Revamping the 'Renal' Diet

Using Foods To Control Phosphorus Physiology

Julia J. Scialla; Pao-Hwa Lin

Disclosures

Nephrol Dial Transplant. 2019;34(10):1619-1622. 

As the primary arbiter maintaining homeostasis of salts, minerals and volume in the internal milieu, the kidneys must continuously respond to changing dietary 'inputs'. As a result, kidney physiologists have long been interested in the role of diet in kidney disease development, progression and complications.[1] Primarily, interest has focused on specific micronutrients, such as sodium, potassium and phosphorus, which are directly excreted by the kidney in a regulated manner and selected macronutrients, such as protein, whose metabolites are excreted by the kidney and affect renal hemodynamics.[2] The prototypical 'renal' diet provides targets for these nutrients, restricting the intake of sodium, potassium, phosphorus and sometimes protein. However, current recommendations are based on theoretical grounds and expert consensus with limited clinical trial evidence.[2,3] Furthermore, in contrast to dietary pattern recommendations for the general population, current chronic kidney disease (CKD) recommendations do not provide adequate guidance on feasible whole-food approaches to achieve these targets (Table 1).[2,3] Qualitative studies demonstrate that patients with CKD often find the current, nutrient-based dietary guidance confusing and difficult to reconcile with other healthful diet messages targeted to the general population or recommended for other diseases, such as diabetes.[8] Despite these limitations, nutrition and prevention are consistently prioritized by patients with CKD for further research,[9] and epidemiologic data suggest a large role of dietary and metabolic risk factors in the growing burden of CKD morbidity.[10] More robust evidence is needed on dietary approaches for CKD prevention and management, to address substantial gaps in knowledge that are of high interest to patients and the public health.[11,12]

In this issue of Nephrology Dialysis Transplantation, Salomo et al.[13] directly evaluate the 'renal' diet, focusing on the impact of a culturally tailored healthful eating pattern on phosphorus homeostasis in CKD. To develop a healthful dietary pattern adapted for CKD, the authors begin with the New Nordic Diet, a dietary pattern developed in Denmark with elements similar to the Mediterranean diet, but with substitutions that reflect commonly available and regional foods.[7] The New Nordic Diet is rich in fruits and vegetables, fresh herbs, potatoes, whole grains, nuts and fish. A prior study of the New Nordic Diet by the same authors demonstrated generally higher phosphorus content than the typical diet comparator.[14] Thus, to adapt this diet for the CKD context, the authors reduced the New Nordic Diet in phosphorus content, focusing on the reduction in rye bread, fish, nuts and dairy to create the New Nordic Renal Diet (NNRD). With these changes, the NNRD was also somewhat reduced in dietary protein and, specifically, animal protein. Other adaptations to intentionally alter sodium, potassium or other nutrients were not reported, but potassium content was lower in the NNRD than the corresponding control diet. More details on the foods contained in the NNRD, such as menus used in the feeding protocol or servings by food groups, were provided in greater detail in prior publications.[7,14]

In brief, the authors recruited 18 adult participants with stage G3b or G4 CKD from diverse etiologies into this randomized cross-over trial testing the impact of the NNRD on phosphorus homeostasis. All participants consumed the NNRD for 1 week, exclusively consuming foods prepared by the study team that were provided for at-home consumption with two distribution times during the feeding period (Days 1 and 4). During a second period, participants consumed their habitual diet, noting intake in a written dietary log on selected days. The two dietary periods were separated by a 7-to 21-day washout and order was randomized. Phosphorus binders were not allowed during the study. To measure the markers of phosphorus homeostasis in blood and urine precisely, participants were admitted to an inpatient clinical research unit on Day 7 of each period. During the habitual diet period, a control diet was fed in this final day. The control diet was higher in phosphorus, protein, calcium and potassium than the NNRD diet.

