Review

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

Stefanie Steiger, Jan Rossaint, Alexander Zarbock and Hans-Joachim Anders
JASN February 2022, 33 (2) 259-278; DOI: https://doi.org/10.1681/ASN.2021091257

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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.

Cardiovascular disease and infections are predominant causes of death in patients with kidney disease. Whereas cardiovascular disease is a primary focus of many research activities in nephrology, awareness, and funding, research on aberrant immune function and infections in patients with kidney disease is sparse. Recently, the coronavirus disease 2019 (COVID-19) pandemic garnered more attention for kidney disease as a risk factor for severe and lethal COVID-19 and that kidney disease can impair the immune response to vaccines.1 However, the molecular mechanisms underlying the increased susceptibility to severe infections and impaired vaccine responses remain unclear, as do possible therapeutic interventions to interfere with the effect of kidney disease on the immune system.

Kidney disease is associated with a state of secondary immunodeficiency (SID), here referred to as SID related to kidney disease (SIDKD). Notably, most chronic organ failures, but also malnutrition, aging, chronic infections, and numerous immunosuppressive drugs, can cause SID (Figure 1). In this review, we highlight the unmet needs relating to SIDKD in terms of awareness, a new definition, epidemiology, pathophysiologic mechanisms, and a call for targeting SIDKD with specific interventions to improve outcomes in patients with kidney disease.

Figure 1.
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.

Toward a New and Uniform Definition of SIDKD

A definition of SIDKD has not been established but would be essential for epidemiologic studies, preclinical science, clinical research, and teaching. Ideally, such a definition would match those used for other forms of immunodeficiency (ID). The European Society for Immunodeficiencies working definitions for the heterogeneous inborn errors of immunity, and definitions of SID used in other medical contexts, provide some guidance.2,3 In general, such definitions include a clinical component indicating increased susceptibility to infections, represented by recurrent or severe infections and/or insufficient vaccine responses. A second component refers to abnormal results of immunophenotyping. For SIDKD, any form of kidney disease, but particularly CKD, would be a conditio sine qua non. Hence, we propose the a definition of SIDKD in Table 1, which is shown in a simplified way in Figure 2A. Of note, kidney disease can also evolve from primary ID. For example, genetic complement deficiencies and defects in phagocytosis or lymphocyte apoptosis may first lead to systemic autoimmunity, followed by immune complex GN. Furthermore, in patients with primary ID, systemic infections, kidney infections, or recurrent use of nephrotoxic antimicrobial drugs may trigger kidney disease (Figure 2B).

Figure 2.
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.

View this table:
Table 1.

Definition of SIDKD

Epidemiology of SIDKD

Without a uniform definition of SIDKD, definite epidemiologic data have remained vague. One approach is to assess infection rates in CKD/ESKD patient cohorts, e.g., by using hospitalization and mortality data.

Impaired Host Defense to Infections

The global influence of COVID-19 has raised awareness of the vulnerability of patients with CKD/ESKD to lethal viral infection.4⇓–6 Cohort studies observed a COVID-19 mortality rate of 17%–44% among the CKD/ESKD population, particularly in those requiring dialysis across countries such as Italy,7,8 Spain,9,10 Korea,11 Turkey,12 Germany,13 the United States,14,15 Sweden,16 and Australia/New Zealand.17 Kidney transplant recipients had an even higher mortality of COVID-19 (37.5%; hazard ratio, 3.36; 95% confidence interval [95% CI], 1.19 to 9.50, P=0.022) compared with patients with ESKD on dialysis (11.3%).18

