ESAs in Patients with CKD and Cancer: Is the Risk Worth the Benefit?

Anemia is a common manifestation of CKD. Currently, there are no guidelines for nephrologists regarding erythropoietin stimulating agents (ESAs or Epo or Darbe) use in patients with CKD with previous or active malignancy. Recently an excellent review of this topic was published in Kidney International by Hazzan et al. Let’s go over some of the key points.

Erythropoietin Biology and Relevance in Malignancy

• Besides stimulating erythropoiesis, Epo has been shown to have both anti-apoptotic and pro-proliferative actions in endothelial cells, brain +/- spinal cord, kidney and heart. Furthermore, Epo has also been shown to promote angiogenesis in endothelial cells. These non-erythroid functions of Epo are not fully understood.
• Epo mediated angiogenesis appears to be physiologic and driven by hypoxia but may play pathological role in proliferative diabetic retinopathy.
• Because angiogenesis is important for tumor survival and progression, it is important to know if cancer cells express the EPo receptor (EpoR). Initial evaluations for the EpoR on cancer cells, tested either for the Epo- receptor antibody (the antibodies used were non-specific) or mRNA transcripts (which were potentially contaminated by other cell types from blood or stromal tissue) and were less informative. Recent development of first specific antibody to the EpoR (A82) with both positive and negative controls will allow more rigorous testing for the EpoR protein on cancer cells. Swift et al. studied 66 cell lines and found either no or very low levels of the EpoR protein. Although current data does not show strong evidence of presence of functional EpoR on cancer cells, we need more evidence to draw a definite conclusion.
• In absence of EpoR, Epo induced supra-physiologic Hb levels would increase oxygen delivery to cancer cells and potentially stimulate proliferation.
• Also, hypothetically, binding of Epo to EpoR expressed on activated macrophages can suppress NF-kB activation and proinflammatory genes, resulting in an immunosuppressive effect. 

Nephrology Literature on ESA usage in Patients with CKD and Cancer

• The TREAT trial was a landmark study in the field of nephrology which was published in 2009 in the NEJM. The TREAT (and CHOIR) trials changed how we treated anemia. In this study, more than 4000 diabetic CKD patients with anemia were randomized to either higher hemoglobin (Hb) target (13 g/dl) with darbepoetin or lower hb target (9 g/dl) in placebo arm. Surprisingly, there was a trend towards increased risk of death due to cancer in the Epo group (darbepoetin alfa group 39 deaths, placebo group 25 deaths, P=0.08). Also, in patients with a previous history of cancer, there was increased mortality due to malignancy in Epo group (darbepoeitin alpha 14/188 deaths, Control 1/160 deaths, P=0.002). These results, for the first time, raised concern regarding possible association of Epo with cancer.
• However, a year later in 2010 Japanese study in CKD stages 4 and 5, failed to show an increased incidence of cancer with Epo. But this study targeted lower Hb (10.1 g/dl) and had a short follow up period.
• Seliger et al found that Epo increased the risk of stroke, only in CKD patients with diagnosis of cancer. But cancer group received higher initial ESA dose even though the pre-ESA Hb was similar in both groups.

Oncology Literature on ESA use in Patients with CKD and Cancer

Head and neck cancer trials had used Epo to increase tumor oxygenation in an effort to increase efficacy of radiotherapy.

• ENHANCE TRIAL 2003 was conducted in head and neck cancer patients given ESAs while under-going only radiotherapy (no chemotherapy). Surprisingly, locoregional progression-free survival was found to be poorer with epoetin (where patients were treated to Hb 14–15 g/dl) than with placebo.
• Similar results were found by DANISH RCT which reported 10% difference in 3-year local/regional control in favor of the control group (P=0.01) compared to darbepoetin group 

Meta-Analysis of Outcomes of Mortality with ESAs

• Cochrane database analysis- Dec 2012 , found strong evidence that ESAs increased mortality during the active study periods (death occurring up to 30 days after active study protocol) (hazard ratio 1.17; 95% CI 1.06–1.29), and borderline evidence that ESAs decreased overall survival (hazard ratio 1.05; 95% CI 1.00–1.11). The increase in mortality risk was seen in studies where patients had Hb higher than 12 g/dl before Epo treatment. 
• Mortality risk was higher in patients who received Epo without concurrent chemotherapy but these trends in patients receiving Epo and concurrent chemotherapy are not clear.
• There is insufficient evidence to know if the risk is dependent on the cancer type. 

