Towards Better Control in CKD: Improving Anemia Management

ANNA CE Satellite Symposium - New Orleans, Louisiana, October 17, 2004

Morbidity of Anemia in Patients with Chronic Kidney Disease



Joel D. Glickman, MD
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This satellite symposium is sponsored by an unrestricted educational grant from American Regent Laboratories, Inc. This activity has been planned and produced in accordance with CE guidelines and policies. From a CE symposium held on October 17, 2004 at the American Nephrology Nurses' Association (ANNA) Fall Meeting in New Orleans, LA. This symposium was approved by ANNA. It was not part of the official ANNA Annual Meeting.
This activity has been awarded 1.5 contact hours by the American Nephrology Nurses Association (ANNA) which is accredited as a provider and approver of continuing education in nursing by the American Nurses Credentialing Center-Commission on Accreditation (ANCC-COA).
Posting Date: January, 2005
CE Credit Eligible Through: May, 2006
CE Credit Hours/Completion Time: 1.5
Target Audiences: Nurses, nurse practitioners, and other healthcare professionals who treat and manage patients with CKD.
Method of participation: Listen to the talk, read the PubMed abstracts linked to data slides and talk references, take the post-test, read the linked abstracts in the post-test answer feedback material.
LEARNING OBJECTIVES:
After participating in this program, the participant should be able to:
  1. Describe the benefits of anemia management in chronic kidney disease (CKD).
  2. Outline the results of a U.S. clinical trial of iron sucrose and erythropoietin in the treatment of anemia in CKD.
  3. Appraise the characteristics of available parenteral iron products.
  4. Explain the critical role of the nephrology nurse in anemia management.
SPEAKER DISCLOSURE STATEMENT:
Speaker is a member of the Speakers Bureau for American Regent Laboratories Inc.

ANNA and HDCN CE POLICY STATEMENTS:
The CE policy and disclosure statements of the American Nephrology Nurses' Association are given in detail on the Symposium Home Page. The CE policy statements of HDCN are listed on this page.

Dr. Van Wyck:
Let me introduce you to Joel, if you do not know him. Joel Glickman is a Clinical Associate Professor of Medicine at the University of Pennsylvania College of Medicine. He is a private practice nephrologist. He has spoken widely on a number of topics, anemia and iron, for example, and he was at the ANNA Spring Meeting in Washington. He is an excellent speaker.

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Morbidity of anemia in patients with chronic kidney disease
He is going to be talking about morbidity of anemia in patients with chronic kidney disease (CKD).

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NKF-K/DOQI stages of CKD Dr. Joel D. Glickman:
I think it is safe to say that at a 20% annual mortality, we have a lot to learn about the care of dialysis patients. I think with the results of the recent ADEMEX study and HEMO study, we have learned that increasing dialysis dose does not necessarily improve outcomes. What is the answer? We know that our patients are not dying of uremia; our patients are dying cardiovascular deaths. We know that that cardiovascular risk does not start when the patient enters the dialysis unit. They are sick by the time we get to see them. They have had hypertension for a long time, they have high lipid levels, have anemia, etc. If we are going to have any impact on improving outcomes in our dialysis patients by improving cardiovascular outcomes, then we have to start treating them in the predialysis period. Because of that, K/DOQI came up with this great classification of kidney disease showing that it is a continuum. It starts when the GFR falls below 90 and then continues on.

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Complications of CKD: Prevalence increases by stage
The reason I like this classification is, you can see from this slide, that the complications of chronic kidney disease increase as we go from stage I, II, III, IV, and finally V. Hypertension goes up, hyperparathyroidism goes up, and hyperphosphatemia goes up, but what we are going to focus on today is the anemia.

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Prevalence of anemia increases by stage of CKD
You can see that in stage I kidney disease, very few people are anemic, by stage III disease about maybe 15%, by stage IV disease where GFR is in the 15 to 29 ml/min/1.73M2 range, somewhere around 50% or so of patients have some degree of anemia.

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Cardiorenal anemia syndrome
I also want to introduce to you - if you do not already know about it - the concept of the cardiorenal anemia syndrome. We know that patients who have cardiac disease are at risk for developing renal disease. But we also recently learned that having renal disease is an independent risk factor for developing cardiac disease just as hypertension, hyperlipidemia, smoking, and diabetes.

