Dietary plant and animal protein intake and decline in estimated glomerular filtration rate among elderly women: a 10-year longitudinal cohort study Free

Abstract

Background

Many older women demonstrate an age-related accelerating rate of renal decline that is associated with increased rates of bone disease, cardiovascular disease and mortality. Population-based protein restriction has been studied principally in patients with reduced renal function. In this investigation, we examined the hypothesis of a differential effect of plant-derived protein compared with animal-derived protein on renal function in older women.

Methods

We assessed dietary intake from a validated food frequency questionnaire and the estimated glomerular filtration rate (eGFR) (using the Chronic Kidney Disease Epidemiology Collaboration creatinine and cystatin C equation) at baseline, 5 and 10 years in the Longitudinal Study of Aging Women cohort. We tested the association between plant- and animal-sourced protein intake and kidney function using linear mixed modeling.

Results

A total of 1374 Caucasian women [mean (standard deviation, SD) age = 75 years (2.7) and mean (SD) baseline eGFR = 65.6 mL/min/1.73 m² (13.1)] contributed to the analysis. The average decline in eGFR was 0.64 mL/min/1.73 m²/year [95% confidence interval (CI) 0.56–0.72]. Higher intakes of plant-sourced protein were associated with slower declines in eGFR after adjusting for covariates including animal protein and energy intake (P = 0.03). For each 10 g of plant protein, the yearly decline in eGFR was reduced by 0.12 mL/min/1.73 m² (95% CI 0.01–0.23), principally associated with fruit-, vegetable- and nut-derived protein. The intake of animal protein was not associated with eGFR decline (P = 0.84).

Conclusions

Older women consuming a diet that is richer in plant-sourced protein have a slower decline in kidney function. These data extend support for the health benefits of plant-rich diets in the general population to maintain kidney health.

INTRODUCTION

Chronic kidney disease (CKD) is a growing public health concern responsible for 956 000 deaths globally in 2013, compared with 409 000 in 1990 [1]. With population aging and rising rates of diabetes, obesity and hypertension (HTN), the need for renal replacement therapy is expected to double by 2030 [2]. The consequences of CKD extend well beyond the loss of kidney function as it contributes to cardiovascular disease, cognitive decline, bone and mineral disorders, and loss of quality of life [3]. Public health-oriented prevention of CKD progression is key to face this expanding public health concern.

Population studies of individuals without risk factors for renal impairment have identified a progressive reduction in renal function with age [4] and older women developing CKD face an increased burden of comorbidities [5]. Thus, population-based interventions aimed at reducing the loss of kidney function in this population are attractive. Protein restriction has long been advocated. Indeed the current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend against high protein intake (>1.3 g/kg/day) in people with CKD who are at risk of progression [6, 7]. However, evidence suggests that the origin of protein may be an influential factor for kidney function. Proteins from plants reduce acidosis while animal proteins contribute to the acid-load and can induce hyperfiltration and proteinuria [8–10]. The evidence for this effect in the general population is mostly theoretical and observational studies are often limited to a baseline assessment of diet even though diet and kidney function are dynamic processes that are better evaluated longitudinally across repeated measurements.

Few studies have focused on older patients with Stages 2 and 3 progressive kidney disease [11]. Thus, we aimed to assess the association between the source, plant or animal, of dietary protein and the age-related decline in kidney function to examine the hypothesis of a differential effect of plant-derived protein compared with animal-derived on renal function. We used data from a cohort study of older women with repeated assessments of food intake and renal function. Our intent was to refine guidelines advising limiting protein intake in this population.

MATERIALS AND METHODS

Study participants

Participants of the Longitudinal Study of Ageing Women cohort were recruited as part of the Calcium Intake Fracture Outcome Study, a 5-year double-blind randomized controlled trial of calcium supplements for the prevention of osteoporotic fractures in older women [12]. In 1998, 24 800 women were randomly selected from the 33 336 women >70 years old on the electoral roll in Western Australia. A total of 5586 (22.5%) responded to the initial invitation. A total of 1222 women were excluded for having a pre-existing metabolic bone disease, receiving bone active agents or having a projected survival of <5 years. In total, 1510 were enrolled in the study. As previously reported, the characteristics of the participants were comparable to the age-matched general population in their medication and their disease burden but had overall higher socioeconomic status [12]. All participants gave written informed consent and the Human Ethics Committee of the University of Western Australia, and the Human Research Ethics Committee of the Western Australian Department of Health approved the study (approval number 2009/24).

