Encyclopedia
Low-protein diets have been recommended as diet therapy for the management of chronic kidney disease. Several studies have reported significantly more favorable results with low-protein diet than with normal-protein diet, the renal protective effects of low-protein diets are still unclear in diabetic patients with chronic kidney disease. Moreover, some studies have reported that extremely low-protein diets may increase the risk of mortality.
- protein restriction
- diabetic kidney disease
- eGFR
1. Introduction
Low-protein diets are typically recommended as diet therapy for the management of chronic kidney disease (CKD) regardless of its type (i.e., diabetic kidney disease (DKD) or non-diabetic chronic kidney disease (non-DM-CKD)). A review article by Kalantar-Zadeh et al. [1] published in the New England Journal of Medicine in 2017 and the clinical practice recommendation for DKD by the 2020 Kidney Disease: Improving Global Outcomes (KDIGO) (KDIGO 2020) [2] both recommend low-protein diets for CKD. Kalantar-Zadeh et al. [1] stated that protein reduction should be prioritized over other nutrients, such as sodium, potassium, and phosphorus. However, its effects on CKD are yet to be proven scientifically as Kalantar-Zadeh et al. [1] stated, “It is possible, though not yet unequivocally proved, that nutritional interventions slow disease progression,” and the KDIGO 2020 [2] stated that “the certainty of the evidence” is “low” or “very low.”
2. Effectiveness and Safety of Low-Protein Diets
Kalantar-Zadeh et al. [1] recommended low-protein diets (Table 1). In their article, they emphasized their preference for low-protein diet over diet recommendations on sodium, potassium, phosphorus, calcium, fibers, alkali, plant-based foods, energy, and fats. Low-protein diets with a protein intake of <1.0 g/kg are recommended for people without CKD but with risk for CKD, such as those with diabetes or hypertension. Although Kalantar-Zadeh et al.’s study [1] is not a review on DKD, further verification is necessary for its low-protein diet recommendation for diabetic patients without CKD. In particular, it is necessary to validate whether there is any rationale for restricting normal-protein diets (1.0–1.5 g/kg) in all diabetic patients.
Table 1.
| CKD Stage | Normal Kidney Function with Increased CKD Risk | Mild-to-Moderate CKD | Advanced CKD | Transition to Dialysis | Ongoing Dialysis | Any Stage with PEW |
| CKD stage (mL/min/1.73 m | 2 | ) | eGFR ≥ 60 with CKD risk | 60 > eGFR ≥ 30 | 30 > eGFR or proteinuria > 0.3 g/day | |
| Daily protein intake (g/kg) | <1.0 | <1.0 | 0.6–0.8 including 50% HBV, or <0.6 with EAA or KA | 0.6–0.8 on non-dialysis days and > 1.0 on dialysis days | 1.2–1.4 | >1.5 |
| Other considerations | Increased proportion of plant-based protein | Consider 0.6–0.8 if eGFR < 45 |
Among the 18 studies [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], eight had significantly more favorable results in the intervention group (low-protein diet) than in the control group (normal-protein diet) in terms of study outcomes. However, these studies did not necessarily examine the renal protective effects of low-protein diets. For example, the amount of protein intake was the same between the intervention and control groups, as reported by Montes-Delgado et al. [10] and Teplan et al. [12], who examined the renal protective effects of high-energy diets and supplements such as erythropoietin (EPO) and keto acids. Lindenau et al.’s study [8] did not report on renal function; however, it provided bone biopsy results. In recent years, there has been an increase in the use of eGFR changes as a surrogate marker when examining outcomes in studies on the kidneys [21][22]. Table 3 presents ten articles that reported changes in renal function as outcomes in genuine intervention studies of low-protein diets for patients with predialysis renal failure.
Among the 18 studies [13,14,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35], eight had significantly more favorable results in the intervention group (low-protein diet) than in the control group (normal-protein diet) in terms of study outcomes. However, these studies did not necessarily examine the renal protective effects of low-protein diets. For example, the amount of protein intake was the same between the intervention and control groups, as reported by Montes-Delgado et al. [25] and Teplan et al. [27], who examined the renal protective effects of high-energy diets and supplements such as erythropoietin (EPO) and keto acids. Lindenau et al.’s study [23] did not report on renal function; however, it provided bone biopsy results. In recent years, there has been an increase in the use of eGFR changes as a surrogate marker when examining outcomes in studies on the kidneys [36,37]. Table 3 presents ten articles that reported changes in renal function as outcomes in genuine intervention studies of low-protein diets for patients with predialysis renal failure.
Table 3.
