Diabetic Kidney Disease Protein Restriction: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Endocrinology & Metabolism
Contributor:
Satoru Yamada

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.

 

 

This entry is adapted from the peer-reviewed paper 10.3390/diabetology2020005

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.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Feedback