Infection-associated mortality rates have also been reported in large CKD outcome trials (Table 2). For example, the Dapagliflozin in Patients with Chronic Kidney Disease trial reported an infection-related mortality rate of 18.6% in >2000 patients with CKD who did and did not have diabetes.19 In the Atherosclerosis Risk in Communities Study, involving >9000 patients in the United States from 1996 to 2011, CKD stage G5 was associated with an adjusted hazard ratio of 3.76 (95% CI, 1.48 to 9.58) for infection-related death.20 Retrospective cohort studies before the pandemic reported a higher infection-related mortality in patients on dialysis compared with kidney transplantation recipients from the United States (adjusted death rate of 18.6 versus 12.8 per year; age 60–64)21 and the European Renal Association–European Dialysis and Transplant Association registry (82-fold in patients on dialysis versus 32-fold in transplant recipients).22 Data from the United States in 2016 report an incidence of 614 hospitalizations per 1000 person-years in patients with CKD,23 which places infections as the second leading cause for hospitalization. A lower eGFR is associated with an increased one- to three-fold risk of hospitalization as CKD stages progress.20,24,25 In >230,000 Canadian patients, the risk for hospitalization due to community-acquired pneumonia increased with decreasing eGFR.26 The influenza A virus subtype H1N1 (swine influenza),27 severe acute respiratory syndrome,28,29 and tuberculosis30,31 are associated with a longer duration in the hospital and a more aggressive clinical course or death in patients receiving dialysis, compared with the general population (Table 2). Similar observations have been documented for parasitic infections, e.g., Plasmodium falciparum or Plasmodium vivax32 and protozoa33 in patients with CKD in developing countries.

View this table:
Table 2.

Selected epidemiologic studies of SIDKD

Dialysis-related infections can occur upon recurrent insertion of arteriovenous fistulas/grafts or dialysis catheters.34,35 The type of dialysis access matters in this context.36,37 Patients undergoing dialysis via catheters have a two-fold higher risk for bacteremia or sepsis38,39 and infection-related death40 compared with those with arteriovenous fistulas/grafts. In addition, patients on hemodialysis (HD) are more susceptible to bacteremia, whereas patients on peritoneal dialysis (PD) have an increased risk for peritonitis.36,41,42 Furthermore, contamination of dialysis equipment and dialysate43,44 with diverse virulent microorganisms42,43 can underlie SIDKD in this population.

Impaired Immune Responses to Vaccines

Another clinical indicator of SIDKD is impaired vaccine response. Data from the ongoing COVID-19 pandemic show that patients on HD and PD may have a humoral antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after receipt of the mRNA vaccine BNT162b2.45,46(preprint)–49 However, the levels of anti-S1 IgG antibodies and SARS-CoV-2 surrogate neutralizing antibodies were substantially lower in patients on dialysis after the first and second vaccination compared with patients without CKD.50,51 Within 12 weeks surrogate neutralizing antibodies start to decrease from 93% to 85% in patients on PD and from 87% to 79% in patients on HD, respectively.52–53 Consistently, diminished seroconversion rates after immunization have been reported for hepatitis B virus (no difference in responsiveness between patients on PD and HD),54⇓⇓⇓–58 diphtheria and tetanus,59,60 pneumococcal,61 and influenza62 vaccines compared with the general population. As vaccine-induced antibody levels and humoral immunity decrease, patients with ESKD benefit from booster vaccinations.63

Sterile Forms of Inflammation

SIDKD also implies an attenuation of noninfectious forms of inflammation, such as the autoimmune disease activity that declines as CKD progresses. In addition, patients with CKD/ESKD who have significant hyperuricemia show an unexpectedly low rate of acute gout attacks.64,65

Although the lack of a common definition of SIDKD makes definite epidemiologic data scarce, numerous clinical observations suggest that SIDKD is prevalent in patients with CKD and ESKD; therefore, mechanistic explanations of SIDKD are required.

Immunophenotype of Patients with Kidney Disease

Biomarkers for SID in clinical use include white blood cell count, total Ig levels, measurement of antibodies to specific pathogens or vaccine responses, and fluid-phase complement factors, but also specific assays of neutrophil and T cell function. Immunophenotyping of patients with CKD/ESKD reveals signs of chronic inflammation and impaired immune effector functions (Figure 3A).66

Figure 3.
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).

