Chronic kidney disease (CKD) is an important contributor to morbidity and mortality in non-communicable diseases. According to the latest data released by The Lancet, as of 2017, approximately 697.5 million people worldwide have been diagnosed with CKD10. In China, the prevalence rate is 10.8%, and the number of patients reached 132.3 million10. CKD is susceptible to infection, and the mortality rate significantly increased in CKD patients with infection11,12. Therefore, CKD patients have been the subject of particular attention to prevent and treat the infection. In recent studies, some investigators indicated that infection was directly or indirectly associated with a disturbed immune response and account for the high incidence of morbidity and mortality among patients with kidney dysfunction. It is suggesting that prevention and intervention approaches for infection should be considered more actively. Although the mechanisms of immune dysfunction in chronic kidney disease have not been fully elucidated, cellular immune dysfunction may play a vital role in the pathogenesis of CKD and infection13,14. In cellular immune, T lymphocytes are not only a major component of adaptive immunity but also a significant barrier to bacterial pathogen infection15. However, at present, the researches on the correlation between CKD T lymphocyte subgroup levels and infection are still rare. The opinions on the change of T lymphocyte in CKD patients are not uniform conclusions. In addition, there is little research in immune function of the T cells to evaluate and predict the risk of infection for patients with chronic kidney disease. Therefore, the present study focused on CKD patients and characteristics of T lymphocyte count, in order to to find a new and feasible strategy to prevent infection in CKD patients.
Recent evidences suggested that renal insufficiency would affect the immune system. However, the previous studies only focused on ESRD or renal transplant patients, and the early stage of CKD patients were received less attention. In our study, we found that T lymphocyte levels gradually declined according with renal function decreases in CKD patients. It is well known that glucocorticoids and immunosuppressive agents could significantly affect the body's immune capacity. In order to exclude these effects, we analyzed the patients in screening group. At last, same results were acquired in CKD and screening patients. It indicates that T lymphocyte levels in CKD patients may related to renal function.
With renal function decreased, many toxic substances which could be filtered by the healthy kidneys, would remain in the CKD patients body and lead to the development of the uremic syndrome. The accumulation of various toxic substances would destroy the function in immune regulation and contribute to the disorders of cellular immune function. Patients with advanced CKD and ESRD exhibited abnormal CD4+/ CD8+ ratios. Recent studies confirmed that the severity of azotemia, iron overload and oxidative stress would directly influence the apoptosis of the naive and central memory T cells of CD4+ and CD8+16,17. In addition, the worse renal function, the malnutrition would more likely occur. A study of 5248 American adults with aged 60 years and over, found glomerular filtration rate less than 30 ml/min/1.73 m2 was an independent factor for malnutrition18. The immune system consumes high amounts of energy, and strongly dependents on nutritional balance19. Therefore, the renal function, nutrition and immunity are closely linked. Based upon the interaction of all of these mentioned factors, T lymphocyte dysfunctions gradually increase according with the loss of renal function in CKD patients.
In our study, the absolute counts of CD3+, CD4+, and CD8+ T lymphocyte cells in the infected group of CKD patients are lower than those in the non-infected group. Especially, the infection rate in CD4+ T cells <410 cells/ μl group was significantly higher than normal group with CD4+ T cells >410 cells/ μl. This feature was not affected by hormones and immunosuppressant. We inferred the total number of lymphocyte subsets could reflect the immune status in CKD patients. T cells represent a significant component of the adaptive immune system and play a central part in cell-mediated immunity20. When naive T cells expose to antigen, it start on clonal expansion, differentiation, generation of the memory T cells and effector T cells. Effector T cells perform their function via secretion of cytokines and destruction of target cells. CD3+ molecules are labeled on the surface of all differentiated mature T lymphocytes, and CD4+ T molecules are labeled on the helper T lymphocytes which were pivotal for the development of protective immune responses. CD4+ T cells could interact with antigen-presenting cells to direct the immune response, activate cytotoxic T cells and macrophages and promote the maturation of B cells into plasma cells to further produce antibodies. Furthermore, they could recruit immune cells such as polymorphonuclear leukocytes (PMN), eosinophils, basophils and so on., and enhance macrophages ability to promote the function of anti-inflammation. CD8 + T cells could destroy virally infected cells and tumor cells, and participate in transplant rejection21. Only T lymphocytes could recognize and respond to processed antigens through the C3b antigen-antibody complex. Therefore, a decrease of the T lymphocytes could reduce the ability to control the inflammatory, and CKD patients would be more susceptible to bacterial infection. In addition, as early stage CKD patients still have reduced lymphocyte counts, immunosuppressive therapies need a comprehensive evaluation.
In previously, some researches have been carried out on using T-lymphocyte counts to monitor patient’s cellular immunity levels, but the study which adequately covers all CKD patients, was still rare. Most studies in this field of using CD4+ T cell counts to assess infection risk of patients, had only focused on acquired immune deficiency syndrome (AIDS)22,23. It is well known that the index of CD4+ T cells <200 cells/μl is always used as a cutoff value for predicting opportunistic infections in acquired immune deficiency syndrome (AIDS) patients. In our studies, the infection of CKD patients was closely related to the levels of T lymphocyte cells,, especially CD4+ T lymphocyte cells. In screening cases, CD4+ T lymphocytes may not be affected by related immune factors such as hormones, immunosuppressive agents or autoimmune diseases. The results remain consistent with CKD patients. CD4+ T<410 cells/ μl was an independent influencing factor for infection in CKD patients and screening cases. Furthermore, we utilized receiver operating characteristic (ROC) curve analysis to determine a useful cut-off score. We found CD4+ T lymphocyte count of less than 469 cells/ μl are at the highest risk of infection in CKD patients. Therefore, the predictive value of CD4+ T <200 cells/μl and CD4 + T <469 cells/μl for infection in CKD patients was compared. We found the sensitivity was obviously improved from 6.9% to 39.9% in our new cutoff in CKD patients. As we all know, infections in CKD patients are relatively hidden, but progress quickly, and significantly affect the prognosis. It is very important for CKD patients to early diagnose and treat the complication of infection. Our data provide a useful cutoff of CD4+ T <469 cells/μl. Although the sensitivity of cutoff value of CD4+ T <469 cells/μl remains to be improved, but for the early diagnosis and treatment of infection, it is still very important for physicians to improve the survival and quality of life in CKD patients. The finding provided a new direction for early clinical treatment of infection in CKD patients.
We all know that CD4+ T cells play a broad role in defending against pathogens. The interaction of cytokines and receptor-ligands stimulate naive CD4+ T cells to interact with dendritic cells in lymphoid tissues and further differentiate into T helper(Th), regulatory T cells (Treg), T follicular helper (Tfh) cells, etc. The above subgroups could secrete specific cytokines, such as IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IL-24, lymphotoxin α , tumor necrosis factor α (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), transforming growth factor (TGF)-β, to participate in innate and adaptive immune responses. It could be seen that the disorder of CD4 +T lymphocyte’s function could not only reduce the body's immunity, lead to infection, but also affect humoral immunity, stimulate the production of cytokines, and further aggravate kidney damage. However, in our present study, due to the limitation of experimental conditions, we couldn't determine the counts of CD4+ T lymphocyte subgroups. The further studies are needed to clarify the function of CD4+ T lymphocyte subgroups in CKD patients.