Anemia in Renal Disease: Update and Case Discussion
ASN Renal Week, Official Symposium, November, 2005
Questions received during this symposium have been paraphrased
and the answers submitted by the panelists are presented.
If the rate of decline in GFR is slower in IV iron-treated patients, do you think that that might be a result of increased oxygen delivery to the declining kidney?
Was there any difference between the efficacy of the smaller repetitious doses of iron versus the 2 larger bolus doses?
First, are there data on the use of pentoxifylline (Trental) as an adjuvant? Second, why do CKD patients responded well with IV iron, regardless of whether they are iron deficient or not?
Which oral iron product do you recommend, given the malabsorption and side effects associated with oral iron? Should we skip oral iron and go directly to IV iron?
Would gastric bleeding clear more quickly if you take reticulocyte count into account?
Could you comment on what you do in the anemic patient with elevated ferritin? Does doing a C-reactive protein help you?
In a nondialysed CKD patient, we check B12 levels and correct their B12 level first. Then, the dose of erythropoietin and the iron required can be reduced. Does B12 deficiency play a role in these patients?
If the patient’s iron saturation is really low, and the ferritin is 800, should you give IV iron to these patients?
There is a recent paper about B12 deficiency being increasingly common in elderly, nonuremic patients. Might B12 deficiency contribute to anemia in dialysis patients?
Panelist Responses(Back to question index) If the rate of decline in GFR is slower in IV iron-treated patients, do you think that that might be a result of increased oxygen delivery to the declining kidney?
Audience: In the ND-CKD abstract you presented, where it appears as if the rate of decline in GFR was slower in the IV iron-treated patients, do you think that that might be a result of increased oxygen delivery to the declining kidney?
Dr. Van Wyck: I would not make too much out of the differences. There were statistical differences, but it was an ad hoc analysis of a secondary outcome. In this setting, statistical differences may not translate to biological differences. I suspect that the appropriate conclusion is that neither IV iron nor oral iron contribute to rate of decline of GFR.
(Back to question index) Was there any difference between the efficacy of the smaller repetitious doses of iron versus the 2 larger bolus doses?
Audience: David, I do not know if your study was powered for the CKD ones. Was there any difference between the efficacy of the smaller, repetitious doses of iron versus the 2 larger bolus doses?
Dr. Van Wyck: It was not. The hemodialysis literature suggests that there is no difference between multiple small doses and less frequent higher doses. But, having said that, there are no studies looking specifically at effect of dosing frequency on efficacy. What Simon is asking is if you gave 200 mg once a month to a hemodialysis patient, is that the same as giving 50 mg a week? I do not know. My impression is that the two methods are equally effective.
(Back to question index) First, are there data on the use of pentoxifylline (Trental) as an adjuvant? Second, why do CKD patients responded well with IV iron, regardless of whether they are iron deficient or not?
Audience: First, on the adjuvant therapy. There was a mention about the use of pentoxifylline, or Trental? Apparently, this agent has an antiinflammatory effect by decreasing interleukin-6 and TNF? Can you elaborate? Second, I would also like to know what is the possible reason why CKD patients responded well with IV iron, regardless if they are iron deficient or not?
Dr. Berns: Thank you. So, there are 2 questions. The first was regarding pentoxifylline as an adjuvant. There is, to my knowledge, only one study so far that has looked at this. It was uncontrolled. And I think what you said is an interesting idea that is going to have to be tested more thoroughly before we have any sense of whether that is effective therapy or not. The second question was for David.
Dr. Van Wyck: The second question is, What utility do baseline iron tests have? In the nondialysis CKD patient who is receiving neither IV iron nor ESA, the relationship between ferritin, TSAT and Hb is known and is clinically helpful: a ferritin below the <25 ng/ml threshold is associated with low Hb values, making this ferritin cutoff a useful marker for iron deficiency anemia; there is no such threshold seen for TSAT however, since TSAT is linearly related to Hb from < 16% TO > 40%, meaning that the lower the TSAT, the more likely it is to be contributing to anemia. In short, ferritin and TSAT show diagnostic utility, albeit for different reasons, in the untreated CKD patient. They show no diagnostic utility, however, in predicting response to IV iron therapy. We found that IV iron was equally effective (or ineffective) at any level of any baseline iron test. It may just be that supraphysiologic iron administration affords efficacy even when physiologic levels of iron are normal or adequate.
