Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease.

AIM: To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. BACKGROUND: CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. METHODS: We studied 14 patients with stages 4-5 CKD (glomerular filtration rate <30mL/min per 1.73 m(2)) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. RESULTS: Ten patients (eGFR 23 + or - 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 + or - 5 g/L, ferritin 92 + or - 26 microg/L, transferrin saturation 15 + or - 3% and circulating IL-6 10.6 + or - 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 + or - 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 + or - 5%, P < 0.003) and decreased serum ferritin (81 + or - 25 microg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 + or - 6 g/L by week 4 (P < 0.001). CONCLUSIONS: Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.

Effects of cell proliferation on the uptake of transferrin-bound iron by human hepatoma cells.

The effects of cellular proliferation on the uptake of transferrin-bound iron (Tf-Fe) and expression of transferrin receptor-1 (TfR1) and transferrin receptor-2 (TfR2) were investigated using a human hepatoma (HuH7) cell line stably transfected with TfR1 antisense RNA expression vector to suppress TfR1 expression. At transferrin (Tf) concentrations of 50 nmol/L and 5 micromol/L, when Tf-Fe uptake occurs by the TfR1- and TfR1-independent (NTfR1)-mediated process, respectively, the rate of Fe uptake by proliferating cells was approximately 250% that of stationary cells. The maximum rate of Fe uptake by the TfR1- and NTfR1-mediated process by proliferating cells was increased to 200% and 300% that of stationary cells, respectively. The maximum binding of Tf by both TfR1- and NTfR1-mediated processes by proliferating cells was increased significantly to 160% that of stationary cells. TfR1 and TfR2-alpha protein levels expressed by proliferating cells was observed to be approximately 300% and 200% greater than the stationary cells, respectively. During the proliferating growth phase, expression of TfR1 messenger RNA (mRNA) increased to 300% whereas TfR2-alpha mRNA decreased to 50% that of stationary cells. In conclusion, an increase in Tf-Fe uptake by TfR1-mediated pathway by proliferating cells was associated with increased TfR1 mRNA and protein expression. An increase in Tf-Fe uptake by NTfR1-mediated pathway was correlated with an increase in TfR2-alpha protein expression but not TfR2-alpha mRNA. In conclusion, TfR2-alpha protein is likely to have a role in the mediation of Tf-Fe uptake by the NTfR1 process by HuH7 hepatoma cell in proliferating and stationary stages of growth.

Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats.

BACKGROUND & AIMS: Hepcidin is an antimicrobial peptide thought to be involved in the regulation of intestinal iron absorption. To further investigate its role in this process, we examined hepatic and duodenal gene expression in rats after the switch from a control diet to an iron-deficient diet. METHODS: Adult rats on an iron-replete diet were switched to an iron-deficient diet and the expression of iron homeostasis molecules in duodenal and liver tissue was studied over 14 days. Intestinal iron absorption was determined at these same time-points by measuring the retention of an oral dose of (59)Fe. RESULTS: Iron absorption increased 2.7-fold within 6 days of switching to an iron-deficient diet and was accompanied by an increase in the duodenal expression of Dcytb, divalent metal transporter 1, and Ireg1. These changes precisely correlated with decreases in hepatic hepcidin expression and transferrin saturation. No change in iron stores or hematologic parameters was detected. CONCLUSIONS: This study showed a close relationship between the expression of hepcidin, duodenal iron transporters, and iron absorption. Both hepcidin expression and iron absorption can be regulated before iron stores and erythropoiesis are affected, and transferrin saturation may signal such changes.