Clinical Implications and Recommendations for ESA use in Patients with CKD and Cancer 
1. The nondialysis CKD/ESRD patient with current cancer:

• Only FDA indication for ESA treatment is for anemia caused by current myelosuppressive chemotherapy; there is no indication for patients with cancer not receiving chemotherapy.
• If acute severe, symptomatic anemia is present, then blood transfusion is the treatment of choice. 
• Suggest generally limiting the Hb target to an upper level of 10 g/dl to prevent risk of stroke and mortality with higher Hb targets.
• For the occasional patients who still have anemia-related symptoms, a slightly higher Hb target may be considered. 
• Intravenous iron may be given to minimize total ESA dose exposure.
• The FDA and some oncology guidelines recommend against the use of ESAs if chemotherapy treatment is with curative intent.
• Hazzan et al feel that ESA treatment is probably reasonable for the advanced non-dialysis CKD/ESRD patient receiving chemotherapy with curative intent but with an upper Hb target of only 10 g/dl. However patient counselling of the risk and benefits is mandatory before Epo use. 

2. The nondialysis CKD/ESRD patient with a previous history of cancer:

• Discuss with patient`s oncologist if the cancer is cured. Ask about risk of recurrence and the risk for other tumors related to the primary malignancy or its treatment.
• For up to 5 years after potential cure, treat with ESAs as if active cancer was present, maintaining an upper limit of Hb of 10 g/dl.
• Even after confirmed cure with very low risk for recurrence, make efforts to reduce ESA dose exposure by ruling out other treatable causes of anemia. (Remember TREAT trial) 

3. The nondialysis CKD/ESRD patient with no active or previous cancer:

• If high risk for cancer such as strong family history of colon cancer or breast cancer or if the patient is a smoker, or past exposure to cyclophosphamide, use conservative Hb targets to minimize any potential risk of ESA, if any.
• If no risk factors for malignancy then treat as per usual CKD/ESRD protocols. 

The article does not discuss situation where patient with active cancer have metastatic disease and limited life expectancy. If patients are on palliative chemotherapy or have stopped cancer treatment, then I feel that in such patients it is reasonable to give them Epo to improve quality of life, after a detailed discussion of the risk involved. This may be one situation where the benefit outweighs harm. These seem to be practical recommendations to me until we have new data on this topic. How do you deal with your patient in this situation? What is the practice pattern at your Centre?

Amit Langote MD
Nephrology Fellow
Ottawa, Canada

Hemoglobin Targets in CKD

For anyone who would like to read a thorough review of the current evidence with regard to Hb targets and the use of ESAs in  patients with CKD and those on dialysis, I strongly recommend the review published in Nature Reviews Nephrology this month. The field of anemia treatment if CKD has changed completely in the last 10 years. Hb targets have gotten considerably lower and the "one size fits all" model is changing into a model based on individualized Hb targets.

Two questions remain to be answered fully:
- In patients with CKD, is it the high Hb that is dangerous or is it the high doses of ESAs?
- What do we do with patients on dialysis who are not even achieving the new lower targets despite escalating doses of an ESA

My personal bias is that it is the ESA that is the problem rather than the Hb dose. Observational studies have shown that patients who achieve high Hb targets without the use of an ESA have no increased risk of CVD. ESAs are known to activate the vasculature and potentially increase the production of profibrotic and prothrombotic circulating factors. Patients who require very high doses of an ESA to achieve a particular Hb target are a high risk group and it may be that the requirement for such high doses is a marker of disease burden.

The Normal Hematocrit Study (NHCT) was published in the NEJM in 1998 and reported that there was a non-significant increase in mortality in patients in the high Hb group. However, there was a benefit in terms of QOL in patients with a higher Hb. This study has been criticized before and further analysis of the outcomes has shown that when the patients were followed for a longer period, there was a statistically significant increase in mortality in the high Hb group. Last year, a paper in KI reanalyzed the results of this study and found that this increase in mortality was evident even earlier that had been reported.

