Secondary Immunodeficiency Related to Kidney Disease (SIDKD)-Definition, Unmet Need, and Mechanisms

Abstract

Kidney disease is a known risk factor for poor outcomes of COVID-19 and many other serious infections. Conversely, infection is the second most common cause of death in patients with kidney disease. However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiologic, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an imminent unmet medical need that requires rigorous research activities at all levels, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known thus far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia and shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.

Keywords: chronic inflammation; immunodeficiency; infection; kidney disease.

Figure 1.

Factors leading to secondary immmunodeficiency. Multiple factors contribute to SIDKD, including HIV, most forms of chronic organ failure (such as heart, liver, and kidney failure), malnutrition, aging, cancer, dysbiosis, gut disorders, chronic infections (such as tuberculosis), and various immunosuppressive drugs.

Figure 2.

Definition and the path toward SIDKD. (A) Kidney disease, i.e., CKD, is associated with SIDKD by ultimately increasing the susceptibility to infections, as represented by recurrent or severe infections and/or insufficient vaccine responses. Such abnormalities also contribute to defective humoral and cellular immune responses. (B) Primary ID can also cause kidney disease, e.g., genetic complement deficiencies and defects in phagocytosis or lymphocyte apoptosis that may lead to systemic autoimmunity and immune complex GN. In patients with primary ID, systemic or kidney infections and recurrent use of nephrotoxic antimicrobial drugs may trigger kidney disease. Thus, all risk factors contributing to SIDKD are associated with increased susceptibility to infection, impaired vaccine response, and attenuated sterile inflammation.

Figure 3.

Immunophenotype in kidney disease. (A) SIDKD is associated with an abnormal immunophenotype, characterized by chronic inflammation as a result of persistent immune cell activation, and simultaneously with immune paralysis due to impaired immune effector functions. (B) Mechanisms that are involved in SIDKD include suppressed innate immune responses, e.g., impaired leukocyte and platelet function, reduced antigen-presenting ability of macrophages and dendritic cells to T and B cells, and impaired adaptive immune responses (e.g., T lymphocyte maturation and activation, reduced antibody production by plasma cells).

Figure 4.

Pathomechanisms of SIDKD. Kidney disease is associated with an impaired urinary clearance of immunoregulatory metabolites, increased production of immunoregulatory proteins and persistent immune activation, extrinsic immunosuppressors, and a leaky gut and shift in the secretome of the intestinal microbiota—all of which contribute to SIDKD. The pathogenic mechanisms of SIDKD include dysregulation of innate and adaptive immune responses, such as a decreased phagocytic capability of immune cells to clear pathogens, reduced respiratory burst (ROS production) to kill bacteria and viruses, enhanced immune cell activation (upregulation of cell surface receptors) and release of proinflammatory cytokines (e.g., IL-1β, IL-6, TNFα) by innate immune cells (e.g., neutrophils, monocytes, macrophages, dendritic cells), increased neutrophil apoptosis but decreased neutrophil extracellular trap (NET) formation, and reduced antigen-presenting ability of macrophages and dendritic cells to activate T and B cells, which results in decreased T-cell proliferation and antibody production by plasma cells. Although leukocyte/lymphocyte interactions with endothelial cells are increased, the ability of leukocytes/lymphocytes to migrate is impaired due to a downregulation of, e.g., β₂ integrins. Subsequently, the dysregulation of the innate and adaptive immune system contributes to bacterial overgrowth, infections, and attenuated sterile inflammation.