Symposium 4.6 – New nutritional targets in CKD

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

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Are low or very low-protein diets still useful and attractive treatment in CKD?

Denis Fouque, France

The nutritional status of patients with chronic kidney disease (CKD) is generally compromised and requires adjustments of dietary protein, energy, and micronutrient intake. High protein intake in CKD patients may lead to increased intraglomerular pressure and glomerular hyperfiltration, causing glomerular injury and aggravating CKD. For this reason, reducing protein intake is recommended in this population.

The latest update of the KDOQI Clinical Practice Guideline for Nutrition in CKD (2020) recommends a low protein diet of 0.55–0.60 g/kg/day or a very low-protein diet providing 0.28–0.43 g/kg/day with additional keto acid/amino acid analogues to meet protein requirements in all CKD patients not on dialysis and without diabetes. In adults with CKD stages 3-5 and diabetes, it is reasonable to prescribe, under close clinical supervision, a dietary protein intake of 0.6-0.8 g/kg/day to maintain a stable nutritional status and optimize glycaemic control.

Figure 1. Beneficial effects of an optimal renal diet at different CKD stages (Fouque et al., NDT 2020)

A very low protein diet is both effective and safe in CKD patients. The lower the baseline dietary protein intake, the slower the progression toward end-stage kidney disease (ESKD) and better survival. For instance, a Cochrane systematic review of 17 studies involving 2996 CKD patients found that very low protein intake reduced the risk of CKD progression to ESKD by 36% compared with low or normal protein intakes. Side effects of very low protein diets such as weight loss, protein-energy wasting, and malnutrition are uncommon. Such a diet can also improve the quality of life (QoL) in CKD patients. One study found that the protein-restricted group of CKD patients had significantly higher QoL scores for general health and physical status compared with the maintenance dialysis group.

The clinical benefits of low protein diets include better digestion, postprandial lightness, less constipation, less salt intake, better sleep quality, less need for drugs (e.g. antihypertensives, phosphate binders, bicarbonates of calcium supplements) and reduced risk of associated side effects, better QoL by postponing dialysis, allowing better preparation/maturation of vascular access and allowing transplant preparation and pre-emptive transplantation. Biological benefits of protein-controlled diets include correction of metabolic acidosis and regulation of calcium and phosphates metabolism.

Protein-controlled diets should be considered as a precision medicine delivery with an emphasis on personalized approaches to CKD management. Patients’ preference and acceptance, engagement, adherence, and compliance to the prescribed dietary therapy are important factors, which may influence the responses and outcomes to the prescribed LPD.

Ketogenic diet: a new tool to improve renal cyst growth in ADPKD

Thomas Weimbs, United States of America

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease characterized by slowly progressive cyst growth in both kidneys, which leads to deterioration of renal function, necessitating dialysis or kidney transplantation. The only approved treatment with tolvaptan has only modest effects and is too expensive. Recent findings suggest that dietary interventions that induce a state of ketosis are very promising in both preventing ADPKD and inhibiting its progression. ADPKD cysts derived from tubule epithelial cells exhibit changes in proliferation, metabolism, and high mTOR activity, which may be related to recently observed changes in the energy metabolism of renal cysts characterized by increased glycolysis and mitochondrial abnormalities, decreased oxidative phosphorylation, and defective fatty acid oxidation similar to the Warburg effect in cancer.

Previously, two separate studies reported a surprising observation that even a mild reduction in food intake (of just 20-40%) had a profound inhibitory effect on ADPKD progression in a mouse model. A recent study by Weimbs et al. analysed the effects of various dietary interventions on PKD progression in animal models. They reported that PKD rats that were kept on a time-restricted feeding regimen, i.e. intermittent fasting, showed improved kidney function and reduced cystogenesis, cyst expansion, and fibrosis compared with a control group that consumed a similar amount of calories but were fed ad libitum. In addition, oral administration of the ketone b-hydroxybutyrate (BHB) for 5 weeks strongly inhibited PKD progression. These findings corroborate previous clinical observations that patients with hyperglycaemia and type 2 diabetes and/or obese or overweight individuals have a faster progression of ADPKD.