The study evaluated the effects of the NNRD compared with habitual diet on 24-h urine phosphorus (primary outcome), fractional excretion of phosphorus in the urine (FEPi), serum phosphorus and intact fibroblast growth factor 23 (FGF23), the predominant regulatory hormone controlling the FEPi. The study was registered at www.clinicaltrials.org as NCT03472105, but was dated after completion of recruitment; therefore, the pre-specification of primary endpoints could not be confirmed. Primary results demonstrated that 24-h urine phosphorus was reduced by nearly 40% on the NNRD when compared with minimal change during habitual diet. This was accompanied by expected reductions in FEPi and stabilization or modest improvement in FGF23 of ~18%. Serum phosphorus was reduced by 0.13 mmol/L on NNRD versus 0.02 mmol/L during habitual diet, but the change was not statistically significant.

The biomarker changes on the NNRD clearly reflect differences in phosphorus loading and may have important implications for patients with CKD. Higher serum phosphorus is consistently associated with vascular calcification and stiffness, higher mortality and cardiovascular disease in observational studies.[15] Higher FGF23 is an even more potent risk factor for mortality and cardiovascular disease,[16] with risk 70–90% higher for FGF23 levels in the top versus lowest tertile in people with CKD.[17] Basic experimentation suggests that these risks may be due to the effects of phosphorus and FGF23 on arterial compliance, endothelial function and left ventricular remodeling.[15,18] Additionally, changes in phosphorus homeostasis likely drive the development of secondary hyperparathyroidism in CKD with downstream consequences for bone.[19] Confirmation that interventions can realize these potential benefits on cardiovascular, parathyroid and skeletal disease outcomes in patients with CKD is needed, but efficacy trials that demonstrate consistent and meaningful improvement of interventions on these intermediate-risk parameters should be conducted first to justify larger studies.

Multiple prior studies have evaluated the role of diet as a plausible intervention for abnormal phosphorus homeostasis. Many have focused on extreme dietary contrasts that may inform physiologic understanding, but do not necessarily reflect what might be expected from realistic dietary changes.[20–27] For instance, prior studies have often used phosphorus-based salts to augment exposure to highly absorbable phosphorus. Other studies have used gastrointestinal phosphorus binding agents to reduce 'dietary' phosphorus exposure. This study of the NNRD is among the first to exclusively use a realistic, unsupplemented, whole-foods dietary pattern to control phosphorus homeostasis in CKD. The authors found favorable effects on the phosphorus axis, which is encouraging for the potential of dietary interventions in CKD. Most profoundly, 24-h urine phosphorus was reduced dramatically. This effect is consistent with the lower overall phosphorus content of the diet and perhaps a shift toward less absorbable phosphorus sources, such as a reduction in phosphorus-based food additives and increase in plant-based sources.[28,29] The dramatic decrease in 24-h urine phosphorus suggests that the dietary intervention achieved its goal of reducing phosphorus absorption; however, in contrast to higher serum phosphorus and FGF23, lower 24-h urine phosphorus is not associated with improved clinical outcomes.[30,31] The reduction in FGF23 with the NNRD was statistically significant, but relatively modest. FGF23 rises exponentially as kidney function falls in CKD.[32,33] Within the range seen in advanced CKD, the accompanying risk also operates on this type of exponential scale, typically reported as risk 'per doubling' or related to logarithmically transformed FGF23.[16] What this means practically is that more dramatic, proportional reductions of FGF23 may be needed to convey important clinical benefits implied by observational studies (Figure 1).

Figure 1.

Schematic depiction of risk factor operating on an arithmetic versus geometric scale. The graphic depicts a theoretical risk factor associated with an adverse outcome as quantified by the relative hazard (RH). If this theoretical risk factor is modeled on the original, or arithmetic, scale with a RH of 1.2 per +20 unit (U) change, then its relationship with the outcome is demonstrated on the black solid line. For a risk factor modeled on a log-transformed, or geometric, scale with a RH of 1.2 per ×2 U change, its relationship with the outcome is demonstrated on the dotted red line. Note that for an intervention that changes the risk factor from 40 to 20, the change in RH is equivalent with the two models; however, for an intervention that changes the risk factor from 140 to 100 (A to B on the black line or C to D on the red-dotted line), the change in RH is much less for the risk factor operating on a logarithmic scale. In patients with CKD, risk associated with FGF23 is typically modeled with FGF23 on a logarithmic scale. Thus, we predict that changes in FGF23 among those with elevated levels must be pronounced to deliver meaningful clinical benefits.

