Hypoxia Inducible Factor and Anemia.

Several new therapies to treat anemia in patients with CKD and ESRD have recently been launched that will likely expand the treatment options. For the last few weeks I have been hearing frequently about Hypoxia Inducible Factors (HIFs) and anemia.

First of all, what are HIFs? They are transcriptional activators that function as master regulators of oxygen homeostasis and play an important role in the body’s response to hypoxia. HIF-1 was discovered in 1992 and purified in 1995. In the original research, the authors reported that HIF-1 activates EPO gene transcription in Hep3B cells that are exposed to hypoxic environments. HIF-1 is a heterodimer, consisting of alfa (HIF-1α, HIF-2α and HIF-3α) and a beta subunit which has three isoforms (Arnt1, Arnt2, Arnt3). Under well-oxygenated conditions, HIF-1α is expressed and bound to Von Hippel-Lindau (VHL) protein and is rapidly degraded via hydroxylation at proline residues (PHD2). PHD2 uses oxygen as substrate and its activity is inhibited under hypoxic conditions which causes accumulation of HIF-1α. This process increases vascularization (angiogenesis) in hypoxic states such as ischemia, tumors, immunological responses, homeostasis and anaerobic metabolism. It also has an important role in tumor proliferation as it has been found that the HIF-α levels are increased in certain types of tumors. In chronic kidney disease, the lack of EPO expression causes anemia which typically is treated with recombinant human EPO (rhEPO). This topic has been covered extensibly at the RFN here, here and here.

This month in JASN, a phase II study was published about an investigational drug for the treatment of anemia, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (GSK1278863). In this research, 73 patients with CKD not on dialysis and 83 patients on hemodialysis were enrolled to receive the experimental drug at different doses (0.5 mg, 2 mg and 5 mg) compared to a control group (placebo for patients not on dialysis and patients on hemodialysis receiving recombinant human erythropoietin -rhEPO-) The results were quite surprising: In the nondialysis group, the experimental drug increased the hemoglobin levels at week 4 (average of 1 g/dl). In the hemodialysis patients that were switched from rhEPO to the experimental drug (5 mg), an increase in maintaining a mean hemoglobin concentration was achieved only in the high-dose group, but not in the lower-dose group. These results suggest that this drug may be a good alternative to rhEPO. Theoretically, high EPO concentrations achieved during rhEPO treatment, contribute to the cardiovascular effects in patients with CKD.

Although this study was short, it brings to light the importance of finding good alternatives to treat anemia in patients with CKD and on hemodialysis. Given the reported adverse events with rhEPO treatment and the promising results of this trial, a phase III trial, a larger population study and longer duration is required to test the safety and efficacy of this drug. Keep your fingers crossed.

Figure from: The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. V H Haase. Kidney International (2006) 69, 1302–1307

Does she drink tea?

I was quickly moving along through my busy university clinic, seeing another CKD patient when the nurse came to inform me that the patient’s hemoglobin was critically low at 5 g/dl, while the patient appeared to be just fine. I reviewed the rest of labs just to find out that the iron studies were even more impressive: iron saturation 3% and ferritin 2 ng/ml.

I inquired about the usual suspects - bleeding from various sources - but no luck there (the patient was post-menopausal and denied GI bleeding, later ruled out by EGD and colonoscopy)... Failing to identify a cause of her iron deficiency, I presented the case to my staff who, after reviewing the data, asked me an unusual question: does she drink tea? To my surprise, indeed, the patient admitted to drinking large quantities of black tea. Still puzzled about the link between the two, I jumped onto Google Scholar.

In the renal world, the only time when we talk about tea is when discussing hyponatremia in patients that are on a “tea and toast” diet. So what did I find out? An interesting South African study demonstrated that black tea inhibits non-heme iron absorption by forming iron tannate complexes. This was confirmed by a UK study which showed that black tea was the most potent out of all polyphenol-rich beverages (coffee, cocoa, etc.) in inhibiting absorption of non-heme iron.

Iron deficiency anemia is common in CKD patients, one of the latest mechanisms to be described involves the hepcidin-ferroportin axis (as recently reviewed in JASN). But today I discovered another one!

Posted by Tomoki Tsukahara

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.

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.

TREAT or don’t treat? Future goals of anemia treatment…

Historically - before CHOIR and CREATE – Goals for anemia management were

• Hb level of 11-13 g/dl
• Iron saturation > 20%
• Ferritin >200.

