Observational studies support that “unhealthy” compared with “healthy” diets are associated with increased risk for a variety of chronic diseases,1 including CKD.2,3 Consequently, investigators continue to try to identify dietary factors which promote CKD and/or exacerbate its progression, as well as identify ones which protect kidney health and avoid or reduce CKD-related morbidity and mortality. Success in these endeavors is anticipated to add to the armamentarium of strategies to slow or stop nephropathy progression, with the ultimate goal of preventing CKD and its devastating consequences altogether. Dietary protein has emerged as a target with therapeutic promise; restriction of total dietary protein in some small-scale studies suggests that it slows nephropathy progression.4 Despite this potential benefit, total protein restriction leads to protein-energy wasting in some CKD patients.5 Furthermore, the largest study to examine the effect of total dietary protein restriction on nephropathy progression, the Modification of Diet in Renal Disease Study, showed that GFR decline at three years was no different between subjects given a low protein diet (0.58 g/kg per day) and a usual protein diet (1.3 g/kg per day).6 These data have led investigators to examine if the type or source of ingested protein might instead mediate a dietary effect on kidney health.
Recent attention has focused on possible differences between plant-sourced and animal-sourced protein on kidney health, particularly in light of observational studies showing that adherence to diets high in plant-sourced protein was associated with higher eGFR2 whereas diets with higher animal-sourced protein were associated with higher risk for reduced GFR.3 Interventional studies support that the addition of plant-sourced protein reduced kidney injury7 and withdrawal of animal-sourced protein was also associated with reduced kidney injury.8 Animal-sourced protein from red meat has received particular attention as being possibly kidney toxic.8
The mechanisms by which animal-sourced protein might be more kidney toxic than plant-sourced protein are incompletely understood. One potential mechanism is the effect of dietary components on intrinsic acid production; observational studies show that high dietary acid is associated with increased ESRD risk in adults with CKD.9 Ingested animal-sourced protein yields acid when metabolized, whereas most plant-sourced protein yields base.10 High dietary acid induced by animal-sourced protein has been associated with subsequent development of hypertension, a CKD risk factor, in children.11 Furthermore, high intake of animal-sourced protein is also associated with an increased risk of type 2 diabetes,12 another CKD risk factor. On the other hand, substituting plant-based for animal-based dietary protein promotes gut flora which produce metabolites considered less kidney toxic than flora promoted by animal-sourced protein.13 These data support further exploration of the potential long-term kidney-toxic effects of animal-sourced dietary protein.
In this issue, Lew et al.14 report their prospective investigation of the effects of protein intake in its various food sources on ESRD risk in 63,257 adults aged 45–74 years in the Singapore Chinese Health Study. Subjects were recruited over 5 years and followed for a mean of 15.5 years. Habitual diet data were collected using a validated semiquantitative food questionnaire. They report that total (animal-sourced + plant-sourced) protein intake was directly associated with ESRD risk (adjusted hazard ratio, 1.24) but this relationship was not dose-dependent across quartiles (P=0.16). By contrast, they report a strong (P<0.001) dose-dependent relationship between red meat intake and increased ESRD risk (adjusted hazard ratio, 1.40) across quartiles. They report no relationship between increased ESRD risk with other animal sources of protein, such as poultry, fish, eggs, or dairy products. Although they report an inverse relationship between consumption of soy food and legumes (i.e., plant-sourced protein) and ESRD risk, the overall adjusted model for this relationship was not significant (P=0.07). Their analysis shows that substituting other food sources for red meat was associated with reduced ESRD risk.
Characteristics which make this observational study an important one include its large (63,257), rather ethnically homogenous and general (as opposed to high-risk) population of adults followed with apparently good data capture. Study subjects were followed for a length of time (mean 15.5 years) which allowed the low ESRD incidence (approximately 1.5% over the time of study) to manifest with a respectable number of patients (951). The population examined and the number of patients with ESRD were both large enough to allow adequate analysis of the effects of dietary components on subjects with and without CKD risk factors at baseline. In addition, dietary intake was assessed using a validated food frequency questionnaire that was developed specifically for this population and which was shown to be internally consistent and reproducible. One weakness of the study is that the dietary assessment was done at study entry only, precluding assessment of possible dietary changes occurring over the long follow-up. Another weakness is that dietary assessment was by self-report without external validation.