(Back to question index) Which oral iron product do you recommend, given the malabsorption and side effects associated with oral iron? Should we skip oral iron and go directly to IV iron?
Audience: Iron causes constipation in all our CKD patients. Iron is also malabsorbed. So, why bother? Given these caveats, which iron pill will you recommend? Also, do you think it is reasonable just to skip it altogether and go directly to IV iron?
Dr. Van Wyck: In the oral iron treated ND-CKD group, we saw poor compliance, as expected, and more GI symptoms than in the IV iron treated group. What I would recommend, if you are going to use oral iron, is to use a cheap one. Ferrous sulfate in my local Walgreens store costs about 5 cents a tablet. Prescribe ferrous sulfate 325 mg 3 times a day for as long as it is needed, but don't start ESA until you have completed your trial. If you are going to use ESA, skip or stop oral iron, because the chance of oral iron failure is high and the cost of ESA failure is also high. If you are considering ESA therapy and want to minimize ESA doses and maximize Hb response, either start with a trial of IV iron alone or start IV iron with ESA.
(Back to question index) Would gastric bleeding clear more quickly if you take reticulocyte count into account?
Audience: Would you have cleared your case of gastric bleeding more quickly if you had taken reticulocyte count into account?
Dr. Berns: I do not know what the practice is actually around the country or around the world. In our particular area, I actually infrequently look at reticulocyte count in that I find them varying for unexplained reasons. But I think your point is a good one. There certainly may have been other markers of iron metabolism that may have been more sensitive, that may have allowed the diagnosis to be picked up earlier obviously.
Audience: I just wanted to make a comment. I feel IV iron is more efficient, but oral iron therapy is also possible. We have shown it in hemodialysis patients. When given oral iron during dialysis 3 times a week, we found that in uncomplicated patients, patients who did not bleed like this patient, we got a mean EPO dosage of 60 units/kg/week. Then, in a follow-up study, I studied iron absorption in dialysis patients and found that, as we know, the absorption impairment is less severe in patients who have spent less time on dialysis. So, there is really a correlation between end-stage renal disease duration and iron absorption. Also, it is less impaired in nondiabetic patients. So, I guess that in this subset of patients, especially if they are nondiabetic, and in patients who have not been for years on dialysis, if they do not have complications of infection or bleeding, oral iron therapy during dialysis can be tried.
(Back to question index) Could you comment on what you do in the anemic patient with elevated ferritin? Does testing for C-reactive protein help you?
Audience: There seems to be quite a controversy about intravenous iron therapy in the face of an elevated ferritin. Could you comment on what you do? For example, suppose the ferritin is approximately 800, and the TSAT is 18. The patient is anemic, with a hemoglobin of 7. What do you do? Do you give that kind of a patient intravenous iron? If you do, how do you do it?
Dr. Van Wyck: I do not routinely give IV iron in that situation, because I don't know that IV iron is safe in patients with high ferritins and I do know that an increase in ESA dose is sufficient to correct the Hb. Just to review, this is a patient with a sub-11 hemoglobin, on an ESA, who has a high ferritin and low TSAT. We know from RCTs that virtually all patients will respond to an increase in ESA dose. From these RCTs we know that ESA therapy within recommended Hb targets is both safe and effective. We have very little efficacy information and no safety information on the safety of IV iron administration in patients with high ferritins.
Audience: My experience is that no matter how high you give the erythropoietin, it does not respond. They do not respond.
Dr. Van Wyck: That is not the case generally. We know that 99.6% of patients with sub-11 hemoglobins, regardless of the cause, will respond to, and will reach target range hemoglobin if they have at least 30,000 units per week. That information was presented earlier.
Audience: We must have different patients in Atlanta. You give them up to 90,000 units, and their hemoglobin remains low.
Dr. Van Wyck: There are selected patients who will need more. That is why I leave room for the trial administration of IV iron to such patients. But I do not routinely give IV iron to patients with ferritins that are high.
Audience: Does doing a C-reactive protein help you in solving that problem?
Dr. Van Wyck: No, usually it is obvious why they have high ferritins and low TSATs. They look sick. They are sick. They have nonhealing wounds, infected catheters, frequent hospitalizations. A C-reactive protein, IL-6, TNF are all usually high, but it does not help to discriminate one from the other.