CREATE changed the tide which was followed by CHOIR. CREATE (Epo-β) had intent to treat with two groups, 13-15 vs. 10.5-11.5 g/dl. Six hundred and three CKD patients participated (301 vs. 302) with eGFR of 15-35 ml/min. The weekly Epo Dose used was 5000 vs. 2000 Units. After duration of three years there were no effects on first cardiovascular events (58 vs. 47, p=0.20). However 127 vs. 111 (p=0.03) reached ESRD in the high Hb/Epo group . There was also more HTN (89 vs. 59, p=0.005), however general health and physical function were improved.

CHOIR (Epo-α) had also intent to treat (13.5 vs. 11.3 g/dl). A total of 1432 CKD patients (715 vs. 717) were included. Approximately 50% of patients were diabetics. The weekly Epo dose used was 11000 vs. 6300 Units. The duration was 16 months and composite events were 125 vs. 97 (p=0.03) and included death, MI, CHF and stroke in the high Epo group. There was no change in quality of life.

After these two studies the goals of anemia treatment changed and aimed for lower Hb levels. During my clinic fellow year in 2007 at the BWH, I learned them to be as follows:

• The goal for Hb was reduced to 11-12 g/dl (NKF) and 10-12 g/dl (FDA) and ESAs were minimized.
  
• Latter was mainly accomplished by aiming towards high Iron saturations (sat>50%)
• Ferritin levels (> 500-800; some even advocating Ferritin > 1000).

Last year at the ASN meeting in San Diego the TREAT study came out (see ref. below). This was the first large placebo-controlled study, and compared to the previous two it was larger and all (!) patients were diabetics. It was a randomized and double-blind study with two groups. The intervention group (N=2012) had a Hb goal of 13 g/dl and was treated with Darbopoetin. The placebo group (N=2026) had a goal to maintain a Hb > 9 g/dl and received rescue doses of Darbopoetin or blood transfusions. All patients were type 2 diabetics and there eGFR ranged from 20-60 ml/min. The targets of the study were not completely achieved (Hb 12.5 vs. 10.5 g/dl). There was no difference in composite events (632 vs. 602, p=0.41) except for increased stroke events (101 vs. 53, P<0.001) p="0.002).">

• many of my colleagues tolerate lower Hb levels (9-12 g/dl).
  
• With this change, more iron infusions are necessary to target higher Ferritin levels (800-1000).
  
• ESAs (or blood transfusions) are used to rescue patients who drop with Hb levels <9-10>

We all are awaiting new guidelines (by FDA, NKF and KDIGO) confirming this approach to renal anemia. Some issues will remain the same though, e.g. Hb variability is associated with mortality in CKD/ESRD and we don’t know if it’s a marker or maker. Also, high ESA dosing (when necessary) and its safety remains a problem. It may affect only a subgroup of our CKD/ESRD patient population, the hyporesponders to ESAs. This subgroup actually may be especially receptive to stroke (Marc Pfeffer, TREAT study, BWH renal grand rounds 3/2010). The definition is unclear, however these are patients requiring high Epo dosing and have poor response. The causes remain unclear but could include inflammation, infection (HIV), malignancy, aluminium toxicity, antibodies, high PTH levels and ACE inhibitors. In conclusion, what did TREAT teach us? Well, as long patients are asymptomatic or “feeling well” despite anemia below current goals, they may be better off with restriction of (high dose) Epo and tolerating “lower” Hb levels.

However, if patients are complaining about “not feeling good”, we probably still treat them with caution. If uremia and low iron stores or other causes are ruled out, they need either ESAs or blood transfusion for (rescue) management of renal anemia. The active issues of ESA dose changing are the management of undertreated (?Hb<10>12 g/dl) and frequency of monitoring. Once a month, as recommended by the NKF, is probably not enough…


Reference:
Link

DRIVE-ing to the Correct Solution Regarding Anemia Management?

Poll results from last week's question regarding anemia management in the dialysis patient.  Interestingly, there was a fairly strong consensus on this one, with over 75% of individuals electing to give a course of iv iron to the dialysis patient in question, who was anemic despite relatively large EPO doses and a ferritin level of 900.  

The relevant trials to cite here are the DRIVE and DRIVE-II trials, in which anemic dialysis patients with an elevated serum ferritin (between 500-1220 ng/ml) and low transferrin saturation (less than 25%) were randomized to receive either a course of iv iron or not.  After 6 weeks, individuals in the iron group were found to have greater hemoglobin levels than the control group, with no obvious differences in complications between the two groups.  While this result would seemingly indicate that "giving a course of iv iron" would be the correct choice, there are still some reasonable doubters out there.  For instance, this CJASN editorial by Drs. Spiegel and Chertow rationally point out that "the long-term safety of unbridled IV iron administration has never been established."  Although we may find it distasteful as physicians wanted to do something to help our patient correct their anemia, I think a compelling case could also be made for the first answer suggested in the poll--"continue current anemia management."  

