An investigation of low-protein diets’ qualification rates and an analysis of their short-term effects for patients with CKD stages 3–5: a single-center retrospective cohort study from China

Chronic kidney disease (CKD) has a global prevalence of around 8–16%. It can diminish quality of life, and increase the risk of cardiovascular disease and mortality. As such, it has been recognized as a global public health problem [1, 2]. In recent years, nutrition management has been considered an important approach for conservative treatment for CKD patients, and accordingly, it is gaining attention [3, 4]. Effective nutritional treatment not only can ensure that CKD patients’ nutritional requirements are met, but also can reduce metabolite accumulation, therefore contributing to the control of uremic symptoms and other complications, such as electrolyte disturbances and acid–base imbalances, sodium and water retention, and mineral and bone disorder (CKD-MBD) syndrome [3].

Low-protein diets (LPD) have long been controversial in nutritional management. The initial results of the modification of diet in renal disease (MDRD) study showed that LPD had little benefit in the short-term, and did not delay CKD progression [5]. However, other scholars have arrived at different conclusions after reanalyzing the MDRD study, arguing that inconclusive evidence should not be mistaken for evidence supporting null hypotheses [6]. In 2011, the Clinical Practice Guidelines issued by the British Renal Society (BRS) recommended a protein intake of 0.75 g/kg ideal body weight (IBW)/day for CKD stage 4–5 non-dialysis patients [7]. In 2019, it was changed to 0.8–1.0 g/kg IBW/day, and the BRS declared that they believed there was insufficient evidence to recommend LPD therapy (1C) [8]. In contrast, the 2020 update of the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Nutrition in CKD pointed out that a protein-restricted diet could reduce the risk of end-stage renal disease (ESRD) or death (1A), and improve quality of life (2C). For patients with CKD stages 3–5 and without diabetes, LPD should be limited to 0.55–0.60 g dietary protein/kg body weight (BW)/day, and for patients with CKD stage 3–5 and diabetes, LPD should be limited to 0.60–0.80 g dietary protein/kg BW/day [9].

However, perhaps due to differences in dietary habits, LPD has been recommended for nutritional therapy for CKD in China since the 2005 Consensus on Protein Nutritional Therapy for Chronic Kidney Disease [10]. The Health Industry Standard of the People's Republic of China—Dietary Guide for Chronic Kidney Disease Patients WS/557–2017 promulgated in 2017 also provides detailed guidance on LPD [11]. The latest Clinical Practice Guidelines for Nutritional Therapy of Chronic Kidney Disease in China (2021 Edition) also still recommends protein diet restriction [12].

Another problem pertaining to LPD is that its implementation in clinical settings is difficult. Results from a US survey showed that average daily protein intakes were 1.3 g/kg/day [13]. Thus, to meet LPD treatment standards, it would be necessary to reduce the total protein intake by more than half, which in turn would affect patients' dietary satisfaction and motivation [14]. Coupled with patients’ varying education levels and diet patterns, the lack of effective monitoring and feedback mechanisms in medical institutions, as well as patients’ minimal understanding of nephropathy, insufficient doctor-patient communication, insufficient family support, and other reasons, LPD treatment compliance is often compromised [15]. Moreover, many nephrologists lack training and experience in LPD; they fear malnutrition and are unable to develop detailed LPD regimens. As such, they do not implement the LPD treatment [16].

Our center emphasizes LPD therapy for CKD, and has established a professional nutrition management team to oversee patients’ dietary intake, and to collect clinical data. The Chinese Nutrition Society established the current protein dietary reference intakes (DRIs) in China in 2013, which include the estimated averaged requirement (EAR) and recommended nutrient intake (RNI). The EAR for protein is 60 g/day for adult males and 50 g/day for adult females (0.9 g/kg/day). The RNI for protein is 65 g/day for adult males and 55 g/day for adult females (1.0 g/kg/day). A study showed that the total dietary protein intake of the Chinese population would vary with the seasons, with an average estimate of 68.48 ± 22.07 g/day [17, 18]. However, due to the specificity of the Chinese diet, which consists of primarily mixed foods, there are few international reports on LPD in Chinese CKD patients. With this in mind, how is LPD adherence among CKD patients with Chinese dietary habits? What effect does LPD have on CKD prognosis? Can restricting dietary protein affect nutritional status? We conducted a retrospective study to observe the LPD qualification rates among patients with CKD stages 3–5, based on our data. We then analyzed the short-term effects of LPD on CKD progression.