Impaired Function of Innate Immunity

In patients with CKD/ESKD, biomarkers of oxidative stress, such as advanced oxidation protein products and myeloperoxidase, and for inflammation, such as high sensitivity C-reactive protein and IL-6, are inter-related.67,68 Thus, uremia leads to chronic low-grade inflammation, in which permanent immune cell activation and secretion of inflammatory cytokines, together with uremic solutes/metabolites, reduce the ability of neutrophils and monocytes to migrate to the inflammation site (Figure 3B).69⇓–71 Mechanistically, selectin-induced slow leukocyte rolling and transmigration are abolished,72,73 and β2 integrins are downregulated.74 Moreover, neutrophils from patients with ESKD are more likely to undergo apoptosis, which decreases the ability of neutrophils to form neutrophil extracellular traps 75,76 and to phagocytose and kill pathogens,77 mechanisms that are associated with an impaired host defense in SIDKD. A number of uremic solutes/metabolites that affect neutrophil oxidative burst have been identified, such as phenylacetic acid, resistin, and methylglyoxal.78,79

Monocytes from patients on PD are hyporeactive to LPS stimulation and release fewer proinflammatory cytokines in comparison to control subjects.80,81 Monocytes and monocyte-derived dendritic cells display decreased endocytosis and impaired maturation when cultured in uremic serum or when obtained from patients with ESKD.82 Moreover, dendritic cells and macrophages have a reduced antigen-presenting capability to activate T cells, which might be due to an abnormal expression of Toll-like receptor 483 and costimulatory molecules CD80 and CD86.84 An increased intracellular uptake of uric acid, related to an impaired renal clearance of uric acid uptake, contributes to uremia-related monocyte dysfunction.74

In patients on HD, higher serum levels of mannose-binding lectin are associated with an increased risk of severe infection.85,86 Mannose-binding lectin can bind to carbohydrates on the surfaces of bacteria and viruses (e.g., SARS-CoV-287) and initiate complement-driven pathogen lysis.88,89 However, uncontrolled complement activation also contributes to hyperinflammation, cell injury, immunothrombosis, and multiorgan failure during COVID-19 infection.90 In addition, monocytes/macrophages from patients with ESKD have increased expression and activity of the macrophage scavenger receptors SR-A and CD36,91⇓–93 but decreased inducible nitric-oxide synthase expression94 and phagocytic capability, e.g., of peritoneal macrophages in chronic PD and PD-induced peritonitis95,96 and potentially also in alveolar macrophages in the context of pulmonary infections. ESKD reduces the cell number and cytotoxicity of natural killer (NK) cells in association with downregulation and modulation of ligand expression for activating receptors on NK cells.97,98 Thus, uremia impairs the functional properties of neutrophils, monocyte/macrophages, and NK cells that are important to maintain a sufficient host defense.

Impaired Platelet Function

Beyond their important role in homeostasis, platelets are important cellular contributors to host defense99 and essential for sufficient neutrophil activation and recruitment into peripheral organs under different inflammatory conditions. However, gut microbial uremic toxins, which accumulate during CKD,100 and altered HDL levels contribute to altered homeostasis and immune effector functions in SIDKD (Figure 3).101 This dichotomy may be explained by the fact that critical factors determining the effective formation of platelet-leukocyte aggregates, e.g., plasma fibrinogen levels involved in bond formation between integrins, GPIIbIIIa on platelets, and Mac-1 on neutrophils, are increased in patients with CKD.102 Furthermore, platelets release more α-granules on stimulation, leading to increased incorporation and expression of P-selectin on the platelet surface, which, in turn, binds to PGSL-1, which is expressed on various leukocyte subsets, including neutrophils.103 Thus, uremic platelet dysfunction not only promotes bleeding complications104 but also immunothrombosis in CKD.105,106