There was another fascinating finding in this report. The original study reported quality of life in patients based on achieved Hb levels. Thus, higher Hb was associated with better QOL irregardless of whether or not the patient was in the high Hb group. There was no difference in QOL between the randomized groups. In other words, it wasn't the ESA that was making the difference - there was a difference between those patients who had high Hb levels compared to those who did not reach those levels that was not related to the use of an ESA: patients who are healthier and respond better to an ESA have higher QOL scores! There was a misinterpretation of these results to mean that high ESA doses were associated with better QOL which has subsequently been proved wrong.

There was an accompanying editorial with that KI article that is definitely worth a read and advocates for new standards in the reporting of clinical trials.

Role of erythropoietin in acute kidney injury: what does the evidence say?

Since the discovery of Erythropoietin in 1977 and subsequent cloning of the gene in 1985, recombinant Erythropoietin (EPO) has been widely used in the management of anemia due to cancer, chemotherapy, and chronic kidney disease.

Although the endocrine effects of EPO in stimulating maturation and differentiation of erythroid precursor cells in the bone in response to hypoxia is widely known, the anti-apoptotic and anti-inflammatory properties particularly in the critical organs such as kidney, heart and brain were discovered only in the last decade.

Researchers from the United States demonstrated that EPO receptors are expressed in the renal tubular epithelial cells, proximal tubular cells, and mesangial cells. EPO induced activation of these receptors leads to activation of Janus activated kinase 2(JAK-2) pathway which in turn stimulates several other signaling pathways (MAPK,NFKB,STAT 3/5), all of which promote anti-apoptotic and proliferative proteins that increase cell survival (read this article).

With this knowledge, researchers from Australia demonstrated that EPO administration both in vitro and in vivo in doses up to 5000 U/kg in animals with ischemic AKI hastened cell recovery and prevented cell death. Several other researchers have demonstrated this effect in different injury models (hypoxia, ischemia-reperfusion, nephrotoxins, sepsis etc).

As would be expected, these promising results in animal studies led to a randomized, double blind, placebo controlled trial (EARLYARF) in 529 ICU patients who were identified at risk of AKI by urinary biomarkers(c-glutamyl transpeptidase and alkaline phosphatase ≥46.3). Administration of 100,000 units of EPO IV in 2 divided doses over 24 hrs did not reduce the risk of developing AKI, quite contrary to what was seen in animal studies.

In my opinion, likely causes for this discrepancy included:

1) Dosing in animals had been much higher (equivalent to up to 350000 units in humans).

2) Optimal timing of EPO administration might be an issue (within 6 hrs of injury)

3) Unclear, if the ideal urinary biomarkers were used.

Further studies with proper dosing and timing of EPO administration and early identification of patients with risk of AKI using ideal urinary biomarkers may answer this question best. Besides, the utility of administering EPO to ICU patients to reduce transfusions has already been refuted, is not cost effective and may be associated with 40% increased risk of thrombotic events (read this blog). This leaves us with no good indication to consider EPO in critically ill patients with AKI (not ESRD).

If you are a big believer of basic research, you may still want to consider EPO for its favorable actions, but with recent negative publicity EPO has been receiving, it appears like the clock is quickly moving towards “may be not or even no”.

Epo: The honeymoon is not over

Having just returned from my own honeymoon, I was taken by this recent hypothesis-piece by Fishbane et al. They have made some observations on the natural history of untreated renal anemia from examining the placebo arm of the recent TREAT RCT. Briefly, placebo-treated patients in TREAT received rescue therapy with Epo only if their Hgb levels fell to less than 9.0 g/dl; Epo was discontinued and patients returned to placebo as soon as their Hgb levels rose above this level. By this design, the placebo arm of TREAT sheds light on a very conservative approach to anemia management in pre-dialysis CKD.

