Evaluation of the Effect of a Daily Dose of Wakame Seaweed on Reducing Circulating Concentrations of Advanced Glycation End Products in Patients With Stage III Chronic Kidney Disease

Persistent glomerular hyperfiltration is a characteristic feature of the early stages of chronic kidney disease (CKD), particularly observed in the initial phases of diabetic nephropathy, and constitutes a major factor in the progression of kidney failure. In this context, the benefit of low-protein diets (less than 0.8g/kg/day) in slowing CKD progression has been demonstrated, though the underlying pathophysiological explanation remains unclear.

Among the proposed mechanisms, a study demonstrated that an oral protein load (cooked red meat) led to a significant 26% increase in glomerular filtration rate, measured by inulin clearance, in healthy subjects 90 minutes after ingestion. This protein-induced glomerular hyperfiltration is used to assess renal functional reserve, defined as the kidney's ability to increase renal blood flow and GFR after a protein load, via modulation of intrarenal hemodynamics.

The precise mechanisms underlying these hemodynamic and functional changes remain controversial. A study suggested that the renal hemodynamic effects of a protein load are primarily related to the amount of Advanced Glycation End Products (AGEs) ingested. Indeed, the experimental models used to study renal functional reserve (e.g., amino acid perfusions, red meat meals) also involved significant AGE exposure.

AGEs are formed through non-enzymatic glycation reactions, where sugars bind to peptides or nucleic acids, leading to cellular aging via increased ROS (Reactive Oxygen Species) production and activation of inflammatory pathways. Methylglyoxal (MG) and Carboxymethyl-lysine (CML), two major circulating and tissue AGEs, are predominantly cleared by the kidneys and accumulate with age.

While it was previously thought that AGEs were primarily endogenously produced, it is now well established that dietary intake is a significant source, especially via harmful cooking methods (high-temperature cooking with oil and little water), both in healthy individuals and those with CKD. An oral AGE load has been shown to significantly increase circulating CML levels within 90 minutes.

In a pilot human study, it has been demonstrated that an oral protein load rich in AGEs led to greater mobilization of renal functional reserve (increased renal blood flow and renal oxidative metabolism) compared to an iso-protein, low-AGE load. This finding supports a key role for AGE content and protein quality, beyond quantity alone, in the nephroprotective effects of low-protein diets.

In animal models, aged mice fed an AGE-rich diet developed chronic kidney disease with glomerular and tubular damage. In humans, dietary AGE intake contributes to inter-individual variation in CKD progression. Reducing dietary AGE intake has been shown to decrease plasma and peritoneal dialysis AGE levels in non-diabetic dialysis patients. Additionally, two months of treatment with sevelamer, a phosphate binder, in patients with diabetic nephropathy (stages II to IV) led to a significant reduction in MG and CML, HbA1c, and markers of inflammation and oxidative stress, while increasing levels of the AGE receptor AGER1. However, this approach involves adding another medication to patients already under high therapeutic pressure, with associated risks of poor adherence.

Seaweed consumption is an ancestral practice in Asia, where life expectancy is generally higher than in Western countries. Regular seaweed consumption may partly explain this longevity. Brown seaweeds are exceptionally rich in fiber, phlorotannins, carotenoids, trace elements (copper, chromium, zinc, selenium, manganese, iron), and vitamins (C, B1, B2, B6, B12). Recent studies have shown that the seaweed Ishige okamurae, native to Okinawa, exhibits anti-AGE properties. The phlorotannin diphlorethohydroxycarmalol (DPHC) from Ishige okamurae has been shown to prevent diabetic nephropathy in mouse mesangial cells by inhibiting AGE-RAGE interactions.

The seaweed Undaria pinnatifida (Up), commonly known as wakame in Japan, has been present along the French Atlantic coast since the 1970s, having been introduced from Asia. Low-temperature dehydration (40°C), in line with traditional Asian methods, helps preserve its biological properties.

Wakame has demonstrated various biological activities, including ACE (angiotensin-converting enzyme) inhibition. A daily intake of 5g over 8 weeks resulted in a 10 mmHg reduction in blood pressure in both Japanese and non-Japanese hypertensive individuals. Wakame also improves postprandial glycemic control in both humans and rats via PPAR activation and improved GLUT4 membrane translocation in myocytes. Fucoxanthin, found in high concentrations in wakame, has recently been shown to possess potent anti-AGE activity.

Wakame also has a pleasant umami and iodine-rich taste with a texture appreciated by chefs, making it a more appealing option for daily use among patients already facing heavy therapeutic burdens.

Dietary changes are essential in nephroprotection, but they are difficult to implement, underlining the importance of developing strategies that are practical, acceptable, and sustainable for patients.

A Michelin-starred chef, known for his regular use of seaweed in cuisine, is the project sponsor and has validated a set of tailored recipes that will be provided to participants to accompany daily wakame supplementation. Some of these recipes are presented in the appendix of the protocol.

To investigator's knowledge, no study has yet evaluated the impact of daily wakame intake on the reduction of circulating AGE concentrations or on nephroprotection.

Thje investigator's hypothesis is that a daily dose of 5g of wakame (equivalent to the average daily intake in Japan) could reduce circulating AGE concentrations (specifically methylglyoxal). Lowering AGE levels beyond that achieved by protein restriction alone could offer additional protection against CKD progression.

Inclusion criteria

• Adult patients not under legal protection
• Patients aged ≥ 18 and < 90 years
• Patients with stage IIIA-B chronic kidney disease (CKD) (estimated GFR by CKD-EPI ≥ 30 mL/min and < 60 mL/min)
• Patients receiving optimized nephroprotective treatment (ACE inhibitors, SGLT2 inhibitors)
• Patients who have signed the informed consent form
• Patients not participating in another clinical study
• Patients affiliated with or benefiting from a social security scheme

Exclusion criteria

• Adult patients under legal protection
• Patients under 18 years old or over 90 years old
• Patients with uncontrolled thyroid disorders
• Patients with decompensated heart failure
• Patients consuming other dietary supplements containing seaweed or iodine (e.g., multivitamins)
• Pregnant or breastfeeding women
• Patients with acute kidney injury
• Patients who decline to participate in the study