Clinical Case 85: Answers and Summary ( iron use in ESRD)

ESRD patient with anemia, Fe sats of 12%, Ferritin 450 needs IV iron. Patient has bacteremia.

A. Proceed to give IV iron as anemia and low Fe sats demands it.  (2%)

B. Given active infection, do not give IV iron till 2 weeks after infection resolved (73%)

C. Given active infection, do not give IV iron till 4 weeks after infection resolves. (24%)

There have been no clinical trials of adequate sample size and duration to provide us sufficient understanding of the safety of intravenous iron. Is bolus iron better or continuous form? Is iron infusion pose an infection risk?

Brookhart et al. retrospectively studied patients on dialysis treated at Davita Inc. dialysis facilities and found that patients receiving 200mg intravenous iron per month had an increased risk for hospitalization or death because of infection. They also found that bolus dosing was more associated with infection. More recently, A CJASN study by Miskulin et al. found a increased risk for infection-related mortality when cumulative iron dose exceeded 1050 mg over 3 months or 2100 mg over 6 months( not statistical but a trend). In an accompanying editorial to the Miskulin study, Fishbane et al (must read) discuss what the USRDS data suggests. As the mean serum ferritin of United States patients on dialysis approximately doubled from 1993 to 2001, the rate of bacteremia/sepsis increased approximately by 40%. From 2001 to 2010, serum ferritin stabilized, and soon enough the bacteremia/sepsis rate also stabilized. In light of these above findings, it is advisable to hold iron infusions in setting of active bacteremia.  

What about other active infections such as cellulitis or pneumonias? No data exists for those at this point. How long do we wait is a good question. Most likely choice is 2 weeks but data for that is not clear. Some of you chose 4 weeks: might also be a reasonable choice.  Another concern might be catheter use.  Infection risk as stated by the Brookhart study that risks are largest among patients with a catheter and the ones with a recent infection. 

Use of Erythopoiesis-stimulating agents in CKD patients with cancer

A recent review in KI 2014 discusses this very important question we face in day to day care of CKD patients. If they have active cancer and CKD- what do we do? What is the Hgb target? If they had a past history of cancer- what do we do?

Hazzan et al review these exact questions. Few take home points from the review.

1.       Based on review of oncology literature:- there is an increase in mortality risk with ESA treatment in cancer. This risk is clearly when ESA is used outside the realm of chemotherapy and the risk may depend on type of cancer but data is not clear on that part.

2.       ESA and having cancer itself pose a thromboembolic risk as well.

3.       Progression of cancer- data is not sufficient based on Cochrane systemic reviews with use of ESA

4.       What to do with CKD and ESA use when patient also has cancer?

  Active cancer:- prior initiating ESA- use PRBCs and correct all reversible causes. If ESA to be used, the authors suggest a target of 10g/dl ( more conservative) and have to treat under the APRISE REMS program( usually heme/onc has to do this) and monitoring of embolic events.

What to do with CKD and ESA with patient with past hx of cancer?

If cured:- CKD guidelines of anemia management( but on conservative side)

If not cured:- treat as if they have active cancer- target of 10g/dl.

Take a look at an in-depth review of this topic in KI

IN the NEWS: Peginesatide for Anemia of Kidney Diseases( PEARLS and EMERALDS)

Anemia treatment in both CKD patients and ESRD patients is challenging. Partial correction is what is recommended at this point. In the past decade, we have seen the rise of erythropoietin and darbopoietin as the major agents used to help manage this condition. Peginesatide was FDA approved in 2012 for use of anemia of kidney disease in dialysis patients. It is a "epomimetic" agents as the authors of the recent four trials published in NEJM suggest. Perhaps a "sensipar" of the anemia world.
Four trails and two manuscripts published in the same issue of Jan 2013 in NEJM this week re the use of this agent in anemia of both ESRD and CKD patients.

Major points: 
1. PEARL 1 and 2( use of this agent randomized comparison to darbopoietin) in CKD patients and EMERALD 1 and 2( use of this agent randomized comparison to erythropoietin) in ESRD patients.
2. Both studies showed non inferiority in terms of Hgb control of 10-12 goal as set by the investigators.
3. Cardiovascular end points of MI, Stroke and other cardiac outcomes were similar in both groups in the ESRD study( EMERALD)
4. In the CKD study( PEARL), there were more significant cardiovascular events in the peginesatide arm. 
5. AKI and unexplained back pain was also noted more in the CKD group peginesatide arm.
6. Neither the two articles nor the editorial could explain the reason for the increased cardiac events or AKI or back pain with the agent( hgb levels were similar and doses in HD were higher than CKD patients)
7. Benefits of using this agent:- once a month as oppose to more frequent dosing in HD patients
8. Caution: new agent, cost and at this point perhaps not recommended in CKD patients.