Impaired Function of Adaptive Immunity

Impaired vaccine responses indicate that CKD/ESKD also suppresses adaptive immunity (Figure 3B).107 This suppression involves aberrant T-cell activation caused by altered dendritic cell and macrophage antigen presentation and increased apoptosis of effector CD4+ and CD8+ T cells.98,108,109 Studies performed in vitro show decreased T helper (Th) CD4 cell proliferation in the uremic milieu.110,111 HD and PD have different effects on Th cell phenotypes and proliferation.112,113 In patients on PD, the maturation of both effector Th1 and Th2 CD4 cell subsets is impaired, and there are increased numbers of central memory T cells and CD8+ naive T cells compared with controls and patients on HD.113 In contrast, patients on HD seem to have sustained Th cell maturation, but the immune response is mainly driven via Th1 CD4 (e.g., production of IFN-γ) rather than Th2 CD4 cells.114,115 A possible explanation for the increased Th1/Th2 ratio in patients on HD could be increased IL-12 production.115 Moreover, the different clinical course of infection, e.g., hepatitis B virus, between patients on dialysis and the general population relates to dysfunctional CD8 cytotoxic T cells, which are needed to eliminate infected cells, and dysfunctional CD4 T cells, which sustain CD8 cytotoxic T cells and induce antibody production from B and plasma cells.103

Patients with CKD/ESKD show a defective or repressed humoral and vaccination response.116 B-cell lymphopenia, due to increased B-cell apoptosis and insufficient B-cell proliferation, is common in patients on HD and controls.117⇓–119 This has been related to decreased Bcl-2 expression and a resistance to IL-7 and B cell–activating factor BAFF/BLyS.117,120 Patients on HD have fewer B1 cells secreting IgM and IgA and B2 cells producing IgG.106,120 Patients on dialysis and kidney transplant patients have poor antibody, memory B cell, and plasmablast responses to vaccines, such as the COVID-19 (BNT162b2),47 hepatitis B virus, and influenza vaccines compared with the general population (Table 2)121,122. Therefore, these patients may not be sufficiently protected against the respective pathogens. CKD and ESKD also impair adaptive immune responses, which are important for host defense but are also implicated in auto- and alloimmunity.

Pathogenic Mechanisms of SIDKD

SIDKD due to Intestinal Barrier Dysfunction

Evidence indicates that the elevated circulating endotoxin/LPS levels and markers of systemic inflammation in patients with CKD stage G3–5 and 5D are caused by a leaky intestinal barrier and enhanced endotoxin translocation from the intestinal lumen into the circulation.123,124 LPS levels were the highest in patients on HD/PD; levels were similar to those in patients with severe liver disease, irradiation-induced intestinal damage, and decompensated heart failure.123 Elevated LPS levels are considered a strong and independent predictor of mortality.123 Wang et al.125 demonstrated that experimental uremia in rats increases bacterial translocation from the gut into mesenteric lymph nodes, liver, and spleen, which was associated with higher levels of serum IL-6 and C-reactive protein.126 The aberrant humoral and cellular immunity in CKD is partially reversible by treatment with antibiotics that eliminate the intestinal flora.127 Endotoxin tolerance and the see-saw phenomenon in sepsis posit that persistent exposure to bacterial endotoxins induces negative regulators of innate immunity that paralyze the innate and adaptive immune system.127,128 In accordance with this concept, CKD-related intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for the state of persistent systemic inflammation in CKD (Figure 4).129

Figure 4.
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.

SIDKD due to Persistent Inflammation

Persistent inflammation is an important trigger of immune paralysis and SID. Indeed, dendritic cells, neutrophils, monocytes, macrophages, and mast cells remain unresponsive to a secondary endotoxin challenge due to an induced suppression of signaling pathways contributing to inflammation. This see-saw phenomenon of immune activation is an important, evolutionarily conserved mechanism that avoids a potentially lethal cytokine storm and septic shock. In patients with permanent triggers of inflammation, this see-saw phenomenon begins at the single-cell level.130 The flood of new immune cells produced daily results in a state of concomitant systemic inflammation and immune paralysis at the organismal level.

The endotoxin tolerance–like concept explains the immunosuppressive state in sepsis, cystic fibrosis, pancreatitis, and tuberculosis.131 In the early phase, cytokine storm–like hyperimmunoreactivity predominates and may be lethal. At later stages, and in chronic disorders, hypoimmunoreactivity (as a sign of SID) prevails, leading to potentially fatal secondary infections.132 Cellular mechanisms that underlie immunosuppression include unresponsiveness of monocytes to LPS challenge ex vivo;133 reactivation of adaptive immune cells, such as T regulatory cells and myeloid-derived suppressor cells134,135; but loss of CD4+ and CD8+ T cells (Figure 4).136,137 However, this induced immune paralysis is not restricted to sepsis or cystic fibrosis, but is also present in other forms of sterile inflammation, e.g., in hepatic and kidney ischemia, coronary occlusion, acute coronary syndromes, and even cancer.138⇓⇓–141