Be sure and check out the newest poll question in the right margin!

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.   

iv iron preparations

Because of the generally poor GI absorption of iron in the setting of ESRD, iron supplementation in dialysis patients is now carried out by intravenous formulations of iron complexed to various carbohydrates. The idea is that these carbohydrate moieties can function as "molecular shields", allowing for the safe delivery of iron to its target tisues while simultaneously preventing iron-mediated oxidative damage. Here are some of the main iv iron formulations and their unique attributes:

1. iron gluconate (Ferrlicit). In my limited experience, it appears to me that Ferrlicit and Venofer control the lion's share of iv iron formulations in U.S. dialysis centers. A typical course of Ferrlicit typically given in the ESRD patient is 125mg iv qdialysis session x 8 doses.

2. iron sucrose (Venofer). Also a popular option, the typical dosing for Venofer is 100mg iv qdialysis x 10 doses. Both Venofer and Ferrlicit offer fairly rapid release of iron. Also, Venofer is FDA-approved for iron repletion in non-dialysis-dependent CKD patients whereas Ferrlicit is not.

3. iron dextran (Dexferrum, Imferon): this is not used much anymore because of a significantly higher risk of anaphylactic reactions than the more modern Ferrlicit and Venofer. Iron dextran was typically given as a smaller "test dose" prior to giving the full dose, as a precaution against anaphylaxis.

4. low-molecular weight iron dextran (CosmoFer, InFed): it is important to distinguish low-molecular weight dextran from high molecular weight dextran because its risk of adverse events is so much lower.

5. ferumoxytol (Feraheme): this is a newly-released formulation of "iron oxide nanoparticles." Sounds very space-age, doesn't it? The reported advantage is that it can be given in large bolus doses--thus making it preferable for the treatment of iron deficiency in CKD, where a patient would otherwise be required to make multiple trips to an infusion center to get their Venofer or Ferrlicit. Further assessments of safety and efficacy are still needed.

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.

hemojuvelin

Several months back I posted something on hepcidin--the 25 amino acid peptide secreted by the liver which appears to be the "master regulator" of iron metabolism, and whose levels appear to be perhaps increased in ESRD patients, providing a possible explanation for the anemia of chronic kidney disease.

Hemojuvelin is a protein which has recently been identified as a critical regulator of hepcidin, and thus also likely an important player in anemia of chronic kidney disease.  Clues as to hemojuvelin's function comes from children with mutations in this gene, which result in severe juvenile-onset hemochromatosis (as evidenced from the positive Prussian blue staining of a liver biopsy specimen, shown above left).  

Hemojuvelin turns out to be a co-receptor, acting at the plasma membrane, for the BMP signaling pathway, which is necessary for the secretion of hepcidin from hepatocytes.  As elevated hepcidin levels are associated with anemia of chronic disease and decreased access to reticuloendothelial stores, it stands to reason that inhibitors of the BMP pathway--either small molecule BMP inhibitors such as this, or a soluble form of hemojuvelin such as this--might be successfully used to decrease hepcidin expression and therefore treat anemia of chronic kidney disease.  

ALSO:  Be the coolest kid on the block to know the Top 10 Nephrology Stories of 2008 according to the Precious Bodily Fluids nephrology blog!

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.  

What is hepcidin?

What is hepcidin and why is it important to nephrologists?

Hepcidin is a 25-amino acid peptide (see left) secreted by the liver which seems to be the "master regulator" of iron metabolism. It works by binding to the iron channel ferroportin, which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells, and degrading ferroportin, thereby shutting off iron transport out of these cells.

In ESRD, hepcidin levels are elevated--probably in part because hepcidin is cleared by the kidneys, and perhaps also because of increased hepcidin expression in the presence of certain inflammatory cytokines. As a result, iron uptake from the gut is diminished (iron can get into the enterocyte via an apical Fe transporter, but can't get out the basolateral surface because it needs ferroportin), and iron is trapped inside of reticuloendothelial cells. This latter phenomenon, "an inability to mobilize iron stores", has long been known to play an important role in the anemia of chronic disease.

One might imagine that hepcidin inhibitors might be a successful pharmacologic intervention for CKD or ESRD patients with anemia.

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.