When you pubmed the drug name " peginesatide" only 27 articles appear ( 2 are listed above). What do they say regarding this agent? One question that comes up is regarding the clearance, distribution and metabolism of this agent. It seems that pharmcology related studies suggest that this agent is cleared via the kidneys and primarily localized to the hematopoetic sites as concentrations of this agent build up. The molecule is 45kDa molecular weight and low volume of distribution. The mean half-life is 25.0 ± 7.6 hours following intravenous administration and 53.0 ± 17.7 hours following subcutaneous administration in healthy subjects. The mean half-life in dialysis patients is 47.9 ± 16.5 hours following intravenous administration. Mean systemic clearance is 0.5 ± 0.2 mL/hr·kg and mean volume of distribution is 34.9 ± 13.8 mL/kg following intravenous administration in dialysis patients. No accumulation is observed following administration every 4 weeks following intravenous or subcutaneous administration( source: Rxlist.com). The pharmacokinetics of peginesatide in patients with CKD on dialysis are not altered by age, gender or race based on population pharmacokinetic analyses. There is something about dialysis or ESRD that less likely balances out the negative effects of this agent found in CKD patients in terms of cardiovascular mortality. 

Topic Discussion: Anemia mechanisms

What are the mechanisms of anemia in CKD?
A recent article in JASN Oct 2012 issue discusses this as a science in renal medicine.
Figure 1 in the article is worth exploring as it summarizes the literature on this topic.

1. Decreased EPO production
2. Uremic inhibitors to action of produced EPO
3. Shortened RBC survival in the uremic state
4. Blood loss during dialysis
5. Decreased iron absorption due to uremic state
6. Other losses of iron via dialysis, chronic bleeding, dysfunctional platelets, blood trapping
7. Impaired iron release from stores
8. Hepcidin excess impairs iron absorption

Topic Discussion: Iron during infections?

We often hear not to give IV iron during an active infection... Is there evidence for that statement?
Iron is important for growth of many bacteria, viruses and fungi.  Certain organisms are more iron laden than others. In hemochromotosis, certain iron laden infections are more common due to the affinity of the organisms to iron.  Various infections caused by organisms including 
Vibrio vulnificus, Vibrio cholerae, E. coli, Yersinia enterocolitica and pseudotuberculosis,
L. monocytogenes, P. shigelloides, CMV are others that have been reported in association with hemochromatosis. Fungi including A. fumigatus and Rhizopus species have also been described.
Iron is a central regulator of immune cell proliferation and function. All lymphocyte subsets, including B and T lymphocytes and natural killer (NK) cells, depend on iron uptake, the blockade of which leads to diminished proliferation and differentiation of these cells. Iron loading of macrophages results in the inhibition of IFN-g-mediated pathways and hence they lose their ability to kill intracellular pathogens. Excess iron burden does
not only help the propagation of pathogens, but also plays a sentinel role in modifying the host immune mechanism, specifically by impairment of cell-mediated immune responses.

Data in CKD patients are conflicting and recent KDIGO work group for anemia in CKD released guidelines for IV iron use.  Although clinical judgement drives the decision, the work group suggested not to use IV iron in active systemic infection but no grade was assigned as evidence either way is weak.  

Detailed guidelines can be found in Kidney International.

Is Iron The answer?

As restrictions have arose in using of erythropoietin agents in dialysis patients, the use of IV iron has risen in the nephrology community. What are the rates of iron overload in such instances?
Studies have shown that excessive use of iron can intensify the oxidative stress associated with chronic kidney disease, and promote endothelial dysfunction and cardiac disease. Excessive iron reduces iron utilization and is involved in the generation of intracellular reactive oxygen species, which induce cell injury; the risk of subtle toxicity from iron excess exists. Unnecessary iron supplementation accelerates hepcidin  production. This effect on ferroportin 1 (FP-1), keeps intracellular iron from being carried even if the iron storage is adequate; it also decreases iron absorption from the intestine.In the most recent issue of the Am J of Medicine, an editorial to a  study done prospectively found that there was iron overload in 84% of a 119 stable HD patients. Some of the amount of iron reached the levels found in hemochromotosis. A prior study had shown that the risk factors were ferritin >500.   The Japanese Society for Dialysis Therapy Guidelines has proposed that a minimal amount of iron should be given to chronic kidney disease patients. Japanese clinicians believe that the risk/benefit ratio for iron supplementation is higher than that accepted in Western countries. So now what?
A proper attention to body's individual iron stores and ferritin levels along with perhaps hepcidin information might be a more prudent way to decide iron treatment. More robust guidelines might be needed.

In the News: Normal hematocrit and the quality of life

As we are learning more and more about targets of hemoglobin, a recent publication by Dr Coyne in Kidney International stuns us even more. The Normal hematocrit trial was the largest trial to date on hemoglobin targets and trying to show that a goal of 13-15g/dl was needed for better quality of life.  This trial was terminated early due to increased deaths and cardiac events in the high target groups.  The trial did show that it had improved quality of life significantly.  The new KI article compares the FDA 1996 clinical trial filed report to the actual publication given in 1998 in NEJM.

