Chronic kidney disease (CKD) causes an elevated occurrence of many conditions involving multiple organs and systems and premature mortality. Furthermore, a considerable number of those with CKD could progress to renal failure, necessitating hemodialysis (1, 2). Given that CKD is a chronically progressive and nonreversible condition, primary prevention becomes imperative, even without kidney damage.

Previous studies showed that dietary interventional measures could be effective in slowing the progression of the disease and reducing associated complications (3). About 90% of protein metabolic waste are excreted by the kidneys. Consequently, a higher protein intake may result in glomerular hyperfiltration and damage the kidney (4, 5). Hence, although the clinical evidence of benefit was limited, some guidelines recommend dietary interventional measures. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline suggested maintaining a protein intake of 0.8 g protein/kg (weight)/d for those with diabetes and CKD not treated with dialysis (6). Additionally, for CKD patients not on dialysis and without diabetes, in adults with CKD 3–5 who are metabolically stable, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) recommended under close clinical supervision, protein restriction with or without keto acid analogs, to reduce risk for end-stage kidney disease (ESKD) and improve quality of life (7). Nevertheless, these guidelines did not provide recommendations of specific sources, as well as the advices of dietary protein intake for the general population.

Previous researchers have focused on the relationship among dietary protein intake and kidney function in population without CKD. A meta-analysis indicated that high-level protein diets were correlated with growing estimated glomerular filtration rate (eGFR) among individuals without CKD (8). However, studies that explored the association between dietary protein intake as well as specific sources and incident CKD were scarce. Two studies reported a beneficial correlation between high-level total protein intake and incident CKD (9, 10), while three studies showed no significant relation of that (11–13). Of those, four studies indicated a beneficial correlation between high-level plant protein intake and incident CKD (10–12, 14), while one study showed no significant correlation (9). In addition, three studies suggested no correlation among high-level animal protein intake and incident CKD (10–12), while one study showed beneficial correlation (9). Therefore, the relation between dietary protein intake as well as specific sources and the incidence of CKD remains uncertain.

With this background, we performed the first systematic review and meta-analysis to determine the exact correlations of dietary protein intake and CKD incidence.

Our data showed that a higher-level intake of total, plant and animal protein can lower a risk of CKD by 18, 23 and 14%, respectively. Specifically, a high-level of fish and seafood with animal protein can lower a 16% risk of CKD. A significant non-linear correlation was found among plant protein intake and incident CKD by dose–response analysis. All studies were prospective cohort studies with a low overall risk of bias.

Current studies’ conclusions remain controversial in terms of the correlation between total protein intake and CKD risk. Other than these studies included in this meta-analysis, a cross-sectional study reported that there was no significant association between total protein intake and incident CKD, involving 5,316 participants aged 27 years or older without diabetes (20). In another cross-sectional study conducted in Japan, high-level total protein intake associated with reduced CKD risk was found in women but not in men, and a beneficial relationship was observed between total protein intake and eGFR in both men and women (21). However, due to the cross-sectional nature, these two studies cannot be pooled in the present meta-analysis. Moreover, a randomized clinical trial revealed that increased total protein intake from 91.4 to 107.8 g/day can increase the level of eGFR and the volume of kidney among healthy overweight or obese men and women (22). Indeed, evidence suggested that the beneficial effect of total protein intake in persons without kidney insufficiency could be attributed to protein-induced hyperfiltration, wherein the kidneys adapt to an increased BUN and Scr (23).

Studies have focused on the preventive effect of various dietary patterns on chronic conditions. “Healthy foods” like vegetables and fruits are typically recommended, whereas there have been concerns raised regarding red and processed meat (24–26). An ARIC Study involving 11,952 adults with an eGFR of ≥60 mL/min/1.73 m² found that higher consumption of red meat and processed meat can significantly increase the incidence of CKD G3. Conversely, foods rich in vegetable protein can significantly reduce the occurrence of CKD (12). Another study conducted in Iran, which included 4,881 participants, found that substituting red or processed meat with foods rich in vegetable protein correlated with a reduced incidence of CKD (27). Further studies also demonstrated that higher plant protein intake was associated with a lower risk of subsequent CKD (11, 20). Similarly, a study involving 7,339 middle-aged and older Korean adults also confirmed that (10). Notably, a recent prospective study with a 9.9-median year follow-up of a large sample size of 117,809 participants from UK biobank revealed that greater dietary plant protein intake was associated with a lower risk of incident CKD (14). However, we found only one study reported no significant correlation between vegetable protein intake and CKD incidence (9).

