Diabetic Kidney Disease Protein Restriction
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.
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.  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)  both recommend low-protein diets for CKD. Kalantar-Zadeh et al.  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.  stated, “It is possible, though not yet unequivocally proved, that nutritional interventions slow disease progression,” and the KDIGO 2020  stated that “the certainty of the evidence” is “low” or “very low.”
2. Effectiveness and Safety of Low-Protein Diets
Kalantar-Zadeh et al.  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  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. Recommended daily protein intake in a review article by Kalantar-Zadeh et al.’s paper.
|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 m2)||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 , 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.  and Teplan et al. , who examined the renal protective effects of high-energy diets and supplements such as erythropoietin (EPO) and keto acids. Lindenau et al.’s study  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 . 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. Abstracts of ten articles selected from Kalantar-Zadeh et al.’s paper that evaluated the renal protective effect of protein restriction intervention.
|Reference Numbers||Patients||Intervention (I) (Daily Protein Intake)||Comparison (C)||GFR (mL/min/1.73 m2) or Ccr (mL/min) Decline per Year in I||GFR (mL/min/1.73 m2) or Ccr (mL/min) Decline per Year in C||Statistical Significance between Groups|
|||Ccr 10–60 mL/min
n = 248
|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)
|||SCr 4–11 mg/dL, n = 64
|0.4 g||Usual Protein||Ccr−1.8 mL/min||Ccr−6.0 mL/min||○|
|||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.|
|||CKD 3–5, n = 456
|0.6 g||1.0 g||Ccr−1.8||Ccr−1.0||n.s.|
|||GFR 25–55 mL/min/1.73 m2, 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
|||GFR < 20,
n = 50
|0.3 g + keto acid||0.65 g||−3.26||−2.89||n.s.|
|||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||○|
n = 53
|0.3 g + keto acids||0.6 g||−3.1||−4.9||n.a.|
|||CKD 4–5, n = 423
12% was DKD
|0.55 g||0.80 g||−2.28||−2.16||n.s.|
|||CKD 4–5, n = 207
|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 . 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 . Of these, two studies that reported heterogeneity revealed extremely high heterogeneity (87.0%  and 90.0% ). 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.  and Valazquez et al.  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 . 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 . 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.  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 entry is from 10.3390/diabetology2020005
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