| First Author (Year Published) |
Reference Numbers | Patients | Intervention (I) (Daily Protein Intake) | Comparison (C) | GFR (mL/min/1.73 m | 2 | ) or Ccr (mL/min) Decline per Year in I | GFR (mL/min/1.73 m | 2 | ) or Ccr (mL/min) Decline per Year in C | Statistical Significance between Groups |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Rosman (1989) |
[6] | [21] | Ccr 10–60 mL/min n = 248 non-DM |
0.6 g (CKD 3), 0.4 g (CKD 4–5) |
Usual Protein | Ccr−3.36(CKD 3) Ccr−1.92 (CKD 4–5) |
Ccr−3.72 (CKD 3) Ccr−2.40 (CKD 4–5) |
n.s. (CKD 3) ○ (CKD 4) |
|||
| Ihle (1989) |
[7] | [22] | SCr 4–11 mg/dL, n = 64 non-DM |
0.4 g | Usual Protein | Ccr−1.8 mL/min | Ccr−6.0 mL/min | ○ | |||
| Williams (1991) |
[9] | [24] | SCr > 1.70 (Male), > 1.47 (Female) mg/dL, n = 95 12/95 (12.6%) were DKD |
0.6 g | 0.8 g | Ccr−6.72 | Ccr−8.28 | n.s. | |||
| Locatelli (1991) |
[4] | [14] | CKD 3–5, n = 456 non-DM |
0.6 g | 1.0 g | Ccr−1.8 | Ccr−1.0 | n.s. | |||
| Klahr (1994) |
[3] | [13] | GFR 25–55 mL/min/1.73 m | 2 | , n = 585 GFR 13–24 mL/min/1.73 m2, n = 255 3% was DKD |
0.58 g study 1 0.28 g + keto acid study 2 |
1.3 g study 1 0.58 g study 2 |
−3.6 −3.6 |
−4.0 −4.4 |
n.s. n.s. |
|
| Malvy (1999) |
[11] | [26] | GFR < 20, n = 50 non-DM |
0.3 g + keto acid | 0.65 g | −3.26 | −2.89 | n.s. | |||
| Prakash (2004) |
[13] | [28] | Ccr 20–50 mL/min, n = 34 20/34 (58.8%) were DKD |
0.3 g + keto acid | 0.6 g + placebo | −2.0 | −8.1 | ○ | |||
| Mircescu (2007) |
[15] | [30] | CKD 4–5, n = 53 non-DM |
0.3 g + keto acids | 0.6 g | −3.1 | −4.9 | n.a. | |||
| Cianciaruso (2009) |
[16] | [31] | CKD 4–5, n = 423 12% was DKD |
0.55 g | 0.80 g | −2.28 | −2.16 | n.s. | |||
| Garneata (2016) |
[20] | [35] | CKD 4–5, n = 207 non-DM |
0.3–0.4 g + keto acids + vegetarian | 0.6 g | −2.9 | −7.1 | ○ |
The KDIGO 2020 recommends low-protein diets with 0.8 g/kg and 1.0–1.2 g/kg of protein for diabetic patients with CKD and dialysis patients, respectively [23]. This systematic review consisting of 11 articles was used as a rationale for these recommendations. However, the certainties of the evidence for all-cause mortality and end-stage kidney disease were low, and those for doubling of serum creatinine levels and changes in eGFR were very low.
Among the seven studies, four stated that low-protein diets were statistically significantly effective in reducing proteinuria or the albumin excretion rate [24][25][26][27]. Of these, two studies that reported heterogeneity revealed extremely high heterogeneity (87.0% [26] and 90.0% [27]). That is, low-protein diets have not been proven to have unequivocal effects on reducing proteinuria or the albumin excretion rate.
3. Considering the Safety of Low-Protein Diets
With the exclusion of studies consisting solely of rapid decliners, none of the above-mentioned studies indicated the renal protective effects of low-protein diets. Moreover, Locatelli et al. [4] and Valazquez et al. [28] reported that the hyperfiltration theory was not valid in terms of protein intake. Several studies may indicate statistically significant differences. However, it is clear from a clinical perspective that the effectiveness of low-protein diets remains unproven. In fact, a case report found that patient education on low-carbohydrate and high-protein diets (a carbohydrate intake of 80–90 g/day with protein accounting for 30% of the total energy intake) helped protect renal function [29]. Furthermore, one randomized controlled study reported that a low-carbohydrate, high-protein diet with low-iron and polyphenol-rich foods improved renal and overall survival than a low-protein diet [30]. Thus, clinicians should always take into consideration the overall renal status of patients prior to recommending diet restrictions without rigorous clinical validation.
Furthermore, Robertson et al. [31] reported that there was no data on the effects of low-protein diet on health-related quality of life and costs. Further study evaluating quality-adjusted life-years associated with low-protein diet is required prior to its recommendation.
The KDIGO 2020 recommends low-protein diets with 0.8 g/kg and 1.0–1.2 g/kg of protein for diabetic patients with CKD and dialysis patients, respectively [5]. This systematic review consisting of 11 articles was used as a rationale for these recommendations. However, the certainties of the evidence for all-cause mortality and end-stage kidney disease were low, and those for doubling of serum creatinine levels and changes in eGFR were very low.
Among the seven studies, four stated that low-protein diets were statistically significantly effective in reducing proteinuria or the albumin excretion rate [49,53,56,57]. Of these, two studies that reported heterogeneity revealed extremely high heterogeneity (87.0% [56] and 90.0% [57]). That is, low-protein diets have not been proven to have unequivocal effects on reducing proteinuria or the albumin excretion rate.
3. Considering the Safety of Low-Protein Diets
With the exclusion of studies consisting solely of rapid decliners, none of the above-mentioned studies indicated the renal protective effects of low-protein diets. Moreover, Locatelli et al. [14] and Valazquez et al. [58] reported that the hyperfiltration theory was not valid in terms of protein intake. Several studies may indicate statistically significant differences. However, it is clear from a clinical perspective that the effectiveness of low-protein diets remains unproven. In fact, a case report found that patient education on low-carbohydrate and high-protein diets (a carbohydrate intake of 80–90 g/day with protein accounting for 30% of the total energy intake) helped protect renal function [59]. Furthermore, one randomized controlled study reported that a low-carbohydrate, high-protein diet with low-iron and polyphenol-rich foods improved renal and overall survival than a low-protein diet [60]. Thus, clinicians should always take into consideration the overall renal status of patients prior to recommending diet restrictions without rigorous clinical validation.
Furthermore, Robertson et al. [52] reported that there was no data on the effects of low-protein diet on health-related quality of life and costs. Further study evaluating quality-adjusted life-years associated with low-protein diet is required prior to its recommendation.