Interestingly, analogous to patients with newly diagnosed type 1 DM who commonly experience a sharp reduction in their insulin requirement after initial presentation, there appears to be a similar “honeymoon period” after initial presentation with renal anemia, during which the hematocrit stabilizes or even increases (see figure) without treatment. An explanation may be that CKD patients presenting with an acute event such as infection may experience an abrupt, transient, decline in serum erythropoietin levels, and worsening of anemia. As they recover from the presenting event, serum erythropoietin levels and Hgb may also improve. However, this improvement would be masked in patients already initiated on maintenance outpatient Epo.


Many Nephrologists feel as though they are stuck between a rock and a hard place when it comes to Epo administration post-TREAT. This observation may encourage them to hold their nerve in CKD patients who initially appear to require Epo, as the anemia may well improve given time, at least in the short term. Of course, most patients with progressive CKD (save those perhaps with APCKD) will ultimately develop intractable anemia. A further RCT is required to know how to treat them, perhaps with a “TREAT placebo arm” vs. “no Epo at all” design. Perhaps, it could be called the DIVORCE trial (Darbepoetin Intermittently Vs Observation in Renal anemia of CKD).

Does CAPRIT trial need a TREAT!!!!!

This morning at ATC, the results of a very interesting trial were presented. I would like to share them with you so we can look at them more carefully once the paper is published. The CAPRIT trial is the first randomized trial in kidney transplant recipients to evaluate the impact of complete normalization of anemia on the progression of the allograft function. Another anemia study!!!

It is a European multicentral trial of 126 patients who received kidney transplants more than 12 months before enrollment with CrCL between 20 and 50 and Hg level less than 11.5 mg/dL. Patients were randomized to either high Hg level group A with target Hg of 13-15 or to the low Hg level group B with Hg goal of 10.5-11.5 and were treated accordingly with ESA to achieve goal. Patients’ characteristics were similar, mainly the age at inclusion, age at transplant and mean GFR (34 and 33). Number of patients on ACEI/ARBs was similar in the two groups, both at the start of the study and at 2 years (the end of the study). Patients with Rapamune were excluded and all patients were on CNI and MMF with or without prednisone. 89% of the patients in group A were treated with EPO v.s 61 % in the lower Hg group with obviously higher dose in the higher Hg group.

There was a significantly higher mean GFR in the high Hg level group compared to low Hg level group and an increase rate of graft survival at 2 years with no difference in adverse events including cardiovascular events, stroke or thrombosis events. How to look at this data few months after the TREAT trial results were reported?

Although we are looking at different population of patients in the two trials but I find it difficult to believe this data in view of all the evidence that higher Hg is harmful, and we probably should wait for larger trial before we change our practice.

Complications of EPO Use

Well, I had hoped to be more of an active blogger during my holiday vacation this year, but my internet access has been much spottier than desired way out in the boondocks of Western France (not that I expect any renal fellows stuck in the hospital to be sympathetic to my plight in the slightest...) I'll post when I can:

Here's a list of some complications of erythropoietin use:

1. Increased thrombotic events. As the CHOIR study and others have now convincingly shown, elevated hemoglobin targets in CKD/ESRD patients are associated with an increased risk of cardiovascular events (the CHOIR study in particular demonstrated a hazard ratio of 1.34 in CKD patients randomized to a high Hgb target compared to a lower Hgb target, using a composite endpoint of death, MI, CHF requiring hospitalization, and stroke).

2. Hypertension: Patients may even experience intradialytic hypertension after receiving erythropoietin.

3. AV graft thrombosis: again, this correlates with the first point, that elevated Hgb concentrations can result in increased thrombotic events.

4. Pure red cell aplasia: rarely, patients can develop anti-EPO antibodies that result in pure red cell aplasia; this was predominantly associated with a form of EPO (Eprex) not marketed within the U.S.

5. Seizures: via a mechanism that appears uncertain.

6. Progression of diabetic proliferative retinopathy: because EPO has some angiogenic activity, it has been suggested to cause worsening of diabetic retinopathy, with some clinical studies appearing to confirm this hypothesis.