People who have cardiac disease are at risk for developing anemia, and it turns out that cardiac patients who are anemic have worse outcomes, and therapy of anemia improves their outcomes. But what we are going to focus on is the last line of the triangle, the relationship between chronic kidney disease and anemia. We know patients with chronic kidney disease develop anemia, but what exactly is the consequence of that anemia and what can we do about it? So the talk is set up into two parts; first we are going to talk about anemia and chronic kidney disease and then we are going to talk a little bit about the management of anemia and chronic kidney disease, specifically the role of iron therapy.

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Goals
Let us start with anemia and chronic kidney disease. The questions I would like to answer are: Does anemia cause progression of chronic kidney disease? Does the treatment of the anemia preserve renal function? Finally, does that treatment actually help patient outcomes?

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Source: Keane WF et al. Kidney Int. 63 (4):1499-1507, 2003.
The more severe the anemia at presentation, the greater the risk of progression of CKD
This data comes from the RENAAL study. The RENAAL study was a study done in type 2 diabetics who had renal disease. The purpose of this study was to look at the effect of an ARB losartan on preventing progression of kidney disease. As you know, they showed that blood pressure control with losartan decreased progression of chronic kidney disease. But a multivariate analysis of this study showed that anemia was an independent risk factor for worsening renal function.

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Source: Keane WF et al. Kidney Int. 63 (4):1499-1507, 2003.
CKD patients with Hb < 11.2 are 3 times more likely to progress than those with Hb > 13.8
As you can see from this graph, as the hemoglobin level decreased from 13.8 down to 11.2, the risk of doubling serum creatinine level or progressing to end-stage renal disease increased. Represented slightly differently, if your hemoglobin level was greater than 13.8, you had a 20% likelihood of doubling your creatinine level or progressing to end-stage renal disease. However, if your hemoglobin was less than 11.2, you had a 60% likelihood of progressing to end-stage renal disease or doubling your creatinine level. That is a little curious, why should anemia worsen kidney function?

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Source: Rossert, JA, et al, JASN 14:S173-177, 2003.
Mechanism of progressive CKD
I would like to show you at least some theoretical considerations. We focus a lot of our attention on the glomerulus. As you know, we talk about glomerular hypertension as a cause of progressive glomerulosclerosis and the effect of proteinuria on progressive glomerular disease, but we tend to ignore the other parts in a nephron, specifically the tubules and the interstitium. We know that as the kidney is diseased, we get tubular atrophy and progressive scarring in the interstitium. It turns out that those two findings on kidney biopsy are more predictive of renal outcome than what the glomerulus looks like. The tubules and interstitium are a very important part of the progressive kidney disease, at least on a pathological basis. How did the tubules and interstitium get diseased? As you remember from renal physiology, the tubules take a dive down from the cortex and medulla, and the oxygen tension level in the medulla is very low. Since it is very low, those tubules are very susceptible to hypoxic injury. That hypoxic injury is mediated by reactive oxygen species. These reactive oxygen species cause further inflammation and scarring.

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Source: Rossert, JA, et al, JASN 14:S173-177, 2003.
Role of EPO in preventing progressive CKD
How does therapy with EPO or improvement of hemoglobin level deal with oxidative stress and reactive oxygen species? For one, if we increase the hemoglobin level, we will increase oxygen delivery to the tissues, and we have less risk of hypoxic injury. Second of all, it turns out that red blood cells are great antioxidants. They do a wonderful job in dealing with reactive oxygen species, and therefore they can decrease the oxidative stress in the kidney. Finally, what I think is the most interesting concept is this concept of apoptosis. Like it or not, every cell in our body has been programmed to die one day, and that programmed death is called apoptosis. It turns out that many cells in our body, neuronal cells, kidney cells, and red blood cells have erythropoietin receptors on them. When erythropoietin binds to those receptors, it prevents cell apoptosis. Recently, there was a study, a basic science study, where they gave, in an in vitro setting, erythropoietin, and deliberately caused an ischemic injury to these renal cells; and with erythropoietin, apoptosis was decreased. I think there is emerging literature that the effect of erythropoietin goes beyond increasing red blood cells, it may prevent programmed cell death of renal cells.