At the end of the study, approval was granted for a 5-year extension [13]. This study is based on the data from the baseline, and 5- and 10-year assessments and included all participants who completed the food frequency questionnaire (FFQ) at baseline and had at least one measurement of kidney function throughout the study.

Dietary assessment

Participants completed a validated semi-quantitative FFQ, the Dietary Questionnaire for Epidemiological Studies version 2 [14, 15], at baseline, 5 and 10 years. The questionnaire measured their usual eating and drinking habits over the previous 12 months and included pictures of portion sizes. We excluded questionnaires with implausible energy intakes [<3350 kJ (800 kcal) or >17 575 kJ (4200 kcal)/day].

We estimated the consumed amount of each food item in grams from the frequency of consumption and the portion size. We calculated the protein intake from each food item using the AUStralian Food and NUTrient Database (AUSNUT) 2011–13 food nutrient database [16]. We obtained the total plant protein intake by combining the protein content from fruits, vegetables, beans and legumes, grain foods and nuts, and the total animal protein intake was obtained by combining the protein content from meat, poultry, fish, eggs and dairy products. For items containing ingredients of both plant and animal origin, we divided each item in its constituting ingredients according to the AUSNUT 2011–13 food recipe repertory [17]. We then calculated the protein content of each ingredient and allocated it to either plant or animal origin following the same definitions as above. For quality assessment, we recalculated the total protein intake from the sum of the plant and animal protein intake and compared it with the protein intake previously measured in the same cohort. The intraclass correlation coefficient was 0.997 [95% confidence interval (CI) 0.996–0.997]. We excluded questionnaires with extreme total protein intake (lower or >3.5 SDs from the mean) to avoid generating estimates based on single measurements.

Covariates of interests

Age, body mass index (BMI), smoking status, physical activity, socioeconomic status, medical history [HTN, prevalent coronary heart disease (CHD), diabetes, cerebrovascular disease, heart failure and peripheral arterial disease] and current medication (antihypertensive agents and statins) were collected at baseline. Participant’s socioeconomic statuses were measured using the Socio-Economic Indexes for Areas 1991 following the Australian Bureau of Statistic method [18]. We coded participant’s comorbidities according to the International Classification of Primary Care-Plus method [19]. We also adjusted for treatment allocation in the original trial.

Outcomes

The outcomes of interest were the interactions of plant and animal protein intake with time on estimated glomerular filtration rate (eGFR). Serum creatinine and cystatin C were measured at baseline, and 5 and 10 years. Serum creatinine was analyzed using an isotope dilution mass spectrometry traceable Jaffe kinetic assay for creatinine on a Hitachi 917 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). Serum cystatin C was analyzed on the Siemens Dade Behring Nephelometer, traceable to the International Federation of Clinical Chemistry Working Group for Standardization of Serum cystatin C and the Institute for Reference Materials and Measurements certified reference materials. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation derived from serum creatinine and cystatin C [20].

Statistical analyses

Descriptive statistics are presented as means and SDs and absolute and relative frequencies as appropriate. We constructed longitudinal mixed linear models with random intercepts. A random slope could not be tested due to the number of participants with kidney function assessed at two time-point or less (Supplementary data, Table S1). After assessing linearity, we parametrized plant and animal protein intake, age at baseline, BMI, total energy intake and time as continuous linear variables. Plant and animal protein intake, total energy intake and BMI were time-dependent variables in that the eGFR was regressed over the concurrent intake of plant and animal protein at 0, 5 and 10 years. In the multivariable models, plant protein intake was always adjusted for animal protein intake and vice versa. Missing covariates were imputed using multiple imputations with chained equations (Supplementary data, Table S2). The outcome variable, eGFR, was normally distributed.

