PRESENTED BY
GIACOMO GARIBOTTO

Presentation Summary

Written by: Milica Maksimovic
Reviewed by: Giacomo Garibotto

There are still several unaddressed questions in dietary treatment of chronic kidney disease (CKD). The major one is our still incomplete knowledge of the response of muscle protein metabolism to low-protein diets low in uraemic setting. A compromised ability to activate these responses could impair nitrogen conservation and favour wasting. In patients with CKD, the whole-body protein turnover response on a low-protein diet (LPD) is characterised by a decrease in amino acid oxidation and a slight (10-15%) decline in protein degradation [1,2].  The effects of LPD on muscle protein metabolism still need to be explored.

In healthy humans, body proteins are preserved at very different protein intakes. Whether there is a 0.8 g/kg or 1.5 g/kg protein intake, there is no change in muscle composition as our body has a high capacity for protein turnover, with rates three to four-fold greater than protein ingested with a diet. The nitrogen balance is maintained through extensive reutilisation of amino acids (60-65% re-synthesised) released from protein degradation.

In case of a decreased dietary protein (e.g. 45 g), the body adapts so that there is a decrease in protein degradation, but protein synthesis is maintained. On this way, the bodyweight and composition remain stable. On the other hand, if the protein intake is even less than 45 g (i.e. beyond the limits of the adaptive mechanisms), not only that there is a decrease in protein degradation but also a decrease in protein synthesis, which results in malnutrition and protein loss. Therefore, the concept of “accommodation” with inadequate protein intake and development of wasting is clearly distinguished from the concept of “adaptation” to low protein intakes. It has been shown that high-protein intakes cause insulin resistance at insulin receptor level, leading to an increase in protein degradation[3]. In contrast, in LPD, animal studies confirm up-regulated muscle intracellular insulin signalling, resulting in a lower protein degradation [4,5].

In young humans, adaptation to a LPD (0.4 g/kg/day) does not result in a more negative whole-body protein balance and does not lower basal muscle protein synthesis rates when compared to a high-protein intake (2.4 g/kg/d)[6]. In contrast to the young subjects, who can thus adapt to a very LPD for a short period without changes in protein synthesis, elderly women on marginal protein intake (0.45 g/kg/day) accommodate to a LPD with losses of body cell mass and muscle function[7]. In the elderly, a higher protein intake of at least 1 g/kg of protein is in general needed, as outlined by the recent Guidelines.

Muscle protein turnover in CKD patients

Overall, in CKD patients with normal acid-base status, the whole body and muscle protein breakdown is maintained [8]. There is a normal sensitivity of whole body amino acid metabolism to high insulin levels. Certain subtle defects are present, such as defective myosin synthesis, but myostatin is preserved in these cases[9,10]. On the other hand, in maintenance haemodialysis patients, systemic inflammation is associated with exaggerated skeletal muscle protein catabolism [11].

It is not yet known how skeletal muscle protein metabolism adapts to a dietary protein restriction in uraemia.

A recent study [12] measured muscle protein turnover in two CKD patients cohorts given two levels of dietary protein: the more often used LPD providing 0.55 g protein/kg/day, or a VLPD providing 0.45 g protein/kg/day supplemented with 0.1 g/kg of essential amino/ketoacids. In patients with CKD and diets containing 1.1 g/kg protein, 66% of amino acid phenylalanine is recycled into protein synthesis. During the LPD, the aminoacid recycling increases to 76%, indicating greater efficiency of protein turnover. Interestingly, recycling of aminoacids from protein degradation was even higher in the VLPD. During the supplemented VLPD, the amino acids recycling increases to even 83% as opposed to 72% on LPD. This suggests the maximisation of recycling of protein degradation to protein synthesis with VLPD with essential amino/ketoacids. Overall, in patients with CKD, skeletal muscle responds to a LPD via a marked decrease in muscle protein degradation and an increase in the efficiency of muscle protein turnover.

Figure 1. The magnitude of daily protein turnover requires reutilization of amino acids released by protein breakdown for protein synthesis. The turnover rates in CKD patients on LPD (upper panel) and VLPD (lower panel) (slides 36 and 42, [13]).

References

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2. Bernhard J, Beaufrere B, Laville M, Fouque D. . Adaptive response to a low-protein diet in predialysis chronic renal failure patients. . J Am Soc Nephrol. 2001;12(6):1249-1254. DOI: /

3. Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR. . Bidirectional modulation of insulin action by amino acids. . J Clin Invest. 1998;101(7):1519-1529. DOI: 10.1172/jci1326

4. Sakuma K, Yamaguchi A. . Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass. . J Cachexia Sarcopenia Muscle. 2012;3(2):77-94. DOI: 10.1007/s13539-011-0052-4

5. Batistela E, Pereira MP, Siqueira JT, et al. . Decreased rate of protein synthesis, caspase-3 activity, and ubiquitin-proteasome proteolysis in soleus muscles from growing rats fed a low-protein, high-carbohydrate diet. . Can J Physiol Pharmacol. 2014;92(6):445-454. . DOI: 10.1139/cjpp-2013-0290

6. Hursel R, Martens EA, Gonnissen HK, et al. . Prolonged Adaptation to a Low or High Protein Diet Does Not Modulate Basal Muscle Protein Synthesis Rates – A Substudy. . PLoS One. 2015;10(9):e0137183. . DOI: 10.1371/journal.pone.0137183

7. Castaneda C, Charnley JM, Evans WJ, Crim MC. . Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. . Am J Clin Nutr. 1995;62(1):30-39. DOI: 10.1093/ajcn/62.1.30.

8. Garibotto G, Russo R, Sofia A, et al. . Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. . Kidney Int. 1994;45(5):1432-1439. DOI: 10.1038/ki.1994.187

9. dey D, Kumar R, McCarthy JT, Nair KS. . A Reduced synthesis of muscle proteins in chronic renal failure.. Am J Physiol Endocrinol Metab. 2000;278(2):E219-225. DOI: 10.1152/ajpendo.2000.278.2.E219

10. Fouque D, Kalantar-Zadeh K, Kopple J, et al. . A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. . Kidney Int. 2008;73(4):391-8.. DOI: 10.1038/sj.ki.5002585

11. Deger SM, Hung AM, Gamboa JL, et al. . Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients.. JCI Insight. 2017;2(22). . DOI: 10.1172/jci.insight.95185

12. Garibotto G, Sofia A, Parodi EL, et al. . Effects of Low-Protein, and Supplemented Very Low-Protein Diets, on Muscle Protein Turnover in Patients With CKD. . Kidney Int Rep. 2018;3(3):701-710.. DOI: 10.1016/j.ekir.2018.01.003

13. Garibotto G. . Muscle protein turnover and low protein diet in patients with CKD. . Oral presentation at 56th ERA-EDTA Congress; June, 14, 2019; Budapest, Hungary. . https://www.enp-era-edta.org/material/21675/webcast-external

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