using natural food sources free of phosphate additives, and implementing a boiling protocol to reduce phosphorus content of meats (7). Likely, long-term nutrition counseling and support from a registered dietitian would also be needed (10). In addition, as noted above, the challenge of achieving very-low-phosphorus intakes while providing adequate protein was also eased in this study because of the lower absolute protein needs as a result of the relatively low body weights in this patient population. In patient populations and settings where average habitual dietary phosphorus intake is much greater, phosphate food additive use is rampant, and provision of nutritious meals during dialysis is rare, it is unclear if such restrictions would elicit a beneficial response on FGF23 and phosphate homeostasis, particularly if implemented as a 8–10 mg/g phosphorus-to-protein ratio when larger average body size could result in phosphorus intakes >1000 mg/d to achieve adequate protein intake of 1.2 g/kg per day. This study by Tsai et al. (4) is a valuable contribution to the nutrition literature in CKD-Mineral Bone Disorder, and further such diet intervention studies of high methodological quality are needed to determine both longer-term effects as well as generalizability to other patient populations on hemodialysis across the world.

Disclosures

Dr. Hill Gallant reports a grant from Chugai Pharmaceuticals Co., Ltd. and personal fees from Sanofi-US and Tricida, Inc., outside the submitted work.

Funding

Dr. Hill Gallant is supported by a grant from National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (K01DK102864).