We conducted a multivariable analysis with the subset of variables, including age, BMI, smoking status, physical activity, socioeconomic status, medical history and current medication, that presented a P < 0.25 in the univariable analyses. The final model was selected using a stepwise backward approach, where we kept variables that were either significantly associated with eGFR at a P < 0.05 or that confounded the effect of the primary explanatory variables. Time, animal, plant protein intake and their interactions were always kept in the model as well as total energy intake for face validity. We also tested for three-way interactions between plant and animal protein intake, time and CKD status at baseline (defined as eGFR <60 mL/min/1.73 m²), diabetes and HTN status (defined as either baseline systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg or need for antihypertensive medication). Protein intake from each food group (i.e. fruits and vegetables, grains, legumes and beans, nuts and seeds, meat, poultry, fish, eggs and dairy products) was also assessed. Diagnostic plots showed normally distributed residuals for all models. To assess the robustness of our findings to truncation of follow-up by death, we performed a sensitivity analysis using a fully conditional model where the slopes of eGFR were stratified by survival time (those who have survived to 10 years versus those who have died before 10 years) [21]. Significance level was set at 0.05 in two-tailed testing. Plant and animal protein intake for each participant was calculated using IBM SPSS Statistics version 24, and the linear mixed models were constructed using SAS^® 9.4 University Edition.

RESULTS

Of the 1460 participating women randomized in the original study, 1445 completed the baseline FFQ, and 1381 had at least one measurement of their kidney function. We excluded three participants for implausible energy intake and a further four participants for having a protein intake further than 3.5 SDs from the mean on all FFQs. In total, 1374 women contributed to the analysis (Figure 1).

Table 1 summarizes the characteristics of the study population at baseline. The average eGFR was 65.6 (SD = 13.1) mL/min/1.73 m², and 367 (33%) participants had an eGFR <60 mL/min/1.73 m². At 10 years, the average eGFR was 60.2 (SD = 15.8) mL/min/1.73 m² and 343 (46%) participants had an eGFR <60 mL/min/1.73 m². The average decline in eGFR was 0.64 mL/min/1.73 m²/year (95% CI 0.56–0.72).

The mean (SD) total protein intake throughout the study was 75.2 (23.6) g/day, or 1.15 (0.41) g/kg of weight/day. At baseline, 248 (18%) participants consumed less than the57 g of protein/day recommended for women >70 years old with a normal kidney function in Australia [22], while 507 (34%) had a high protein intake (>1.3 g/kg/day). The mean (SD) animal and plant protein intake for the three assessments were, respectively, 51.4 (22.9) g/day [0.75 (0.31) g/kg/day] and 28.9 (9.5) g/day [0.40 (0.15) g/kg/day]. On average, 63% (SD = 11) of the plant protein intake came from grains, 27% (SD = 9) from fruits and vegetables, 3% (SD = 7) from legumes and 3% (SD = 4) from nuts. As expected, higher plant-sourced protein intake was associated with higher overall plant consumption (Supplementary data, Figure S1). Supplementary data, Table S3a summarizes the characteristics of the study population at baseline stratified by quartile of plant protein intake. On average 39% (SD = 16) of the animal protein intake came from dairy products, 31% (SD = 15) from meat, 15% (SD = 11) from fish, 9% (SD = 7) from poultry and 5% (SD = 4) from eggs. Supplementary data, Table S3b summarizes the characteristics of the study population at baseline stratified by quartile of animal protein intake. Despite grouped evidence of participants with higher consumption of animal protein to also have high consumption of protein from plant sources, after adjustment for total energy intake, those consuming more plant-derived protein had a reduced intake of animal protein (Pearson correlation coefficient = −0.41, Supplementary data, Figure S2).

Association between plant protein intake and age-related decline in eGFR

In the unadjusted analysis, increased plant protein intake was strongly associated with a slower decline in eGFR (P = 0.01 for interaction with time). For each 10 g increase in plant protein intake, the yearly decline in eGFR was 0.13 mL/min/1.73 m²/year (95% CI 0.03–0.23) less. Adjusting for the adverse effects of age at baseline did not materially affect the relationship between plant protein intake and the slope of decline in eGFR (P = 0.03 for interaction with time). For each increase of 10 g of protein from plants, the yearly decline in eGFR was 0.12 mL/min/1.73 m²/year (95% CI 0.01–0.23) less. Multi-variable analysis adjustment for age, BMI, diabetes status, physical activity, usage of antihypertensive drugs, history of CHD or ischemic cerebrovascular disease and total energy intake did not substantially alter the relation between a higher intake of plant protein and a slower decline in eGFR (P = 0.03 for interaction with time) (Table 2). For each increase of 10 g in plant protein intake, the eGFR decline was slowed down by 0.12 mL/min/1.73 m²/year (95% CI 0.01–0.23) (Figure 2). Furthermore, the association between plant protein and the rate of eGFR decline was not modified by the presence of CKD, diabetes or HTN at baseline (P for three-way interaction = 0.81, 0.50 and 0.24, respectively) (Figure 3). Likewise, the estimate for plant protein on the slope of eGFR was similar in participants who survived until the end of the 10-year follow-up versus those who did not (P for three-way interaction = 0.69). As expected, older age, increasing BMI, usage of anti-hypertensive drugs, diabetes, CHD and ischemic cerebrovascular disease were associated with a lower eGFR. Interestingly, physical activity was associated with a higher eGFR (Table 2).

