Deficiency and Infection in Chronic Kidney Disease

Uremic toxins

Effects on immune cells

Low molecular weight (LMW) toxins

Phenylacetic acid (PAA)

Macrophages: inducible nitric oxide synthase

PMNLs: oxidative burst, phagocytosis, increased integrin expression, and decreased apoptosis

Dinucleoside polyphosphates

Leukocytes: oxidative burst

Guanidino compounds

Monocytes/macrophages: pro- and anti-inflammatory

Indoxyl sulfate

Endothelial cells: upregulation of E-selectin

P-cresyl sulfate

Leukocytes: oxidative burst

Homocysteine (Hcy)

Increased ICAM-1 expression, damage of DNA and proteins

Methylglyoxal (MGO)

PMNLs: increased apoptosis and oxidative burst

Monocytes: increased apoptosis

Middle molecular weight (MMW) proteins

Immunoglobulin light chains (IgLCs)

PMNLs: chemotaxis and decreased apoptosis

Retinol-binding protein (RBP)

PMNLs: chemotaxis, oxidative burst, and decreased apoptosis

Leptin

PMNLs: chemotaxis and decreased apoptosis

Resistin

PMNLs: chemotaxis and decreased apoptosis

Tamm–Horsfall protein (THP)

PMNLs: decreased chemotaxis and apoptosis, increased phagocytosis

High-density lipoprotein (HDL)

Loss of anti-inflammatory properties

PMNLs polymorphonuclear leukocytes (Adapted from Cohen G, Horl WH. Toxins. 2012;4:926–90 [3])

12.2.1 Immune Deficiency Caused by Immunosuppressive Agents

Immunosuppressive drugs have become some of the most successful treatments for some glomerular-nephritis patients and transplant patients, but these patients also appear to show increased susceptibility to infections because of immune deficiency (Table 12.2) [5–9].

Table 12.2

The mechanism of action of immunosuppressive agents

Drug	Mechanism
Steroids	Reductions in leukocyte migration, in neutrophilic and monocytic phagocytosis, and in T-cell function
Azathioprine 6-Mercaptopurine methotrexate	Proapoptotic effects on T lymphocytes
Cyclosporine Tacrolimus (FK506)	Induction of antibody, leukocyte, and lymphocyte formation and of differentiation into proinflammatory Th17 cells
Mycophenolate mofetil (MMF)	Inhibition of both T-lymphocyte and B-lymphocyte activities

12.2.2 CKD-Associated Innate Immune Deficiency

The innate immune system consists of monocytes, macrophages, polymorphonuclear leukocytes (PMNLs), neutrophils, eosinophils, basophils, dendritic cells, and natural killer cells. The effects of CKD on the innate immune system may be due to the accumulation of uremic toxins, increased levels of proinflammatory molecules, alterations of TLRs, increased oxidative stress, decreased erythropoietin production, and increased parathyroid hormone concentration. The disturbances of innate immune cells associated with CKD are summarized in Table 12.3 [10].

Table 12.3

The dysfunction of innate immune cells associated with CKD

Innate-immune-cell type	CKD-associated changes	Altered functions
Monocytes and macrophages	CD14⁺CD16⁺ subset expansion	Production of cytokines Decreased phagocytic capacity ROS Production of osteoactivin
PMNLs	Increased apoptosis of PMNLs	Decreased phagocytic capacity
Dendritic cells	Reduction in numbers of DCs Functional anomalies of DCs	Impaired defense against microbial infection and a poor response to vaccination
Neutrophils	Reduction in the killing capability of neutrophils Unchanged number of neutrophils capable of phagocytosis and producing ROS	Reduced ability to kill microorganisms and increased susceptibility to infection
Eosinophils	Increased number	Associated with vascular disease in CKD patients
Natural killer cells	Decreased number of NKG2D-positive NK cells	Associated with high levels of the circulating HLA-related molecule MICA

PMNLs polymorphonuclear leukocytes; DCs dendritic cells; ROS reactive oxygen species

12.2.3 CKD-Associated Adaptive Immunity Deficiency

Patients with CKD exhibit T-cell lymphopenia, which is primary due to loss of naïve CD4⁺ and CD8⁺ T cells and central memory CD4⁺ T cells; aberrant activation of terminally differentiated memory cells; and an imbalance between suppressive regulatory T cells (Treg cells) and T helper 17 cells (T_H17 cells). The aberrations of T cells are related to uremic toxins, oxidative stress, secondary hyperparathyroidism, an iron overload, and inflammation.

Significant B-cell deficiency and dysfunction have been demonstrated in CKD, which are mediated by increased apoptosis and impairment of maturation. Uremia toxin-induced B-cell lymphopenia may increase the frequency of infections and cause a defective response to vaccination in patients with CKD. The T-cell and B-cell anomalies associated with CKD are summarized in Table 12.4 [11–13].

Table 12.4

The T-cell and B-cell anomalies associated with CKD

Type of adaptive immune cells	CKD-associated changes	Mechanism and altered function
Naïve T cells	Loss of circulating naïve CD4⁺ and CD8⁺ T cells, central memory CD4⁺ T cells Remaining naïve T cells show aberrant activation and higher expression of CD24, CD69, CXCR3, and CXCR5	Increased apoptosis Reduced IL-17 homeostatic signals Impaired thymic output
Effector memory T cells	Increased number of CD8⁺ T_EMRA cells	Transplant rejection
Treg and Th17 cells	Decreased number of Treg cells Increased number of Th17 cells	Increased apoptosis Increased angiogenin Increased production of 2,3-dioxygenase and arginase Decreased production of interleukin 2
B cells	Decreased numbers of CD5⁺ innate B cells and CD27⁺ memory B cells	Increased apoptosis BAFF downregulation Reduced antibody production Increased production of proinflammatory cytokines