Audience: I tell you what I do. I do the C-reactive protein, and if it is high, I empirically treat it with antibiotics. The C-reactive goes down, and then you can treat with iron at the lower dosage, and the patients respond much better.
Dr. Van Wyck: Then I encourage you to do the trial and publish the results. Thanks for your comments.
(Back to question index) In a nondialysed CKD patient, we check B12 levels and correct their B12 level first. Then, the dose of erythropoietin and the iron required can be reduced. Does B12 deficiency play a role in these patients?
Audience: You demonstrated 30,000 units of erythropoietin. I think in India we cannot afford this much erythropoietin. Whenever there is iron resistance, you see normal ferritin and a normal iron. What we usually do in India, we check a B12 level. In our tropical country (India), serum B12s are very low. In a nondialysed CKD patient, we check B12 level, and correct their B12 level. Then the dose of erythropoietin and iron is lower, and the hemoglobin comes up. So, in your resistance case also, I think you never ask for B12 level, and in your list also. In erythropoietin nonresponsiveness, we in India, we always see a B12 level – at least I see – and then check for the B12 level, raise up their B12 level by giving B12 injectable, and then we get a good response.
Dr. Berns: Thanks for your comment. I did have B12 and folate on my list. In the United States, it is quite uncommon, but it certainly is something that needs to be considered.
Audience: But, in our tropical country, I think, we have a lot of B12 deficiency and we get it checked.
Dr. Berns: Sure. I appreciate your comment. Thank you.
(Back to question index) If the patient’s iron saturation is really low, and the ferritin is 800, should you give IV iron to these patients?
Audience: Just continuing on the same topic, Dr. Van Wyck, if the patient’s iron saturation is really low, let us say, 5% or 7%, and the ferritin is 800, some of the patients who have been in the hospital for chronic osteo or things like that, would there be a case for giving IV iron to these patients?
Dr. Van Wyck: Can you take the osteo out for a moment?
Audience: OK, let's take the osteo out.
Dr. Van Wyck: Let us say vasculitis with a TSAT of 3% and a ferritin of 1000. The patient is on dialysis, and the MCV is 70. So, we know that this is iron deficiency, erythropoiesis of longstanding. So, all of those factors are in. We suspect that this is iron deficiency. I might try a gram of IV iron. But if it does not work, I would not give it again. The only data on IV iron in such patients shows a transient response, which does not last very long. But there will be better data.
(Back to question index) There is a recent paper about B12 deficiency being increasingly common in elderly, nonuremic patients. Might B12 deficiency contribute to anemia in dialysis patients?
Audience: There was a paper recently, picking up on what my colleague said about B12, about B12 deficiency being not rare in elderly patients, nonuremic patients. But we never hear about this issue in dialysis patients. And you think, if these nonuremic patients can become B12 deficient - and of course they cannot absorb it, you have to give 300 or 1000 mcg to correct it – but if all of these nonuremic patients, or a substantial number of them can get B12 deficient, why is it that ESRD patients who also tend to be elderly, it does not seem to be a problem or at least we are not recognizing it? I cannot remember anybody really being treated for B12 deficiency. And I just wonder if it might contribute, uncommonly, but maybe more commonly than you may realize, to anemia.
Dr. Berns: There has been very little study of this. There actually have been a couple of studies looking at folate and B12 supplementation in those who are not deficient. And it does not seem to work in, or help, in those circumstances. It seems to be uncommon for whatever reason. And,as you suggested, I think you are correct, in that we would expect it to be probably more common than it is. But, we look in all of our CKD and our dialysis patients. It is a limited sample, but we just find it very, very rare nowadays. But, you will find an occasional patient, as somebody else had suggested earlier. It is something that should be looked at, either before therapy or during therapy if the patient is proving to be less responsive than you would like.
Dr. Van Wyck: In all the ESA trial literature, there is one patient from France who had B12-deficient anemia who responded to B12. No other problems with B12. It is an interesting problem what you say. B12 deficiency, not pernicious anemia, but B12 deficiency, is a problem in the elderly, and it is a common problem. Our patients are that old, but they do not have B12 deficiency that contributes to anemia very often.
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