There is compelling evidence supporting the benefit for plant proteins in promoting kidney health. More pronounced inflammation will be induced by a high-level animal protein intake rather than vegetable protein intake. For instance, the inflammatory macrophage responding and a series of cytokines releasing were observed in a colitis mice model fed with a diet rich in animal proteins rather than plant proteins (28). Moreover, consuming animal proteins significantly burdens the kidneys (29). Diets high in vegetables and low in animal protein exhibit higher proportions of glutamic acid, cystine, proline, phenylalanine, and serine compared to diets low in vegetables and high in animal protein (30). These differences in amino acid content likely led to distinct nitrogen loads and acidogenicity levels (31, 32). It’s worth noting that plant-based foods are also notably rich in dietary fiber, which plays a crucial role in altering gut microbiota composition, lowering circulating cholesterol levels, mitigating inflammation (33–36), and reducing the occurrence of CKD (37). Taken together, the mounting evidence substantiated a clear association among a high-level vegetable protein and diminished incident CKD.

Interestingly, our meta-analysis also suggested a beneficial correlation among a high-level animal protein intake and incident CKD. Caution must be exercised when interpreting this finding. Previous studies revealed that high-level of red meat and processed meat intake significantly increased the incidence of CKD (12, 27, 38). In the contrary, fish and seafood were reported an inverse correlation with CKD incidence (9, 12, 27). Two studies included in animal protein analysis derived from Japan and Korea in which fish and seafood were main consumption of animal protein (39, 40), this may explain the inverse relation among high animal protein intake and lower risk of CKD in this meta-analysis. Mechanistically, the protective effect of fish and seafood may be attributed to an anti-inflammatory effect of long-chain n-3 polyunsaturated fatty acids from seafood (41). However, after removal of these two studies, the beneficial effect of high-level animal protein intake was not statistically significant.

We found no significant heterogeneity among studies within total protein and animal protein intake, but these studies focused on plant protein presented a significant high heterogeneity. Subgroup analysis showed that the heterogeneity was non-statistically significant among studies that derived from Western countries, had a sample size ≥7,000, had a follow-up time ≥ 10 years, adjusted for race, adjusted for carbohydrate, adjusted for LDL cholesterol and adjusted for TG, which suggested the potential sources of heterogeneity. Sensitivity analysis showed that Alvirdizadeh et al.’s study (11) may be part of the sources of heterogeneity in plant protein. This study reported a risk estimate of OR, while others reported HRs that considered time factor.

Our meta-analysis has several strengths. One is that it was the first meta-analysis paying attention to the effect of high-level protein intake on CKD incidence. In addition, subgroup analysis can identify potential sources of heterogeneity. Importantly, the included studies were all prospective cohort studies with a low overall risk of bias, which provided a methodologic rigor to allow these results to be interpreted with high confidence.

However, there are some limitations to our meta-analysis. Firstly, the number studies on this topic was still small. Secondly, a significant high heterogeneity was observed in studies within plant protein intake. Thirdly, the definitions of CKD were inconsistent. Four studies adopted eGFR<60 mL/min/1.73 m² as the diagnostic criteria (9–11, 13), while one study used records (14) and another study considered CKD stage 3 as the outcome (12). Lastly, the measurement indexes of protein intake were not standardized. Two studies used %energy of protein intake as the indicator (9, 13), while four studies used absolute intake as the indicator (10–12, 14). In addition, the criteria of categories were also inconsistent, although a dose–response meta-analysis was performed to determine the relation of the detailed intake and CKD risk, the data was still limited. These factors may cause bias to the results. Future studies should standardize the criteria of CKD diagnosis, measurement indicator and categorizing protein intake. Additionally, studies should also focus on the precise sources, detailed intake and duration of dietary protein relevant for potential decreased risk of CKD. In addition, studies should be focused more on subgroup population as well as the population with different disease such as obesity, hypertension and diabetes.

This study showed that a high-level intake of dietary total protein, plant protein and animal protein intake (especially for fish and seafood) can significantly reduce 18, 23 and 14% CKD risk. Future studies should focus on the specific sources, detailed intake and duration of dietary protein relevant for potential decreased risk of CKD.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

YC: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Visualization, Writing – original draft, Writing – review & editing. GuZ: Data curation, Methodology, Software, Writing – original draft, Writing – review & editing. ZS: Formal analysis, Supervision, Validation, Writing – original draft, Writing – review & editing. GaZ: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. XR: Data curation, Investigation, Writing – original draft, Writing – review & editing. TZ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.