FGF23 is primarily produced in bone, and we do not yet know how bone senses phosphorus exposure and responds, or the exact timescales in which this happens.[34] Several controlled feeding studies suggest that the FGF23 response is generally slow, occurring later than responses of other hormones, such as parathyroid hormone.[24,25,35] We also do not know when the nadir response will be reached. It is possible that the relatively modest short-term changes in FGF23 seen here could translate to much larger long-term reductions or at least stabilization of FGF23 on a phosphorus-reduced diet such as the NNRD. Earlier use of NNRD in CKD could also have a larger impact if the rise in FGF23 typical of CKD can be prevented. In these cases, phosphorus-reduced diets such as the NNRD hold substantial promise as interventions. Longer term studies are needed to test for clinically meaningful effects on FGF23, FGF23 trajectories in CKD and on clinical outcomes.

The design of the study has several limitations that need to be considered in interpreting the results. The investigators used a composite of a controlled and free-living diet design. During the NNRD period, all foods were provided for take-out. In contrast, during the habitual period, diet was uncontrolled except for the final day. Controlled feeding provides the best evidence base for efficacy studies, particularly on short-term outcomes, but provides less evidence on real-world effectiveness or feasibility. Although most participants reported the diet palatability as 'very good', it is unknown if this level of acceptance would be maintained or translated to long-term dietary change outside of a controlled setting. On the other hand, although the NNRD period was controlled, the 'effect' of a controlled feeding study is always a relative or comparative effect. In this study, the lack of controlled feeding during the habitual period makes it difficult to precisely determine the comparator. The final day of the habitual diet period included a diet that was higher in phosphorus, protein and calcium than the NNRD, but these differences may not have been reflected in the ad libitum portion of the habitual diet period. For instance, if individuals naturally consumed lower phosphorus foods, that might reduce the difference between NNRD and the habitual period and underestimate the potential effect on FGF23, which takes days to fully manifest. Based on weighted dietary food records on Days 1 and 4 of the habitual period, the content of phosphorus, protein and calcium was similar to the final day of controlled feeding, but the standard deviation was wide. Finally, dietary interventions are by definition complex. They involve intended nutrition changes, such as lower phosphorus intake, but also correlated changes in other nutrients (e.g. calcium) and often effects that may not be known or understood. One critical example in controlled feeding is separating effects of weight change from effects of the diet itself. The NNRD diet was designed to be isocaloric, but how changes in weight were mitigated or monitored was not reported.

Despite these limitations, dietary studies focused on patterns that are culturally tailored and acceptable to patients are critically needed for CKD. Ultimately long-term studies will be needed to prove diet effects, but these will require substantial investments. Diet is both a health-promoting or -mitigating behavior and a source of cultural expression, social engagement, pleasure and identity. Diet is often shared among families and friends, even passing robustly through social networks. For these reasons, changing diet is not a simple calculus and needs to involve cultural tailoring, engagement of families and social networks, and consideration of preferences. Short-term studies with an eye toward efficacy, cultural tailoring and long-term acceptability are critical to optimally design, implement and succeed in dietary interventions. This study takes a critical step in this direction. Continuing to develop diet advice will require broadening from our nephron-centric focus and singular nutrient approach to palatable dietary pattern approaches. Finally, patients with CKD have substantial comorbidity including diabetes mellitus, hypertension, heart disease and obesity, each of which often imposes additional dietary restrictions and guidance. New dietary guidelines broadening our focus to simultaneously address both kidney and overall health and expanding toward whole-food approaches are urgently needed. More research on dietary patterns and health in CKD will facilitate this transformation.

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