Oxpentifylline Versus Placebo in the Treatment of Erythropoietin-resistant Anaemia: A Randomized Controlled Trial

David Wayne Johnson; Carmel Mary Hawley; Brenda Rosser; Elaine Beller; Charles Thompson; Robert G Fassett; Paolo Ferrari; Stephen MacDonald; Eugenie Pedagogos; Alan Cass


BMC Nephrology 

In This Article


The development of erythropoiesis stimulatory agents (ESA), such as recombinant human erythropoietin (EPO) and darbepoetin alpha (DPO), has resulted in substantial health benefits for patients with end-stage kidney disease (ESKD), including improved quality of life, reduced blood transfusion requirements, decreased left ventricular mass, diminished sleep disturbance and enhanced exercise capacity.[1,2] Unfortunately, a considerable proportion of such patients exhibit a suboptimal haematologic response to ESA, which in most cases is due to inadequate iron supply to the erythron.[3] Other known causes of ESA-resistance include infection, neoplasia, severe hyperparathyroidism, aluminium intoxication, vitamin B12 deficiency, folate deficiency, inadequate dialysis, myelosuppressive agents, haemoglobinopathies, myelodysplasia and antibody-mediated pure red cell aplasia.[4] However, even after exclusion of these conditions, a significant minority (approximately 10%) of patients exhibit ESA-resistant anaemia and have been shown to have greatly increased morbidity and mortality.[4] Inhibition of erythropoiesis by cytokines, such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) may play an important role in these patients.[5]

Although there is no currently effective treatment for patients with ESA-resistant anaemia, oxpentifylline (pentoxifylline) may represent a promising novel therapeutic strategy. Oxpentifylline has been used for more than twenty years in the treatment of peripheral and cerebral vascular diseases because of its potent haemorrheological properties, which include preservation of erythrocyte water and cation content.[6,7] The drug has subsequently been found to exhibit important anti-inflammatory properties, including anti-apoptotic, anti-oxidant, anti-TNF-α and anti-IFN-γ actions.[8,9,10,11] These actions appear to be mediated via inhibition of phosphodiesterase.[12] Two small, prospective, non-randomized studies have demonstrated that oxpentifylline may significantly improve haemoglobin levels in chronic kidney disease patients with ESA-resistant anaemia (vide infra)[13,14] Navarro et al[14] treated 7 anaemic patients with advanced chronic kidney disease (CKD) (creatinine clearance < 30 mL/min) with oxpentifylline (400 mg daily per os) for 6 months. Haemoglobin levels significantly increased from 99 ± 5 to 106 ± 6 g/L (p < 0.01), whilst serum TNF-α concentrations decreased from 623 ± 366 to 562 ± 358 pg/ml (p < 0.01). No changes were observed in untreated controls. Similarly, Cooper and associates[13] administered oxpentifylline (400 mg daily per os) for 4 months to 16 ESKD patients with EPO-resistant anaemia (defined as a haemoglobin level < 107 g/L for 6 months before treatment and an EPO dose ≥ 12,000 IU/week). Among the 12 patients who completed the study, mean haemoglobin concentration increased from 95 ± 9 to 117 ± 10 g/L (p = 0.0001), whilst ex vivo T cell generation of TNF-α and IFN-γ were significantly reduced.

Hepcidin may also play a role in ESA-resistant anaemia. This agent is produced by hepatocytes and secreted into the blood in response to iron status, anaemia, hypoxia and pro-inflammatory cytokines, especially IL-6[15,16,17] and IL-1.[18] Recently published data suggests that hepcidin binds to ferroportin (FPN1), a cellular iron exporter, resulting in internalisation and loss of function.[19] FPN1 is highly expressed in macrophages of the reticuloendothelial system and enterocytes in the duodenum and mediates iron release. In macrophages, the binding of hepcidin to FPN1 and its subsequent internalisation would result in iron accumulation within the cell and less release of iron. Patients with CKD may have elevated levels of IL-1, IL-6 and TNF-α.[20,21] It is possible that elevated levels of these cytokines in CKD increase hepcidin production and reduce iron release from macrophages in the bone marrow resulting in reduced availability of iron for erythropoiesis. In fact, prohepcidin was found to accumulate in renal insufficiency.[22,23]

In most signaling pathways involving TNF-α and IL-6, IL-6 is a downstream component from TNF via nuclear factor kappa B.[24] Thus, interference with TNF-α production can interfere with IL-6 signalling. In experimental models, oxpentifylline has been shown to reduce IL-6 expression.[25,26,27]

The available studies suggest that oxpentifylline may represent a significant advance in the treatment of ESA-resistant anaemia in chronic kidney disease, but they are limited by their lack of adequate controls and the associated potential for selection, observer and co-intervention biases. A prospective, randomized, double-blind, placebo-controlled trial is required to definitively test the hypothesis that oxpentifylline corrects ESA-resistant anaemia in chronic kidney patients. This study also offers the opportunity to explore the role of the novel peptide, hepcidin, as a possible mediator of iron availability and ESA-resistance.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.