# Chronic Kidney Disease-Associated Defect in Humoral Immune Response Is Driven by Inflammation

## TL;DR

Chronic kidney disease weakens the immune system's antibody response mainly due to inflammation, not directly from toxins in the blood.

## Contribution

The study identifies systemic inflammation, not uremic toxins, as the main cause of immune dysfunction in CKD patients.

## Key findings

- Indoxyl sulfate does not directly impair T–B cell cooperation in CKD.
- Uremic toxins do not correlate with vaccine-induced antibody levels in CKD patients.
- Systemic inflammation disrupts lymphoid architecture and reduces antibody production in CKD.

## Abstract

Advanced chronic kidney disease (CKD) is associated with impaired humoral immunity, contributing to increased infection-related mortality and suboptimal vaccine responses, as notably observed during the COVID-19 pandemic. CKD is also marked by the accumulation of uremic toxins, but whether they directly influence T and B cell functionality remains unclear. In this translational study, we integrated clinical and biological data from 106 CKD patients with mechanistic insights from in vitro and in vivo murine models to identify the mechanisms underlying CKD-associated defects in humoral responses against T cell-dependent antigens. Contrary to our initial hypothesis, indoxyl sulfate—despite its known ability to activate Aryl hydrocarbon Receptor signaling in monocytes—did not directly impair T–B cell cooperation in coculture assays. Similarly, plasma levels of ten major uremic toxins showed no correlations with vaccine-induced antibody titers in patients. Instead, systemic inflammation emerged as the primary driver of defective humoral immunity. Murine models further confirmed that inflammation, rather than uremia alone, induces lymphopenia, disrupts lymphoid architecture, and ultimately impairs antibody production. These findings indicate that CKD-associated inflammation, rather than a direct effect of uremic toxins on adaptive immune effectors, underlies humoral immune dysfunction in CKD. Targeting inflammation may, therefore, offer a promising strategy to improve vaccine efficacy and reduce infection-related complications in this vulnerable population.