An analysis of the food sources of plant protein found a slower average decline in eGFR with higher protein intakes from fruits, vegetables and nuts (P for interaction with time <0.001, 0.02 and 0.03, respectively). However, protein from grain foods, legumes and beans were not related to eGFR change (Supplementary data, Table S4).

Association between animal protein intake and age-related decline in eGFR

In neither the unadjusted analysis nor the age-adjusted analysis was animal protein intake significantly associated with the rate of decline in eGFR (P = 0.30 for interaction with time). Furthermore, we found no association between animal protein intake and the rate of decline in eGFR after adjusting for multiple potential confounders (change in the rate of decline in eGFR for each 10 g of animal protein intake increase was 0.01 mL/min/1.73 m²/year (95% CI −0.04 to 0.05; P = 0.84). Restricting the analysis to nondairy animal protein did not alter the results (−0.01 mL/min/1.73 m²/year, 95% CI −0.07 to 0.04; P = 0.68).

In a subgroup analysis, animal protein intake appeared to be associated with a more rapid decline in eGFR among participants with a baseline eGFR <60 mL/min/1.73 m² (Figure 3). However, the three-way interaction term for this subgroup did not reach statistical significance (P = 0.051). The association between animal protein and the rate of eGFR decline was not modified by the presence of diabetes or HTN at baseline or by whether the participant survived or died before the completion of the follow-up (P for three-way interaction = 0.89, 0.46 and 0.84, respectively) (Figure 3).

An analysis of food sources of protein from each food group using tertile of intake did not identify any association of protein from meat, processed meat, poultry, fish and dairy with eGFR decline. However, higher intake of protein from eggs was associated with a slower decline in eGFR (Supplementary data, Table S5).

DISCUSSION

In this longitudinal analysis of 1374 older women followed for 10 years, we report an association between the consumption of plant-derived proteins and reduced age-related decline in kidney function, but no beneficial or adverse association of animal-derived protein with eGFR. The mean eGFR decline over 10 years was 6.4 mL/min/1.73 m², which is significantly less than the 1.1 mL/min/1.73 m²/year observed in Canadian women with similar age and baseline kidney function [23]. Nevertheless, women with higher intakes of plant-derived protein still experienced a substantially slower rate of decline in eGFR of 1.2 mL/min/1.73 m² fewer for each increase of 10 g of plant protein, one-third of the average daily intake. The protective association of plant-based protein with the slope of eGFR was independent of baseline CKD status, diabetes or HTN, each of which was associated with a substantially lower average eGFR.

These findings are supported by a cross-sectional analysis of diabetic patients and a study of younger Iranian subjects [24, 25]. The 11-year longitudinal analysis of the Nurses’ Health Study, a cohort similar to ours in terms of kidney function, identified nondairy animal protein to be associated with a greater change in eGFR of the magnitude of −1.2 mL/min/1.73 m² per 10 g/day of intake [11]. They did not identify beneficial or adverse associations with the intake of vegetable protein. In a cohort of older males (80%) with a history of myocardial infarction, each increase of 0.1 g/kg ideal body weight in total protein intake was associated with a change in eGFR of −1.2 mL/min/1.73 m², but no difference was observed between protein of plant versus animal sources [26]. In exploratory analyses, we found that protein from fruits, vegetables and nuts, representing 30% of the plant protein intake, was associated with a slower decline in eGFR. Thus, our findings may relate to other constituents of fruits, vegetables and nuts in addition to their protein content. Several previous studies support this hypothesis. An analysis of the Atherosclerosis Risk in Communities cohort found participants consuming the most vegetable protein sources to have a 24% (95% CI 9–36) lower risk of incident CKD compared with those consuming the least [27]. While not focussing on protein intake per se, healthy plant-based diets, such as the Mediterranean and Dietary Approaches to Stop Hypertension diets, which are likely to be rich in plant protein, have also been linked with lower incidences of CKD in younger individuals [28–34].