In this study, we observed the qualification rate and short-term clinical benefits of LPD for patients at our center with stages 3–5 CKD.

The results showed that the LPD qualification rate was only about 50% at the 5th follow-up time point (the 24th month), which is similar to the results from studies in other countries. An Italian cross-sectional study showed that adherence to dietary prescriptions in children and adolescents was 56% [30]. Another retrospective study from Brazil included 321 non-dialysis CKD patients, 158 of whom had adhered to LPD, and the adherence was 49% [31]. There are many reasons for the low LPD qualification rate. In this study, the proportion of diabetic kidney disease patients in the non-LPD group (19.6%) exceeded that in the LPD group (7.2%) (Table 2). Previous studies have shown that implementing LPD is more complicated when patients have diabetic nephropathy. Blood glucose management is more difficult for them as well, and their adherence to management is lower. Therefore, this may be one of the reasons for the low LPD qualification rate in the non-LPD group [32, 33].

Meanwhile, according to the characteristics of the patients in the center, we considered that the reasons for the low qualification LPD rate may have included: (1) The LPD implementation process was indeed cumbersome; (2) The patients in our study were middle-aged or elderly, and the dietary structure was difficult to change; (3) cooking methods and food-pairing for Chinese cuisine is rich and varied, and it is not easy for patients to follow an LPD alone when they are accustomed to eating with family. Therefore, clinicians could improve CKD patients’ low LPD qualification rates in two ways. First, for patients of means, low-protein or protein-free products could be recommended, and energy supplements and keto acid preparations should be taken as needed [34, 35]. Second, personalized nutrition prescriptions could be formulated based on patients' dietary habits and disease conditions. In China, low-protein foods are recommended for CKD patients, including wheat starches, sweet potato starches, cassava starches, mung beans, pea starches and products derived from them; recipes could also be recommended according to patients’ unique situations, to diversify diets. This would not only meet patients’ tastes, but also increase the diversity of patient choices, thereby improving their compliance with LPD [11]. However, the ideal situation would be for patients need to keep in regular communication with the clinical team. Throughout chronic disease management, patients’ dietary habits and dietary structure would gradually approach the LPD standards due to continuous precise nutritional guidance and dietary education. This could improve the compliance of patients with CKD stages 3–5 to LPD [36]. In addition, there is still a lack of reports on whether the nutrient intake qualification rate for patients receiving dietary guidance has continued to improve, or has reversed [37]. The results of this study showed that the DPI qualification rate of 161 patients increased from 11.80% at baseline to 54.40% at the 5th follow-up time point. Therefore, we believe that although the dietary structure in China is complex, LPD is still feasible, and also would optimize the diet of CKD patients through better management.

The results of this study also indicate that LPD could offer short-term benefits for patients with CKD stages 3–5. We performed statistical analysis using a parametric test, a non-parametric test, and a mixed linear model. The primary outcome measure results showed that LPD could reduce urinary protein excretion, reduce UPCR in CKD stages 3–5 patients, and may also slow eGFR decline. The secondary outcome measures showed that LPD reduced TG and decreased body weight, BMI and FFM; it may also have an effect on WHR, TBW and Hb.

CKD patients in Japan, another country with East Asian cultural roots, have also been treated with LPD under comprehensive management. Based on the pooled results of meta-analyses from several clinical studies, Japanese scholars also believed that LPD could reduce urinary protein excretion, protect renal function and alleviate subjective symptoms [38]. The mechanism through which LPD reduces urine protein excretion may be a factor in inhibiting the renin-angiotensin system (RAS) [39]. In clinical practice, the application of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) reduces proteinuria, and delays CKD progression in patients with large amounts of proteinuria. Studies have also shown that the overexpression of transforming growth factor-β (TGF-β) influences CKD progression and proteinuria occurrence, and that the combined treatment of ACEI/ARB and LPD reduces TGF-βexpression [40, 41].

