Improving Outcomes Requires Understanding the Problem

The initiation of maintenance hemodialysis in patients with kidney failure prevents imminent death and alleviates uremic symptoms, reversing uremic coma; improving appetite; and reducing dysgeusia, nausea, and vomiting. However, despite advancements in dialysis technology and general medical care, the survival and quality of life for patients on dialysis remain poor. Even with optimal care, the current 5-year survival rate on hemodialysis is only 41%, without significant improvement over the past decade.1 Furthermore, most patients on hemodialysis experience a persistent decline in physical function, mental health, and quality of life.2 Although the dysregulation of solutes typically handled by the kidneys is considered the hallmark of uremia, the full scope of this dysregulation remains uncharted, limiting innovations in dialysis care. It is well recognized that dialysis cannot replicate all the biological functions of the kidneys. Although it provides some solute clearance like the native kidney, other iatrogenic aspects of dialysis are less well understood. First, the dialysis filter's clearance is nonselective compared with the kidneys' highly selective solute handling, which involves tubular secretion of toxins and waste products and reabsorption of essential substances. Nonselective removal by dialysis can lead to deficiencies in micronutrients (e.g., vitamins, trace elements, amino acids), often requiring supplementation. Second, dialysis may introduce substances into the bloodstream by backfiltration of contaminants from the dialysate or leaching of chemicals from the dialysis circuit. The stringent quality standards for preparing ultrapure dialysate are aimed at reducing the backfiltration risk from microbial toxins, but do not mitigate potential risk from prolonged exposure to synthetic compounds. Emerging evidence suggests that microplastics, nanoplastics, and plastic additives (e.g., plasticizers) may accumulate in the body and are associated with cardiovascular risks.3,4 Hemodialysis treatments may introduce these substances into a patient's bloodstream.5 Finally, dialysis may activate inflammatory responses due to interactions with the dialysate and dialyzer. Despite these concerns, the complete extent of endogenous and iatrogenic solute dysregulation in patients on hemodialysis remains insufficiently studied. How can we better characterize solute dysregulation in ESKD? Traditionally, research has focused on identifying individual substances with known toxicities and assessing their associations with outcomes in ESKD. However, untargeted metabolomics offers a broader approach, enabling the analysis of hundreds of known metabolites and thousands of unidentified peaks, some of which may represent uremic solutes. In the February issue of Kidney360, Suba et al. used untargeted metabolomics to investigate a new solute potentially contributing to adverse outcomes in patients on dialysis.6 They analyzed metabolomics data from a prior study comparing patients on dialysis with healthy controls. Of the 195 metabolites found at lower levels in patients on dialysis, 13 were reduced by at least 70%, including ergothioneine, which was 88% lower. Ergothioneine, a diet-derived histidine derivative synthesized by microbes and fungi, is an antioxidant that is robustly absorbed in the gut, reabsorbed in the proximal tubule, and concentrated in tissues prone to oxidative stress, such as erythrocytes. To explore ergothioneine further, the authors developed an assay and measured ergothioneine levels in three cohorts: individuals without CKD (n=12), those with advanced CKD (eGFR <30 ml/min per 1.73 m2; n=12), and those with ESKD on hemodialysis (n=11). Key findings included a four-fold reduction of ergothioneine levels in erythrocytes and a two-fold reduction in plasma in the CKD group compared with controls, and a thirteen-fold and five-fold reduction, respectively, in the ESKD group. Advanced CKD and non-CKD groups showed similar renal tubular reabsorption, with urinary excretion of <0.1 mg/d. Hemodialysis removed approximately 0.8 mg/d of ergothioneine, close to the estimated daily intake of 1.1 mg/d. Together, these cross-sectional snapshots suggest that patients with advanced CKD may be depleted of ergothioneine before dialysis initiation and that the nonselective dialysis removal of ergothioneine perpetuates and worsens the deficiency. The study was not designed to determine why patients with CKD had ergothioneine depletion, although the authors suggest that reduced dietary intake or altered gut absorption may play a role. The lack of prospective data also limits conclusions about the clinical effect of ergothioneine deficiency in CKD and further ergothioneine depletion in ESKD with dialysis initiation. Nevertheless, the authors must be congratulated on a thorough and systematic approach to continuing work on uremic solute dysregulation with patient recruitment, rigorous laboratory methods, and meticulous clearance studies. We concur with the authors' call for further research to evaluate the clinical consequences of ergothioneine depletion, potentially through observational cohorts or randomized trials of ergothioneine supplementation. Oxidative stress, a known contributor to poor outcomes in CKD, has been targeted in past trials, such as the Homocysteinemia in Kidney and End Stage Renal Disease study, which aimed to reduce oxidative stress by homocysteine lowering, but failed to improve survival in ESKD.7 An ergothioneine repletion trial could revisit the oxidative stress hypothesis. This work highlights the critical need for a deeper understanding of solute dysregulation in hemodialysis because true scientific breakthroughs in improving care are unlikely without it. Mechanistic studies of uremia, such as this one, remain rare but are indispensable for advancing patient outcomes. Leveraging modern laboratory techniques, artificial intelligence, and high-throughput screening, alongside the scaling up of dialysis solute kinetic research demonstrated here, could pave the way for novel therapeutics in ESKD. We must reject the complacency that accepts the current dialysis morbidity and mortality rates as normal and continue to seek transformative innovations in care.