Steven Fishbane, MD from The University of Pennsylvania, came to our fellowship program to discuss Fe and hemodialysis. He began by talking about hepcidin and then went on to discuss the iron targets in light of the DRIVE trial and then touched on IV Fe and proteinuria and finished with a discussion of platelets and mortality and its relationship to recent anemia trials.
He started by talking about why Fe deficiency is so prevelant among CKD and dialysis. As an explanation he did a brief overview of Hepcidin.
Fe is a powerful growth factor for bacteria.
During an infection the body decides to withold Fe.
Inflammation leads to increases in hepcidin which increases ferritin.
Hepcidin decreases intestinal iron absorption and increases Fe sequestration in RE system. The end result is a decrease in serum Fe and TSAT.
DRIVE Study by Daniel Coin and Morin was designed to see if giving Fe in patients with a high ferritin and low TSAT was effective.
Enrollment:
- Hgb less than 11
- ESA over 22,500 U/week
- Ferritin 500-1200
Ave TSAT 18, Ferritin 761, CRP 27, Hgb 10.3, ESA 34,000 U/wk
All patients had their ESA bumped 25% and randomized to either 1g of Fe or placebo.
The primary end-point was a change in hemoglobin over 6 weeks. The hemoglobin rose 10.2 to 11.3 in control and 10.4 to 11.9 in the Fe group over 6 weeks.
47% of the treatment group had an increase in hemoglobin of 2g versus 29% in the control group.
DRIVE-II by Kapoian
6 week follow-up after the randomized trial. Observational
Hgb increase was sustained despite the Fe group getting the Epo cut by 20% with no change in the in the epo dose of the control group.
Ferritin initially rose to 934 from 760+.
No different in responce in the patients with ferritin 500-800 vs 800-1200.
TSAT was not predictive of response low TSAT and high initial TSAT had the same response.
Prospectively studies cannot find link between IV Fe and infection.
Here is some criticism of the DRIVE study by the National Anemia Action Council:
The purpose of the DRIVE study and its six week extension, DRIVE II, was to determine the efficacy and safety of supplemental intravenous iron in anemic hemodialysis patients receiving recombinant erythropoietin who had a transferrin saturation <> 500 ng/mL. The intravenous iron group did increase their hemoglobin levels slightly more than control patients not given intravenous iron without additional toxicity, leading the authors to conclude that intravenous iron in this situation was both safe and effective. Unfortunately, the design and power of both studies were not sufficient for the investigators to reach these conclusions.
First, the decision to increase the dose of recombinant erythropoietin in each group by 25 % confuses the response to ESA and iron. In a chronic inflammatory state, such as chronic renal disease, the problem is not impaired iron availability but insufficient erythropoietin, which is required to mobilize iron and upregulate transferrin receptor expression. It is well recognized that erythropoietin trumps hepcidin in this situation and the authors merely confirmed that phenomenon.
Second, in the control groups of both DRIVE and DRIVE II, there were a disproportionate number of women, who are more likely to be iron deficient, and their response to recombinant erythropoietin proved this, reducing the effectiveness of comparisons.
Third, both DRIVE and DRIVE II were open label observational studies and in addition physician discretion was also allowed with respect to erythropoietin dosing and iron administration. This discretion can introduce significant bias, weakening the conclusions of the studies.
Fourth, no attempt to estimate blood loss, iatrogenic or otherwise, was made for either experimental group. Fifth, the difference in the hemoglobin level achieved with supplemental iron was not striking and also pushed the hemoglobin level above that currently recommended for safety reasons. Finally, since the serum ferritin and transferrin saturation increased in the iron-supplemented group, a state of iron overload was achieved that was unnecessary and the 12 week observation period was certainly not long enough to exclude the possibility of iron-induced organ toxicity.
It is clear that more data derived from larger prospective trials that are conducted for longer periods are needed. Until this data becomes available, anemic hemodialysis patients not responding to conventional doses of recombinant erythropoietin, in whom the serum ferritin is greater than 500 ng/mL, should first be evaluated for a source of blood loss or infection. Then the patient should be given a higher dose of recombinant erythropoietin for a minimum of 6 weeks with serial transferrin saturation and ferritin measurements before resorting to intravenous iron supplementation.
Fishbane then spoke about the possibility of proteinuria induced by iron sucrose. He showed the Agarwal data on proteinuria and IV iron. He stated that with out knowing how long the proteinuria lasted it was impossible to guess if this was important clinically.
Platelets in Nephrology
Fe deficiency causes reactive throbocytosis
ESAs raises platelets
ESAs cause fe deficiency
Increased RBC push platelets along the walls of the blood vessel. So treatment may cause a lot of atherothrombotic complications because they have both more platelets and red cells.
In DRIVE 20% drop in platelets with Fe treatment.
Streja Et al. used the Davita retrospective database to show a nice human association of TSAT and platelets with thrombosis. Importantly he showed no increase in mortality for Hgb over 13 when the data was controlled for the platelet count. Dr. Fishbane was unable to suggest a how one could design a prospective RCT to test this theory.
3. You then can select the volume yoiu want to look at. Volumes are like folders on your computer.
When you select either of the above directories you will need to accept the connection on the iPhone. This provides some degree of security.
To upload the files, launch an FTP client. I use Transmit by Panic software. Enter the ftp address at the bottom of the DataCase home screen and drag the files you want over to the iPhone.
You can view any of the files you uploaded on the iPhone right in the DataCase application.
