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Yamada, S. Diabetic Kidney Disease Protein Restriction. Encyclopedia. Available online: https://encyclopedia.pub/entry/9251 (accessed on 19 April 2024).
Yamada S. Diabetic Kidney Disease Protein Restriction. Encyclopedia. Available at: https://encyclopedia.pub/entry/9251. Accessed April 19, 2024.
Yamada, Satoru. "Diabetic Kidney Disease Protein Restriction" Encyclopedia, https://encyclopedia.pub/entry/9251 (accessed April 19, 2024).
Yamada, S. (2021, May 01). Diabetic Kidney Disease Protein Restriction. In Encyclopedia. https://encyclopedia.pub/entry/9251
Yamada, Satoru. "Diabetic Kidney Disease Protein Restriction." Encyclopedia. Web. 01 May, 2021.
Diabetic Kidney Disease Protein Restriction
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This entry is adapted from the peer-reviewed paper 10.3390/diabetology2020005

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. 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        
CKD, chronic kidney disease; PEW, protein-energy wasting; HBV, high biologic value; EAA, essential amino acids; KA, ketoacids. Reprinted with permission from ref. [1]. Copyright 2017 Massachusetts Medical Society.

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.

Table 3. Abstracts of ten articles selected from Kalantar-Zadeh et al.’s paper that evaluated the renal protective effect of protein restriction intervention.

First Author
(Year Published)		 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
Rosman
(1989)		 [6] 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] 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] 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] CKD 3–5, n = 456
non-DM		 0.6 g 1.0 g Ccr−1.8 Ccr−1.0 n.s.
Klahr
(1994)		 [3] 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		 −3.6
−3.6		 −4.0
−4.4		 n.s.
n.s.
Malvy
(1999)		 [11] GFR < 20,
n = 50
non-DM		 0.3 g + keto acid 0.65 g −3.26 −2.89 n.s.
Prakash
(2004)		 [13] 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] CKD 4–5,
n = 53
non-DM		 0.3 g + keto acids 0.6 g −3.1 −4.9 n.a.
Cianciaruso
(2009)		 [16] CKD 4–5, n = 423
12% was DKD		 0.55 g 0.80 g −2.28 −2.16 n.s.
Garneata
(2016)		 [20] CKD 4–5, n = 207
non-DM		 0.3–0.4 g + keto acids + vegetarian 0.6 g −2.9 −7.1 ○
Abbreviations: Ccr, creatinine clearance; Cr, creatinine; SCr, serum creatinine; GFR, glomerular filtration rate; CKD, chronic kidney disease; EPO, erythropoietin; PD, peritoneal dialysis; ESRD, end-stage renal disease; HD, hemodialysis; CRF, chronic renal failure; n.a., not available; n.s., not significant. ○ indicates that intervention was statistically superior to control. Adapted with permission from ref. [1]. Copyright 2017 Massachusetts Medical Society.

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.

 

 