Link Between CMV Status & EPO Requirements

Why do some dialysis patients require so much more Epogen than others? Some patients manage to hit their targets with relatively low doses, and may even require "holding" EPO injections to avoid the upper hemoglobin range where excess thromboembolic events occur; other patients struggle to achieve a Hgb greater than 10 despite massive doses of EPO and seemingly adequate iron stores. The variables are manifold, but one common assertion is that individuals with a high degree of chronic inflammation tend to be the ones with the greatest resistance to EPO.

A more novel link is reported in this month's JASN: a manuscript by Betjes et al describes an association between ESRD patients with CMV-positivity and those with EPO resistance. It turns out that individuals infected with CMV have an altered profile of T-cells: they tend to have high percentages of CD4+ T-cells which lack the co-stimulatory molecule CD28, whereas patients who are CMV negative contain very small (less than 5%) numbers of these cells. These CD4+ CD28- cells apparently are very pro-inflammatory, capable of secreting large amounts of IFN-gamma and TNF-alpha, which the authors cite as a plausible mechanism to explain why CMV-positive dialysis patients tended to have higher EPO requirements (12,000 units versus 6,300 units per week) than CMV-negative dialysis patients.

The study is potentially significant in that it implicates a common virus in aspects of the chronic inflammatory state known to be associated with poor outcomes in CKD and ESRD, and even points towards antiviral medications as a potential therapy for preventing some of the cardiovascular complications of ESRD. Of course, the big caveat is that the association does not necessary reflect causality; for instance, it may be possible that "sicker", more chronically-inflamed dialysis patients may simply be more susceptible to acquiring CMV seropositivity.

TREAT Trial

The TREAT trial was one of the bigger stories to emerge from this years ASN. This was a large, multicenter trial of darbepoeitin (Aranesp) vs. placebo in 4000 predialysis CKD patients with type 2 diabetes and anemia. The two groups did not differ in the two primary endpoints of all-cause death or cardiovascular event and death or end-stage renal disease and on the plus side, compared with placebo, treatment with Aranesp did result in some improvement in fatigue, less need for red-cell transfusions and a reduction in cardiac revascularization. However, there was also a significantly increased risk of fatal or nonfatal stroke (5% versus 2.6%; HR 1.92, 95% CI 1.38 to 2.68), which was not explained by systolic blood pressure.

The Aranesp group was treated to achieve a target hemoglobin of 13 g/dL, which is higher than I generally aim for, and it may be that a more restrictive dosing strategy could mitigate the risk of stroke. Even still, these findings create a lot of uncertainty and unease as to how best manage anemic CKD patients in the clinic.

As a footnote, this study also lends fuel to the growing literature on ESA’s driving the progression of cancer. In patients with a history of malignancy at baseline, cancer death was an order of magnitude more common in the darbepoetin group (7.4% versus 0.06%, P=0.002).

ESA Glycosylation

There are numerous formulations of recombinant human erythropoietin, but only a few of which are used in the U.S.  Generally speaking, all of the formulations have the exact same 165 amino acid core sequence which encodes the human erythropoietin protein; the main aspect in which they differ is in their degree of glycosylation.

Glycosylation refers to the enzymatic attachment of sugar molecules onto a protein via Asparigine residues (N-linked glycosylation) or via Threonine or Serine residues (O-linked glycosylation).  It turns out to be extremely important for stability of EPO, as non-glycosylated recombinant erythropoietin has an extremely short (and therefore not clinically useful) half-life.  A breakthrough in the manufacture of recombinant human erythropoietin came with the manufacture of transfected EPO within Chinese hamster ovary (CHO) cells, a cell line which is avidly glycosylates proteins.  

Epoetin-alpha (either Procrit or Epogen in the U.S., and Eprex in Europe) is grown in CHO cells and consists of about 40% carbohydrate.  These medications are all about 30kD and have a half-life of about 7-8 hours.

Darbepoeitin-alpha (Aranesp) has a slightly modified amino acid sequence which adds an additional 2 N-linked glycosylation sites,  which increases the drug to 51% carbohyrate content, 37.1 kD in size, and a half-life of between 21-24 hours.  

There are other recombinant human erythropoietins (e.g., epoetin-beta, epoetin-delta, epoetin-omega) but these are not commonly used in the U.S.   