An impaired intestinal barrier is a possible source of persistent exposure to bacterial endotoxins, as indicated by increasing endotoxin serum levels at later stages of CKD.123,127

Shifts in the Secretome of the Intestinal Microbiota

The secretome of the intestinal microbiota is an integral component of human physiology and changes in the microbiota composition, which affect the secretome, disturb physiology and homeostasis.142⇓–144 Kidney disease–related alkalosis, intestinal wall congestion, azotemia, and other metabolic disturbances alter the composition of the intestinal microbiota and hence its secretome.127,145 Among many other aspects of physiology, a uremia-related altered intestinal secretome implies changes in numerous immunoregulatory metabolites, including a reduction in short-chain fatty acids, such as butyrate and acetate, that usually suppress inflammation (Figure 4).146,147 Other gut-derived metabolites that affect the immune system include indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, and phenylacetylglutamine.147,148 Mechanistically, indoxyl sulfate and p-cresyl sulfate are associated with systemic inflammation and an altered host defense in patients with CKD, e.g., by inducing glutathione peroxidase, TNFα, and IL-6 release in monocytes149; impairing respiratory burst activity and phagocytosis in neutrophils; and causing eryptosis (programmed death of red blood cells) partly by increasing cytosolic calcium.150

A high salt diet can reduce the intestinal population of Lactobacillus murinus, which decreases indole-3-lactate levels, affecting Th17 cell function in a way that can aggravate experimental hypertension and multiple sclerosis.151 It is possible that CKD or CKD-related medications, dietary restrictions, and use of antibiotics alter the intestinal microbiota,152 leading to concomitant systemic inflammation and ID. Moreover, fecal transplantation in CKD can induce metabolic changes that lead to sarcopenia and immune dysregulation. Mice receiving a fecal transplant from CKD patients had significantly higher plasma trimethylamine N-oxide levels and a different gut microbiota composition than mice receiving a fecal transplant from non-CKD patients.153 These findings suggests that CKD modifies the composition of the intestinal microbiota and its secretome, which, together with barrier dysfunction and bacterial translocation, might explain the persistent systemic inflammation and defective host defense associated with CKD.

Impaired Urinary Clearance of Immunoregulatory Metabolites

Low-molecular-weight solutes involved in both systemic and organ-specific metabolism may impair urinary clearance and exhibit increased production, or decreased breakdown, in kidney disease (Figure 4). For example, p-cresyl sulfate induces an increase in oxidative burst and phagocytosis in human macrophages, but decreases their antigen-presenting ability to T cells by downregulating HLA-DR and CD86.154 Moreover, indoxyl sulfate promotes leukocyte-endothelial interactions through the upregulation of vascular endothelial adhesion molecules, such as E-selectin, via JNK- and oxidative stress–dependent pathways155; can induce the expression of adhesion molecules, such as MAC-1; and increase production of reactive oxygen species (ROS) in a manner dependent on NADPH oxidase and p38 MAPK in monocytes.156 In patients with common variable ID that present with defective B cell to plasma cell development, several studies report a strong association between trimethylamine N-oxide and asymmetric dimethylarginine with systemic inflammation, immune cell activation, and gut microbial abundance.157⇓–159

Whereas the above-mentioned metabolites drive systemic inflammation, CKD-related hyperuricemia instead suppresses innate immunity.74 This phenomenon occurs through the intracellular uptake of soluble uric acid into CD14+ monocytes via selective urate transporters, such as the glucose transporter 9 (SLC2A9), which inhibits Toll-like receptor signaling, production of proinflammatory cytokines, and migration of CD14+ monocytes in patients with CKD/ESKD.74 Hyperuricemia also attenuates β2 integrin activation and integrin trafficking in neutrophils, which impairs neutrophil recruitment to sites of DAMP/PAMP-driven sterile inflammation (own unpublished data). This effect highlights a previously unexpected immunoregulatory role of asymptomatic serum UA levels of 7–12 mg/dl in those with CKD/ESKD. Further studies are needed to clarify the pathophysiologic effects of asymptomatic hyperuricemia in SIDKD, especially whether urate-lowering therapy can improve host defense in CKD/ESKD.