References

  1. Kalantar-Zadeh, K.; Fouque, D. Nutritional management of chronic kidney disease. N. Engl. J. Med. 2017, 377, 1765–1776.
  2. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020, 98, S1–S115.
  3. Klahr, S.; Levey, A.S.; Beck, G.J.; Gaggiula, A.W.; Hunsicker, L.; Kusek, J.W.; Striker, G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N. Engl. J. Med. 1994, 330, 877–884.
  4. Locatelli, F.; Alberti, D.; Graziani, G.; Buccianti, G.; Redaelli, B.; Giangrande, A. Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Lancet 1991, 337, 1299–1304.
  5. Rosman, J.B.; ter Wee, P.M.; Meijer, S.; Piers-Becht, T.P.; Sluiter, W.J.; Donker, A.J. Prospective randomised trial of early dietary protein restriction in chronic renal failure. Lancet 1984, 2, 1291–1296.
  6. Rosman, J.B.; Langer, K.; Brandl, M.; Piers-Becht, T.P.; van der Hem, G.K.; ter Wee, P.M.; Donker, A.J. Protein-restricted diets in chronic renal failure: A four year follow-up shows limited indications. Kidney Int. Suppl. 1989, 27, S96–S102.
  7. Ihle, B.U.; Becker, G.J.; Whitworth, J.A.; Charlwood, R.A.; Kincaid-Smith, P.S. The effect of protein restriction on the progression of renal insufficiency. N. Engl. J. Med. 1989, 321, 1773–1777.
  8. Lindenau, K.; Abendroth, K.; Kokot, F.; Vetter, K.; Rehse, C.; Fröhling, P.T. Therapeutic effect of keto acids on renal osteodystrophy. A prospective controlled study. Nephron 1990, 55, 133–135.
  9. Williams, P.S.; Stevens, M.E.; Fass, G.; Irons, L.; Bone, J.M. Failure of dietary protein and phosphate restriction to retard the rate of progression of chronic renal failure: A prospective, randomized, controlled trial. Q. J. Med. 1991, 81, 837–855.
  10. Montes-Delgado, R.; Guerrero Riscos, M.A.; García-Luna, P.P.; Martín Herrera, C.; Pereira Cunill, J.L.; Garrido Vázquez, M.; López Muñoz, I.; Suárez García, M.J.; Martín-Espejo, J.L.; Soler Junco, M.L. Tratamiento con dieta hipoproteica y suplementos calóricos en pacientes con insuficiencia renal crónica en prediálisis. Estudio comparativo [Treatment with low-protein diet and caloric supplements in patients with chronic kidney failure in predialysis. Comparative study]. Rev. Clin. Esp. 1998, 198, 580–586. (In Spanish)
  11. Malvy, D.; Maingourd, C.; Pengloan, J.; Bagros, P.; Nivet, H. Effects of severe protein restriction with ketoanalogues in advanced renal failure. J. Am. Coll. Nutr. 1999, 18, 481–486.
  12. Teplan, V.; Schück, O.; Knotek, A.; Hajný, J.; Horácková, M.; Skibová, J.; Malý, J. Effects of low-protein diet supplemented with ketoacids and erythropoietin in chronic renal failure: A long-term metabolic study. Ann. Transplant. 2001, 6, 47–53.
  13. Prakash, S.; Pande, D.P.; Sharma, S.; Sharma, D.; Bal, C.S.; Kulkarni, H. Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure. J. Ren. Nutr. 2004, 14, 89–96.
  14. Brunori, G.; Viola, B.F.; Parrinello, G.; De Biase, V.; Como, G.; Franco, V.; Garibotto, G.; Zubani, R.; Cancarini, G.C. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: A prospective randomized multicenter controlled study. Am. J. Kidney Dis. 2007, 49, 569–580.
  15. Mircescu, G.; Gârneaţă, L.; Stancu, S.H.; Căpuşă, C. Effects of a supplemented hypoproteic diet in chronic kidney disease. J. Ren. Nutr. 2007, 17, 179–188.
  16. Cianciaruso, B.; Pota, A.; Bellizzi, V.; Di Giuseppe, D.; Di Micco, L.; Minutolo, R.; Pisani, A.; Sabbatini, M.; Ravani, P. Effect of a low- versus moderate-protein diet on progression of CKD: Follow-up of a randomized controlled trial. Am. J. Kidney Dis. 2009, 54, 1052–1061.
  17. Di Iorio, B.R.; Cucciniello, E.; Martino, R.; Frallicciardi, A.; Tortoriello, R.; Struzziero, G. Acuto e persistente effetto antiproteinurico della dieta ipoproteica artificiale nella malattia renale cronica [Acute and persistent antiproteinuric effect of a low-protein diet in chronic kidney disease]. G. Ital. Nefrol. 2009, 26, 608–615. (In Italian)
  18. Jiang, N.; Qian, J.; Sun, W.; Lin, A.; Cao, L.; Wang, Q.; Ni, Z.; Wan, Y.; Linholm, B.; Axelsson, J.; et al. Better preservation of residual renal function in peritoneal dialysis patients treated with a low-protein diet supplemented with keto acids: A prospective, randomized trial. Nephrol. Dial. Transplant. 2009, 24, 2551–2558.
  19. Jiang, N.; Qian, J.; Lin, A.; Fang, W.; Zhang, W.; Cao, L.; Wang, Q.; Ni, Z.; Yao, Q. Low-protein diet supplemented with keto acids is associated with suppression of small-solute peritoneal transport rate in peritoneal dialysis patients. Int. J. Nephrol. 2011, 2011, 542704.
  20. Garneata, L.; Stancu, A.; Dragomir, D.; Stefan, G.; Mircescu, G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J. Am. Soc. Nephrol. 2016, 27, 2164–2176.
  21. Coresh, J.; Turin, T.C.; Matsushita, K.; Sang, Y.; Ballew, S.H.; Appel, L.J.; Arima, H.; Chadban, S.J.; Cirillo, M.; Djurdjev, O. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA 2014, 311, 2518–2531.
  22. Inker, L.A.; Heerspink, H.J.L.; Tighiouart, H.; Levey, A.S.; Coresh, J.; Gansevoort, R.T.; Simon, A.L.; Ying, J.; Beck, G.J.; Wanner, C. GFR slope as a surrogate end point for kidney disease progression in clinical trials: A meta-analysis of treatment effects of randomized controlled trials. J. Am. Soc. Nephrol. 2019, 30, 1735–1745.
  23. Evert, A.B.; Dennison, M.; Gardner, C.D.; Garvey, W.T.; Lau, K.H.K.; MacLeod, J.; Mitri, J.; Pereira, R.F.; Rawlings, K.; Robinson, S.; et al. Nutrition therapy for adults with diabetes or prediabetes: A consensus report. Diabetes Care 2019, 42, 731–754.
  24. Pedrini, M.T.; Levey, A.S.; Lau, J.; Chalmers, T.C.; Wang, P.H. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis. Ann. Intern. Med. 1996, 124, 627–632.
  25. Pan, Y.; Guo, L.L.; Jin, H.M. Low-protein diet for diabetic nephropathy: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2008, 88, 660–666.
  26. Li, X.F.; Xu, J.; Liu, L.J.; Wang, F.; He, S.L.; Su, Y.; Dong, C.P. Efficacy of low-protein diet in diabetic nephropathy: A meta-analysis of randomized controlled trials. Lipids Health Dis. 2019, 18, 82.
  27. Li, Q.; Wen, F.; Wang, Y.; Li, S.; Lin, S.; Qi, C.; Chen, Z.; Qiu, X.; Zhang, Y.; Zhang, S.; et al. Diabetic kidney disease benefits from intensive low-protein diet: Updated systematic review and meta-analysis. Diabetes Ther. 2020.
  28. Velázquez López, L.; Sil Acosta, M.J.; Goycochea Robles, M.V.; Torres Tamayo, M.; Castañeda Limones, R. Effect of protein restriction diet on renal function and metabolic control in patients with type 2 diabetes: A randomized clinical trial. Nutr. Hosp. 2008, 23, 141–147.
  29. Nielsen, J.V.; Westerlund, P.; Bygren, P. A low-carbohydrate diet may prevent end-stage renal failure in type 2 diabetes. A case report. Nutr. Metab. 2006, 3, 23.
  30. Facchini, F.S.; Saylor, K.L. A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes 2003, 52, 1204–1209.
  31. Robertson, L.; Waugh, N.; Robertson, A. Protein restriction for diabetic renal disease. Cochrane Database Syst. Rev. 2007, 17, CD002181.
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