Bundling

It's a hot topic amongst dialysis centers around the country: bundling. Here's my attempt to explain it in a brief manner. If anybody has corrections or comments about this explanation, feel free to make them known.

With the Social Security Act of 1973, all U.S. ESRD patients were given the right to free dialysis--and since that time, the ESRD Program has comprised a very significant portion of the overall Medicare Budget. The Centers for Medicare and Medicaid Services (CMS), a division of the Department of Health and Human Services (HHS), is in charge of administering the ESRD Program and setting the reimbursement prices for dialysis centers.

Currently, CMS divides the ESRD budget into two distinct services. First, there is a "bundled" payment which takes into account all the nursing, dialysis equipment, and many of the routine lab tests; essentially, one lump sum per patient per dialysis treatment is given which does not vary. Second, there is a category of "separately billable" items which includes the injected medications administered during dialysis and a few of the more recent lab tests. According to the current plan, each "separately billable" item is reimbursed at a rate 6% above the manufacturers' average sales price (ASP). Dialysis centers can make a profit from this policy, and accordingly, the more "separately billable" items are ordered, the greater the ability to generate profit. This has been especially welcomed by dialysis units, as the bundled payment has not been adjusted for inflation and the units rely more and more heavily on "separately billable" items to cover the increasing costs of running a center.

There is now a strong push by CMS to change the ESRD policy such that the entire dialysis process--both the dialysis treatment itself as well as any injectable medications or labs--become a single "bundled payment." According to this report by the Government Accountability Office (GAO), a single bundled dialysis care payment would "increase efficiency and clinical flexibility."

The medication Epogen is central to understanding the current move towards a bundled payment. Epogen was by far the most pricey "separately billable item" within the ESRD budget, accounting for about $2 billion annually. In the report, the fact that Amgen (the company which makes Epogen) has no competition on the market is cited as a reason for these staggering costs. The report goes on to suggest that placing Epogen within a bundled payment would force physicians to use the drug more judiciously and allow them to adapt strategies that could minimize Epogen doses--for example, subcutaneous rather than intravenous dosing.

The proposal of bundled dialysis payments is, understandably, still a controversial one. Will dialysis units be fairly compensated in a bundled system? We don't have the proposed numbers yet to judge. Will patients still have access to important drugs and breakthroughs? Some have even suggested that a bundling policy might discourage some dialysis centers from taking African-American patients, who tend to have higher Epogen requirements, and therefore lead to racial discrimination; medically complex patients might also fall into the category of an "undesirable dialysis patient" from a cost perspective. The one thing that is for sure is that whatever the policy turns out to be, it will undoubtedly have major effects on nearly every nephrologist practicing with the U.S.

The Erythropoietin Receptor

As we all know, erythropoietin is secreted predominantly by the kidney (85% from the kidney, 15% from the liver) in response to hypoxia and its function is to stimulate erythropoiesis in the bone marrow.  What  is the receptor on which erythropoietin works?  

The Epo receptor is a member of the cytokine receptor family expressed on the cell surface of erythroid precursors.  Although the Epo receptor itself does not have kinase activity, it is bound by the tyrosine kinase Jak2, also called Janus kinase 2.  The activation of downstream transcription factors by Jak2 (e.g., the Stat family of transcription factors) results in accelerated erythrocyte maturation.

Interestingly, a common mutation in the Jak2 gene (V617F) accounts for the majority of cases of polycythemia vera--the hematologic condition in which there is a primary elevation in the hematocrit which can result in thrombotic complications.  These patients have a low circulating EPO level, but as the EPO receptor is constitutively active, there is always accelerated erythropoeisis.  

Route of EPO Administration

In the U.S., erythropoietin is typically delivered as 3x/week intravenous injections in the ESRD population. This turns out to be a fairly significant cost, as Medicare-related payments for EPO comprise about 25% of the ESRD budget, which itself is a significant chunk (about 6-7% as of 2002) of the overall Medicare budget.

This cost could probably be decreased by moving to subcutaneous dosing of erythropoietin. One study in France showed in a 1-year crossover study in which ESRD patients received subcutaneous dosing for 6 months, followed by intravenous dosing for 6 months, the EPO dose required to keep the Hgb within a usual target range was far less in the subcutaneous group (74 Units/kg/week) compared to the intravenous group (156 Units/kg/week).

