Could anti-inflammatory cytokine therapy improve poor treatment outcomes in dialysis patients?
Mortality in dialysis patients is greater than that in the general population across all age groups. The disparity in mortality is greatest among patients aged under 35 years. Chronic kidney disease (CKD) is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome, which helps to explain the high mortality rates among patients with CKD. Paradoxically, CKD patients exhibit signs of immune suppression as well as immune system activation. Chronic inflammation and immune system activation are not only integral to the MIA syndrome, but also may underlie resistance to erythropoietin treatment in patients with anaemia. Chronic immune system activation is reflected by abnormally raised T-lymphocyte and monocyte expression of both pro- and anti-inflammatory cytokines. Patients who respond well to erythropoietin treatment exhibit fairly normal expression of these cytokines. Patients who persistently fail to respond, however, express abnormally raised levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are also known to inhibit erythropoiesis. Paradoxically, these patients also express abnormally high levels of the anti-inflammatory cytokines interleukin (IL)-10 and IL-13. Although anti-inflammatory in nature, these cytokines might also affect erythropoiesis. One strategy to overcome the problem of chronic inflammation in anaemic patients with CKD may be treatment with the phosphodiesterase inhibitor, pentoxifylline. Preliminary results suggest that once-daily treatment with 400 mg of pentoxifylline orally not only can reduce T-cell expression of TNF-alpha and IFN-gamma, but can also restore the response to erythropoietin and improve haemoglobin levels. Ongoing studies will investigate further the use of pentoxifylline in erythropoietin resistance.
Renal Unit, King's College Hospital, East Dulwich Grove, London SE22 8PT, UK. iainc.macdougall@virgin.net
Iain C
IC
Macdougall
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000627:therapeutic use*; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000097:blood; D007378:Interleukins / Q000097:blood; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D010431:Pentoxifylline / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D011994:Recombinant Proteins; D006435:Renal Dialysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016207:Cytokines; D007378:Interleukins; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D000068817:Epoetin Alfa; D007371:Interferon-gamma; D010431:Pentoxifylline