An important issue for which the study of Lew et al. provides helpful insight is the relative importance of total protein intake compared with the type or quality of protein intake with respect to ESRD risk. Their analysis supports that high red meat intake is a more important determinant of ESRD risk than overall protein intake. Specifically, their analysis showed that the strong association between red meat intake and ESRD risk was not confounded by increased overall protein intake. These data support continued study of the type or quality of dietary protein that determines ESRD risk with less emphasis on overall or total protein intake, particularly when these data are considered in light of the negative findings of the Modification of Diet in Renal Disease Study.6
Although Lew et al. showed a strong, direct association between red meat intake and ESRD risk, their data suggest the need for further study of an additional or complementary role of plant-sourced protein to potentially reduce ESRD risk, as suggested by other observational2 and interventional7 studies. The authors report that subjects who had the highest red meat intake also had the lowest intake of fruits and vegetables. As mentioned, there was also a trend toward an inverse relationship between soy and legume intake and ESRD risk that was not significant after adjustment. If, indeed, high dietary acid intake contributes to ESRD as suggested,9 the combination of a high intake of acid-producing red meat and a low intake of base-producing plant-sourced protein would yield a high-acid diet and potentially induce kidney injury.7 Further studies must determine the relative importance of a high intake of animal-sourced protein compared with a reduced intake of plant-sourced protein in enhancing ESRD risk. Such clarification will help determine whether decreased intake of animal-sourced protein, addition of plant-sourced protein, or a combination thereof is the best approach to provide adequate protein nutrition and kidney protection for CKD patients.
The substitutional analysis reported by the authors points to possible future dietary strategies which might provide kidney protection while reducing the risk for protein-energy wasting in CKD patients. This analysis supports that substitution of red meat intake with non-red meat or plant-sourced protein might reduce ESRD risk. Such a strategy might conceivably limit or avoid kidney-toxic protein while providing needed but non-kidney toxic dietary protein to simultaneously attain kidney protection while maintaining adequate protein nutrition. Substitution with common, non-kidney toxic dietary protein might be simpler to prescribe by clinicians, likely easier to follow by patients, and presumably cheaper than substituting with non-nitrogen ketoanalogues, which have also shown promise in slowing nephropathy progression.15
It is interesting that red meat but not non-red meat animal protein was associated with increased ESRD risk. Considering increased acid production as a possible mechanism by which animal-sourced protein increases ESRD risk, red meat does indeed increase acid production when metabolized but does not do so dramatically more than non-red meat sources of animal protein.10 The authors were unable to identify differences in meat preparation or other factors to account for this difference. This raises the question of whether acid production is indeed the mechanism by which red meat increases ESRD risk or, alternatively, if there are additional contributing mechanisms which are not characteristic of non-red meat animal protein as suggested by the authors. This again points to an additional area of needed research.
The analysis reported by the authors supports that red meat increased ESRD risk in subjects with conditions that increase their ESRD risk as well in those without these conditions. Specifically, when the authors stratified their cohort into those with and without at least one underlying ESRD comorbidity risk factor in an effort to identify a possible independent role of red meat in raising ESRD risk, they report a positive dose-response relationship between those with and without an underlying comorbidity risk factor. It is certainly possible that these subjects had some as yet unidentified ESRD comorbid condition(s) which predisposed them to ESRD when ingesting red meat. On the other hand, these data suggest the need to explore whether red meat, and possibly other dietary components, can lead to de novo ESRD in subjects without identifiable ESRD risks. These data also increase the urgency to identify kidney toxic dietary components and if these components can promote ESRD even in subjects who have no identifiable risk factors.
Diet remains a relatively underused component of the clinician’s armamentarium in the fight to prevent patients with CKD progressing to ESRD and its detrimental consequences. The study of Lew et al. gives more direction to the research needed to clarify how the increasingly important tool of diet can help reduce ESRD incidence and its associated morbidity and mortality.
The authors acknowledge the support of the Academic Operations division of Baylor Scott and White Health in the studies by our research group quoted in this manuscript.
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