Immune Paralysis due to Increased Production of Immunoregulatory Proteins

A decline in kidney excretory function is associated with overexpression of certain immunoregulatory proteins (Figure 4). For example, fibroblast growth factor 23 (FGF23) levels drastically increase with CKD progression, which has a direct effect on neutrophil functions, including selectin-mediated slow rolling, chemokine-induced adhesion and arrest under dynamic flow, and ROS release. The resulting neutrophil recruitment defect impairs pathogen control in bacterial pneumonia in mice.71 Mechanistically, FGF23 binding to its counter-receptor FGFR2 on neutrophils counteracts selectin- and chemokine-triggered β2 integrin activation by activating protein kinase A and suppressing the activation of the small GTPase Rap1. Reduced neutrophil rolling and arrest on activated endothelium, associated with elevated FGF23 blood levels, was also observed in whole blood samples from patients with CKD stage G3–5.71

Levels of the middle-molecular-weight proteins leptin,160,161 resistin,161,162 and modified ubiquitin70 increase in patients with CKD/ESKD compared with healthy controls,162 which contributes to neutrophil dysfunction. Leptin can inhibit neutrophil migration by impairing neutrophil locomotion via MAPK- and Src kinase–related F-actin polymerization.160 In contrast, resistin162 and p-cresol163 decrease the respiratory burst activity of neutrophils, whereas complement factor D and angiogenin overexpression inhibit neutrophil degranulation164⇓–166 and glucose-modified proteins (glycated proteins) promote neutrophil apoptosis.167

SIDKD due to Extrinsic Immunosuppressors

Extrinsic factors contribute to SIDKD (Figure 4). For example, there is a concern that iron administration for renal anemia could decrease host defense. Indeed, iron can decrease the phagocytic capacity of neutrophils and macrophages.168,169 Iron can also impair the proliferation of T cells, lower IL-2 and IFN-γ production, and reduce the antibody response of B cells.170⇓–172 Infection may be a long-term complication of iron therapy in patients with CKD and may play an important role in suppressing immunity, especially in cases of iron overload.173 A meta-analysis of randomized controlled trials showed that intravenous iron therapy is associated with a 30% greater risk of infection compared with oral iron and no iron therapy.174 However, modern intravenous iron formulations do not seem to increase infection rate in patients on HD.175

Steroids and other immunosuppressant drugs are frequently prescribed to patients with CKD/ESKD and kidney transplant recipients for their anti-inflammatory and immunosuppressive effects. However, many clinical trials176⇓⇓⇓–180 (including the STOP-IgAN181 and TESTING182,183 trials) assessing the use of steroids, e.g., corticosteroids, prednisolone (initially 20–60 mg/d, then tapered, for 4–24 months), reported a high rate of serious adverse outcomes (STOP-IgAN, 55%; TESTING, risk difference, 11.5% [95% CI, 4.8% to 18.2%]), including an increased risk of infections and certain opportunistic infections (STOP-IgAN, 25%; TESTING, 8%). Another cohort study reported similar results, with a 40% higher risk of serious adverse events (46.1 per 1000 person-years; relative risk, 1.4 [95% CI, 1.3 to 1.6]) in patients with CKD treated with corticosteroids most of them infections184 Steroids are an independent risk factor for SID because they also increase the risk of infection in patients without CKD who have rheumatoid arthritis, asthma, vasculitis, or inflammatory bowel disease.185⇓⇓⇓–189 However, infectious complications are not increased in those receiving a daily dose <10 mg or a cumulative dose of >700 mg of prednisone.189 The extent to which SID is more severe in patients treated with steroids who have CKD versus those without CKD has not been established and will certainly also affect the many confounding factors contributing to SID. Mechanistically, these agents inhibit the release of proinflammatory cytokines (e.g., IL-1β, IL-6, TNFα) in monocytes/macrophages, the recruitment and respiratory burst in neutrophils, and cause lymphopenia and impair lymphocyte function.190⇓⇓–193 Although these drugs are sometimes needed to control the underlying kidney disease,194 balancing protective and dysregulated host immune responses can be intricate in patients who are critically ill and experience reinfection, e.g., with COVID-19.1,51

