**6. Hemodialysis-associated hemosiderosis in the pre-ESA era**

Post-mortem studies performed at the end of the 1970s and early 1980s showed that iron deposits were abundant in the adrenal glands, lymph nodes and lungs of dialysis patients with severe hepatosplenic siderosis, and generally sparser in the heart, kidney and pancreas [30-32]. In the liver, the earliest detectable iron deposits were observed within cells lining the sinusoids and in Kupffer cells; as hepatic siderosis progressed, iron appeared within hepatocytes, first in the peripheral zones of the hepatic lobules in the vicinity of portal triads and subsequently throughout the lobules [30]. In the spleen, the principal site of iron storage was also the cells lining the splenic sinusoids, while the white pulp was generally spared [30]. Even in case of massive hepatic siderosis there was no cytological evidence of cell damage, but reticulin and trichrome stains showed an increase in the hepatic fibroconjunctive network, together with loss of liver cells [30-32]. Similarly, most patients who had marked hemosiderosis and underwent liver biopsy had focal portal fibrosis [33]. These post-mortem studies also showed a strong link between iron overload and both blood transfusions and intravenous highmolecular-weight iron dextran (IMFERON®); interestingly, the closest relationship was between hepatic siderosis and IV iron [5][31-32]. Iron overload was usually absent in patients who had received little or no IV iron [31], whereas massive hepatosplenic siderosis was only seen in patients with a dialysis vintage of more than 3 years [5][32]. Adrenal involvement was observed in 11/24 unselected patients in the work of Pitts and coworkers [32] but in 17/18 patients with severe hepatosplenic siderosis studied by Ali [30]. Pancreatic involvement was less frequent, affecting 7/24 patients studied by Pitts and coworkers and 5/18 patients with severe hepatoplenic siderosis studied by Ali [30]. Interestingly, significant cardiac iron deposits were found in respectively 16.6% (4/24) and 22% (5/22) of unselected patients in the autopsy studies of Pitts [31] and Gokal [32], whereas cardiac involvement was found in 44% (8/18) of the patients with severe hepatosplenic siderosis studied post-mortem by Ali [30].

In the pre-ESA era, one strategy to avoid blood transfusion-related iron overload in dialysis patients with transfusion-dependent anemia was to use young instead of mature erythrocytes for transfusions [33]. Tissue iron depletion with the chelator desferrioxamine was advocated to prevent hemosiderosis or to cure organ dysfunction due to iron overload [33].

At the beginning of the 1990s, the advent of recombinant human erythropoïetin allowed simultaneous treatment of anemia and iron overload by allowing massive mobilization of iron stores and effective phlebotomy (by partial letting of the extracorporeal circuit) at the end of dialysis sessions in patients rendered non anemic [34], together with the first successful use of non invasive radiological tools (liver quantitative computer tomography) to diagnose hemo‐ dialysis-associated hemosiderosis and to monitor iron stores [35].