In contrast, animal-derived protein in the relatively small amounts consumed in this population was not associated with the change in eGFR, other than for a possible greater decline in eGFR among participants with a baseline eGFR <60 mL/min/1.73 m². It is important to note that the mean total protein intake in this cohort was 1.15 g/kg/day, which is less than the level of concern outlined in KDIGO guidelines of >1.3 g/kg/day. Therefore, insufficient exposure of the cohort to high protein intakes could have prevented us from observing a negative effect of animal protein. In comparison, in a younger Iranian population, participants consuming over seven times more the meat than the reference group had a 73% higher risk of developing CKD [35].

Some potential limitations are evident. This is an observational study demonstrating an association rather than causality. Second, as in all epidemiological studies of nutrition, the particular effect of a nutrient cannot be separated from those of other constituents of that diet. Thus, the benefits of plant protein in general, and fruits, vegetables and nuts in particular, may be due to the other constituents of plant foods such nitrate- and sulfur-containing compounds that have been the focus of other studies in this cohort [36, 37]. Third, food consumption questionnaires are subject to measurement errors that can lead to biased estimates of effect. The dietary assessment utilized in this study has been validated against weighted food records and included visual aids for portion sizes [15]. Finally, the evaluation of kidney function was limited to eGFR, assessed by creatinine clearance and cystatin C, and would have been improved by measurement of proteinuria.

Strengths include the focus on a substantial population of community-based older women, an increasing demographic worldwide. Second, while the rate of progression of kidney disease was slower than in other studies, 33% had CKD Stage 3 or higher at baseline, and 13% progressed to this category over 10 years. Third, we based our assessment of kidney function on both creatinine and cystatin C, which has been shown to be superior to a single marker, particularly in the elderly population at risk for muscle wasting [20, 38]. Cystatin C is also less influenced by diet and protein intake than serum creatinine [39]. Finally, we assessed dietary intake and renal function at three time points over 10 years, and we used longitudinal mixed linear models, which are reliable statistical designs to assess the progression of eGFR through time [40].

In conclusion, this study has identified a beneficial association between plant-based protein and eGFR that may be related to other compounds within plant foods. A patient-centered approach to dietary advice with a focus on the promotion of plant sources of dietary protein rather than restriction may be considered. Importantly, from a public health point of view, encouraging high intake of fruits, vegetables and nuts may prevent or slow renal deterioration in older women in addition to their benefit on other organ systems.

SUPPLEMENTARY DATA

Supplementary data are available at ndt online.

FUNDING

The study was supported by Healthway Health Promotion Foundation of Western Australia (Grant number 6018 1998 2000) and the National Health and Medical Research Council of Australia (project grant 254627, 303169).

A.B.-J. was supported by scholarships from the Fond de Recherche du Québec en Santé (Formation de maîtrise pour les détenteurs d’un diplôme professionnel, #35837) and from the National Health and Medical Research Council (GNT1151246) for the completion of this study. J.R.L., G.W. and J.M.H. were supported by National Health and Medical Research Council Fellowships. The contents of the published material are solely the responsibility of the individual authors and do not reflect the views of the FRQS or the NHMRC.

AUTHORS’ CONTRIBUTIONS

A.B.-J., J.R.L. and G.W. designed the study; J.C.C., J.M.H. and R.L.P. revised and approved the analytical protocol; J.R.L., R.L.P. and W.H.L. collected the data; A.B.-J., J.R.L. A.T.-P. and G.W. analysed the data; A.B.-J. made the tables and figures; A.B.-J. first drafted the manuscript and A.B.-J., J.R.L. J.C.C., J.M.H., R.L.P., W.H.L., A.T.-P. and G.W. revised and amended the manuscript; all authors approved the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors have no relevant conflict of interest to declare. The results presented in this article have not been published previously in whole or part, except in abstract format.

REFERENCES