The removal of metabolic/uremic waste products by passing blood through synthetic tubing and dialyzer membranes during HD triggers the activation of monocytes, neutrophils, platelets, and the complement system; the release of inflammatory cytokines and ROS; and apoptosis.195,196 Neutrophil activation with decreased β2 integrin expression197 and neutrophil degranulation,198 along with the neutrophil extracellular trap formation associated with the release of DNA, myeloperoxidase, histones, and S100 proteins, can trigger endothelial activation,199 which ultimately contributes to vascular inflammation and cardiovascular disease.200 This may explain, at least in part, the cell-mediated immunosuppression and immune paralysis seen in patients with ESKD who are on HD.

Summary and a Call for Action

More awareness is needed for the unmet need of infection-related morbidity and mortality and the other clinical consequences of SID in patients with kidney disease. The ongoing pandemic provides a unique opportunity in this context, with kidney disease a major risk factor for lethal COVID-19 and a poor vaccine response. As a starting point, we provide a practical definition of SIDKD to endorse focused research on the epidemiology of this important cause of death in patients with kidney disease. As a community of kidney researchers, we have to improve patient outcomes in this domain as we do in CKD-related cardiovascular disease. To develop better preventive and therapeutic strategies, we first need to understand the pathophysiology of SIDKD (Table 3). Some mechanisms are discussed here but, undoubtedly, there are more to discover. SIDKD offers plenty of research opportunities for established and next-generation researchers, and opportunities for industry to invest in a naive domain for therapeutic interventions. The unmet needs of SIDKD require more attention at all levels.

View this table:
Table 3.

Approaches to improve SIDKD

Disclosures

H.-J. Anders reports receiving consultancy or lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eleva, GlaxoSmithKline, Janssen, Kezar, Lilly, Novartis, Otsuka, and PreviPharma; and serving as a scientific advisor for, or member of, JASN and Nephrology Dialysis Transplantation. S. Steiger reports receiving research funding from Eleva. A. Zarbock reports serving as a scientific advisor for, or member of, AM Pharma, Anesthesia & Analgesia, Guard Therapeutics, Journal of Immunology, Novartis, and Piaon; and receiving consulting fees, unrestricted research grants, or lecture fees from AM Pharma, Anomed, Astellas, Astute Medical, Baxter, BiMerieux, Braun, Deutsche Forschungsgemeinschaft, Else-Kröner Fresenius Stiftung, Fresenius, Guard Therapeutics, La Jolla Pharmaceuticals, Novartis, and Ratiopharm. The remaining author has nothing to disclose.

Funding

S. Steiger was supported by the Deutsche Forschungsgemeinschaft grants STE2437/2-1 and STE2437/2-2 and the Ludwig-Maximilians-Universität München Excellence Initiative. H.-J. Anders was supported by the Deutsche Forschungsgemeinschaft grants AN372/14-4, 20-2, 27-1, and 30-1 and the Volkswagen Foundation grant 97-744. A. Zarbock was supported by the Deutsche Forschungsgemeinschaft grants ZA428/17-1, ZA428/18-1, and SFB1009A05. J. Rossaint was supported by the Deutsche Forschungsgemeinschaft grant RO4537/4-1 and the Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg grant Ross2/010/18.

Acknowledgments

Because H.-J. Anders is an editor of JASN, he was not involved in the peer-review process for this manuscript. A guest editor oversaw the peer-review and decision-making process for this manuscript.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

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Secondary Immunodeficiency Related to Kidney Disease (SIDKD)—Definition, Unmet Need, and Mechanisms
Stefanie Steiger, Jan Rossaint, Alexander Zarbock, Hans-Joachim Anders
JASN Feb 2022, 33 (2) 259-278; DOI: 10.1681/ASN.2021091257
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