Figure 2. BHB ketone effectively inhibits fibrosis in the ADPKD model of mice (Torres et al., Cell Metab. 2019)

A recent retrospective case series study that surveyed 131 ADPKD patients who have experimented or are currently on a ketogenic diet showed that their overall health and well-being improved in 86% of them, whereas 67% of them reported that their major health issues related to ADPKD were reduced. Almost every single patient-reported improvement in blood pressure control and about 2/3 of patients even reported eGFR improvement. Ninety-two percent of the patients considered the ketogenic diet feasible and 83% of them would recommend it to everyone with ADPKD.

The ongoing KETO-ADPKD Feasibility Clinical trial is examining the safety, efficacy, feasibility and optimal dietary approach of the ketogenic diet in 63 ADPKD patients and the first results are expected in fall 2022.

Role of kidney proximal tubules to balance nutrient and uremic toxins levels

Rosalinde Masereeuw, Netherlands

The human gut is inhabited by a complex and metabolically active microbial ecosystem which is involved in a significant cross-talk between the human metabolism. Metabolites unique to microbial metabolism enrich the human metabolome, thereby providing energy, vitamins, and trophic signals. However, not every microbial metabolite is beneficial. On the contrary, most of them undergo intense phase II metabolism, and numerous metabolites are actively excreted from the body through the kidneys. Hence, the kidney excretory capacity is an essential part of the human microbial symbiosis. Several microbiota-derived metabolites, including Indoxyl sulfate (IS), p-Cresyl Sulfate (pCS) and Trimethylamine N-oxide (TMAO)were found to accumulate in the blood parallel to the loss of kidney function, and proven to be associated with clinical outcomes in patients with CKD. This paradigm has been coined the gut−kidney axis.

Remote metabolite sensing and signalling is a mechanism to minimize perturbations of body homeostasis due to environmental metabolic challenges. Membrane transporters such as the organic anion transporters (OATs) are thought to be involved in metabolite sensing and are widely expressed in epithelial barriers, including the kidney proximal tubule segment. Jansen et al. found that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through epidermal growth factor receptors (EGFR) and downstream signalling to induce their secretion by up-regulating OAT1. This was especially triggered after prolonged high-protein intake. Remote metabolite sensing and signalling were observed in kidneys from healthy volunteers and rats in vivo, promoting OAT1 expression and increased removal of IS. Using 2D and 3D human proximal tubule cell models, researchers also showed that IS induces OAT1 via aryl-hydrocarbon receptor (AhR) and EGFR signalling, controlled by miR-223. Furthermore, it was found that concomitantly produced reactive oxygen species control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling.

Figure 3. Remote sensing and signaling by indoxyl sulfate (Jansen et al., PNAS 2019)

Remote metabolite sensing and signaling is an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion. Future studies should further characterize the gut metabolome in CKD.

Further reading

Ikizler TA, Burrowes JD, Byham-Gray LD, et al. KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update [published correction appears in Am J Kidney Dis. 2021;77(2):308]. Am J Kidney Dis. 2020;76(3 Suppl 1):S1-S107. doi:10.1053/j.ajkd.2020.05.006

Hahn D, Hodson EM, Fouque D. Low protein diets for non-diabetic adults with chronic kidney disease. Cochrane Database Syst Rev. 2018;10(10):CD001892. Published 2018 Oct 4. doi:10.1002/14651858.CD001892.pub4

Fouque D, Ikizler TA. Editorial: Implementing low protein diets in clinical practice in patients with chronic kidney disease. Nephrol Dial Transplant. 2020;35(10):1643-1645. doi:10.1093/ndt/gfaa242

Torres JA, Kruger SL, Broderick C, et al. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab. 2019;30(6):1007-1023.e5. doi:10.1016/j.cmet.2019.09.012

Jansen J, Jansen K, Neven E, et al. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion. Proc Natl Acad Sci U S A. 2019;116(32):16105-16110. doi:10.1073/pnas.1821809116

Nigam SK, Bush KT, Bhatnagar V, Poloyac SM, Momper JD. The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology. Clin Pharmacol Ther. 2020;108(1):40-53. doi:10.1002/cpt.1818