The results of this study also suggest that LPD both causes weight loss, and lowers BMI and TG. Obesity and hyperlipidemia are the most prevalent independent risk factors for CKD [42]. Meanwhile, high BMI and lipid metabolism disorders were both risk factors for CKD co-occurring with cardiovascular disease [43]. A previous study has revealed that kidney disease progression is correlated with obesity and high BMI (> 30 kg/m²), and has a U-shaped relationship with mortality [44]. In addition to body weight, a cross-sectional study in China has also shown that hypertriglyceridemia is correlated with increased urinary albumin-to-creatinine ratios (ACR) [45]. The results of the meta-analysis also showed that LPD could reduce proteinuria, cause weight loss, adjust lipid metabolism, and reduce the onset of azotemia, thereby delaying the patient’s time to end-stage renal disease [46, 47]. It is important to note the “obesity paradox” in CKD patients: a study has shown that obesity is correlated with a lower risk of death in patients with CKD, especially ESRD [48]. This is because obesity may represent the body's nutritional reserves, and studies have suggested that adipose tissue may help chelate uremia toxins in CKD patients [49]. Therefore, in nutrient management, we need to distinguish between the pathological state of abnormal lipid accumulation and the good nutritional state of body fullness, according to patients’ varying conditions, and differentiate between the effects of lipid packing, dyslipidemia, and obesity on patients during different periods. We also must avoid abnormal lipid distribution, lipid loss, and muscle consumption, and provide the most beneficial nutritional guidance for patients [50, 51].

LPD is a safe treatment for CKD patients; it causes few adverse reactions, and few studies have reported protein-energy waste (PEW) during LPD [46, 52]. There were no cases of PEW in this study, which may be related to the absence of patients included in hemodialysis or peritoneal dialysis. In addition, we effectively avoided PEW by several methods, including (I) prescribing nutritional supplements such as keto acids to appropriate patients; (II) recommending low-protein staple foods to increase dietary energy intake; (III) providing ongoing nutritional counseling to optimize dietary nutritional intake; (IV) enhancing management of chronic kidney disease comorbidities; and (V) instructing patients to perform appropriate exercise. Such LPD treatment also does not increase the phosphorus burden, and the data at the beginning and end of this study showed that the median serum phosphorus of patients was about 1.2 mmol/L. At the 5th follow-up time point, we observed no statistically significant differences between ALB and other nutritional monitoring indicators such as AMC and AC, between the two groups. However, the results of the comparison of the difference between the two patient groups and the MLM in this study suggested that during the LPD implementation, patients tended to decrease their body weight and FFM. Although the decline was not large, it still reminds us that we should regularly monitor patient nutrition, follow patients’ nutritional status, and adjust nutrition programs in real-time according to actual situations, so as to prevent lipid loss and muscle waste.

This study has its weaknesses. In addition to the common limitations of non-randomized methods, the follow-up period was not long enough. Moreover, this was a single-center retrospective study, and we did not investigate the specific reasons for LPD non-compliance. We were also unable to perform Kaplan-Mayer and Cox analysis of the primary outcome indicators because no patients had entered the endpoint event by the time data collection was complete. To ensure the integrity of the 24-h urinary urea excretion results and other data, the patients included in the study were screened. Therefore, the sample size of this cohort is small, the patients are younger, and there are fewer comorbidities, and their follow-up adherence may have been better than patients who were not included. The results and limitations of this study highlight the need for further study, and we hope to further verify the therapeutic effects of LPD with prospective and/or randomized studies in the future.

The results of this study suggest that LPD treatment can reduce UPCR in patients with CKD stage 3–5, and may delay the decline in eGFR. Meanwhile, it also reduces BMI, TG, body weight, and FFM. We found no adverse reactions during LPD implementation, yet we still recommend regular nutritional status assessment to prevent PEW. However, with Chinese dietary habits, the LPD qualification rate for patients with CKD stages 3–5 is still low. Yet guidance and education offer room for additional improvement, and thus, further studies are needed to improve LPD qualification rates according to the characteristics of the Chinese diet.