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


PMNLs: chemotaxis and decreased apoptosis


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) [59].

Table 12.2

The mechanism of action of immunosuppressive agents




Reductions in leukocyte migration, in neutrophilic and monocytic phagocytosis, and in T-cell function


6-Mercaptopurine methotrexate

Proapoptotic effects on T lymphocytes


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


Production of osteoactivin


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


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


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 (TH17 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 [1113].

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+ TEMRA 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

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Oct 20, 2020 | Posted by in NEPHROLOGY | Comments Off on Deficiency and Infection in Chronic Kidney Disease

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