Few summary points

1. Higher quality of life was not achieved and was almost reaching statistically significance

2. Higher target hemoglobin had increased risk of death, non access thrombotic events and hospitalization rates( statistical significance) - not noted in the actual paper

3. Renal community guidelines to treat anemia were based on this original paper

Swinging of the pendulum as some call it is what is happening. More data and more data supporting not to target higher doses of hemoglobin.  The real question to ask is could the renal community guidelines be different and the early 2000s be different if this was known earlier to us as physicians.  

Some of us feel disgusted by this corrupt data presentations and really applaud this author for showcasing what should have been published much earlier.

Just because a major journal publishes an article, it doesn't make the validity of the publication accurate. 

take a look at the KI publication and the original trial as well

http://www.nature.com/ki/journal/vaop/ncurrent/full/ki201276a.html ( open access)

http://www.ncbi.nlm.nih.gov/pubmed/9718377 ( original 1998 publication)

http://www.nejm.org/doi/full/10.1056/NEJMc076523 ( a follow up 2008 publication on this matter)

History of Erythropoietin development

1878: Bert and Jourdanet described symptoms of anemia and mountain sickness from hypoxia
1906: Carnot and Deflandre observed that serum from an anemic donor rabbit injected in normal rabbits resulted in increased erythropoiesis.  It was initially called hematopoietin: potential circulating factor
1953: Erslev demonstrated that plasma from anemic rabbits contained a factor capable of stimulating erythropoiesis and predicted its potential as a treatment modality. Did a quantitative infusion study regarding this notion as well.
1957: Jacobson and other such as Goldwasser found that the kidney was the source of this hormone that controlled the production via experiments with each organ being removed in animals.
1985: Few milligrams of erythropoietin from over 2.5L of urine of patients with aplastic anemia was collected and purified by Miyake et al
1985: The human erythropoietin gene was cloned
1985: Eshbach et al had the the first treatment of someone with initially just 2.5 units/kg on dialysis followed by no response and then increased dose of 15 units/kg with good response leading to potential treatment success.
1985: Mass effort to large scale production
1989: FDA approves recombinant EPO for use in chronic renal failure patients on dialysis
1990: FDA approves recombinant EPO for use in chronic renal failure without dialysis and other non renal causes.

A good references that summarize as above is
http://www.nephrologyrounds.org/crus/nephUS_0304.pdf

New drug labels for kidney disease patients -- what do they mean?

Check this out on anemia in ckd :New drug labels for kidney disease patients -- what do they mean?

eAJKD: Anemia story

Check out the latest commentary by Fishbane and Hazzan on eAJKD.
Also, look at their commentary in Nature Nephrology on similar article.

In the News: ESA dose responsiveness? Some thoughts

A Japanese study just recently published in AJKD looked at dose responsiveness to ESA and effect on mortality. They defined 6 categories of ESA responsiveness based on a combination of ESA dosage.  They studied the relationship between hemoglobin level, ESA responsiveness and outcomes among hemodialysis patients. The authors found that mortality in patients on hemodialysis may be affected by ESA responsiveness and by the interaction of hemoglobin and ESA dose. Low hemoglobin level and high ESA dose were strongly associated with an increased risk of mortality. 

Dr Steven Fishbane and Azzour Hazzan wrote an editorial to the article in nature nephrology. 

Dr Hazzan puts his thoughts as a post here as well:

Recently there have an intense interest in anemia in patients with CKD and how best to manage it. In the early years of dialysis, anemia was found to be more common in patients with CKD and associated with higher mortality. This has been proven through many studies albeit not of a good quality-RCTs. However; recently we have found that our approach to normalize the hemoglobin level may have been  counterproductive. The reason being; increase stroke risks and probably higher cardiovascular mortality as well. Of the more definitive studies- the TREAT- looked at about 4000 patients with diabetic  CKD-Non dialysis. The treatment arm was darbepoetin to achieve levels of 13 versus using darbepoetin to keep HGb from falling under 9. The investigators found that patients with hemoglobin artificially driven towards normal,  had double fatal and non-fatal strokes risks. The question is why?

There are many stipulations. One possibility is the ESA dose effect? and patient's response to ESA. 

The above mentioned study by Fukuma et al. has investigated the relationship between hemoglobin level, erythropoietin responsiveness and outcomes among Japanese hemodialysis patients. The authors found that mortality in patients on hemodialysis may be affected by ESA responsiveness and by the interaction of hemoglobin and ESA dose. Our editorial piece looks into that and other studies. Basically it would be hard with this kind of studies to make any definitive conclusions to answer this question. Is it the EAS dose or is it  the fact that more severe anemia signify sicker patients and therefore higher mortality? In other words; acute and chronic illness, severity of illness, inflammation and co-morbidity are all highly intertwined with hemoglobin level and ESA dose, making analysis vulnerable to severe confounding variables.

In summary, we should exercise caution in treating anemia and use the lowest dose possible. 

Post by Dr. Azzour Hazzan

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21890255

http://www.ncbi.nlm.nih.gov/pubmed/22009249

In The News-Final Blow on anemia agents

Check out the latest nytimes 2011 article on anemia:

http://www.nytimes.com/2011/06/25/health/policy/25drug.html?ref=gardinerharris