I would imagine that the main barriers towards achieving this would be (a) financial--as it stands now, dialysis units make more money if they administer greater amounts of EPO, (b) legislative--the Social Security Act which has made the Medicare ESRD Program into what it is today specifies that self-administered medications are not covered by Medicare, (c) patient preference--most patients would prefer to avoid another needle stick each dialysis session, and (d) the status quo--that's just the way we're used to doing things.

DRIVE Study

There are numerous reasons as to why an ESRD patient might be "EPO-resistant", and perhaps the most obvious one to exclude initially is iron deficiency: you can't make more red blood cells if you don't have enough iron (pictures in lump metal form on the left). Generally speaking, iron deficiency is traditionally diagnosed by having a low MCV, a transferrin saturation less than 20%, and a ferritin level <200.>

However, there is some confusion as to what to do with patients who are EPO-resistant despite having apparently "adequate" iron stores based on the values above. Using ferritin as a marker for iron stores has some caveats associated with it, as ferritin is upregulated during inflammation and thus may underestimate the degree of functional iron deficiency in a dialysis patient.

With this mind, the makers of Ferrlicit designed the DRIVE study, in which dialysis patients with a low Hgb (<11.0g/dL), high ferritin (500-1200 mg/dL), and low transferrin saturation (<25%) were randomized to receive (or not) 1 gram of iv iron administered over dialysis sessions. Both this trial as well as the follow-up DRIVE-II study reported that the iron-treated
group developed higher Tf-sat's and a reduced EPO requirement, suggesting that in some patients an elevated ferritin is not a good marker for iron deficiency. Although the authors report no significant safety issues in the iron-treated group compared with the control group, there is still some concern about the use of continuous iv iron in patients with chronic
inflammation.

Pure Red Cell Aplasia

One of the rare but serious side effects of recombinant erythropoietin therapy is the possibility of pure red cell aplasia, an autoimmune condition in which antibodies against erythropoietin result in T-cell-mediated destruction of erythroid precursors.  It may be recognized by an escalating EPO requirement and need for transfusions despite adequate iron stores.  It has been reported much more frequently in Europe (with a formulation called Eprex, not used in the U.S.) and is thought to be at least partially due to the practice of subcutaneous administration there rather than in the U.S. where intravenous EPO therapy, for reasons of reimbursement, is the rule.  The diagnosis of pure red cell aplasia requires a bone marrow biopsy which demonstrates a lack of erythroid precursors with a preservation of megakaryocyte and myeloblast lineages; in a recent case at our hospital one of the major manufacturers of EPO products was contacted and performed an assay looking for EPO-specific antibodies.  Being a rare condition, there is limited data on how best to treat acquired pure red cell aplasia, but standard practice currently consists of withdrawing EPO and giving a course of immunosuppressive therapy with Cytoxan and prednisone.

  

There are other causes of pure red cell aplasia:  a genetic condition (Diamond-Blackfan Syndrome) as well as other forms of acquired disease, which include leukemia/lymphoma, viral infection (e.g., hepatitis C, HIV, parvovirus B19), or drugs.  It may also be a prodrome to a full-blown myelodysplastic syndrome.  

Erythropoietin and Sickle Cell Disease

Heard an interesting presentation at our Renal Grand Rounds today regarding a young patient with end-stage renal disease secondary to sickle cell disease who is continually admitted for sickle cell crises.

The question arose whether or not erythropoietin therapy would be beneficial in the treatment of his anemia. If the EPO stimulates predominantly HgbS production, one could make the case that it may actually induce sickling. However, there is some data (Little et al, Heamatologica 2006) that when given in conjunction with hydroxyurea, erythropoietin actually increases HgbF production and is safe in the setting of sickle cell disease.

Sickle cell disease has a variety of renal manifestations--largely as the result of vaso-occlusive phenomena--which includes secondary FSGS, hypertension, chronic hematuria, renal infarction and papillary necrosis, nephrogenic diabetes insipidus, Type I RTA, and occasionally ESRD.