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Does treatment of anemia slow the progression of CKD?
Anemia is a risk factor for progression of end-stage renal disease. It may make sense on a basic science level, that is nice and dandy. Does it do anything in actuality? If we look at the studies on progression of end-stage renal disease, we find that there is not a lot out there. The reason that there is not a lot out there is our concern initially was that if we treated anemia in patients in chronic kidney disease, we would worsen the renal disease, that it would cause progressive renal insufficiency. The theory there was that if the hemoglobin level was higher, it would alter renal hemodynamics and may cause renal disease. It turns out it is not true. For certain, all the studies have shown that there is no worsening of renal function when you correct the anemia. But to date there have been only about 5 or 6 studies looking at the beneficial effects on therapy of anemia on progressive kidney disease, and I would just like to show you two of them.

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Source: Jungers P et al. Nephrol Dial Transplant 16:307-312, 2001.
Epoetin-treated CKD patients show slower rate of decline of renal function than untreated patients
In this retrospective study, they took patients and treated them with erythropoietin. As you can see from the yellow curve, that patients treated with erythropoietin had an increase in their hemoglobin level from beloe 9.0 g/dL up to about 11 or so, whereas patients with equivalent renal dysfunction who were not anemic, not treated with erythropoietin, over the course of the year their hemoglobin levels dropped from 11 to almost 9. If we look at their renal function on the right side of this slide, we can see that patients treated with erythropoietin, the yellow line, had a slower progression of kidney disease, whereas the patients in purple, that is not treated, had worsening of their kidney function.

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Source: Gouva C, et al. Kidney Int 66:753-760, 2004.
Early treatment of anemia slows the progression of CKD: A randomized, prospective clinical trial
But in more recent and a more sound study that was published in Kidney International over the summer, they looked at the impact of treating anemia in patients with chronic kidney disease prospectively. They took people who had hemoglobin levels of 9 to 11.6 and either they treated them immediately with erythropoietin or they did not treat them at all.

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Source: Gouva C, et al. Kidney Int 66:753-760, 2004.
Early treatment of anemia is associated with slower CKD progression
We could see, again in the yellow, that patients who were treated with erythropoietin had a dramatic increase in the hemoglobin level from 10 to almost 13 range, whereas the patients who were not treated had no change in the hemoglobin level. Though both groups had some decrease in their kidney function, the decrease in the kidney function was much more dramatic in the patients not treated. Moreover, when they looked at their primary end points, which was doubling of serum creatinine or progression to end-stage renal disease, the patients who were not treated for their anemia, had double the risk of progressing to end-stage renal disease or having a doubling in their creatinine level. I think this study was probably the best study to date demonstrating that therapy of anemia retards the progression of chronic kidney disease. That is nice too, but do patients do better? There are a lot of studies that are looking at survival of patients who were treated for anemia while on dialysis, but there are far fewer studies in the pre-ESRD patients.

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Source: Xue JL et al, Am J Kidney Dis 40:1153-1161 2002.
In geriatric patients, improved survival is associated with intensity of anemia treatment
This study, I kind of like, it is a little bit complicated. What they did was look at the effect of treating patients with erythropoietin before the initiation of dialysis and then looked at their survival once they were on dialysis. The question is, does treatment of anemia before you start dialysis impacts your survival on dialysis? They separated them up into several groups; those patients who received no erythropoietin at all, those patients who received erythropoietin in 25% of the months prior to initiation of dialysis, 25% to 50%, etc., the patients who received EPO 100% in the months prior to dialysis. As you can see here, the bottom curve, the one on the bottom, the patients with the worst survival were the patients who did not receive any erythropoietin before the initiation of dialysis. So, there is something here, that therapy of anemia before the initiation of dialysis impacts the survival. Why that might be? We come back to cardiovascular events once again.

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Source: Modified from Levin A, et al. Am J Kidney Dis 34:125-134, 1999.
Anemia, like hypertension, is a critical CV risk factor
We know that anemia is associated with LVH. We know that anemia is associated with cardiovascular events. In this study from 1999, you can see that for every 0.5 g/dL decrease in hemoglobin level in predialysis patients, there is a 32% increased risk of a cardiovascular event. I think it all sort of comes together, that anemia is worse for progressive kidney disease, that therapy of anemia improves outcomes, and that outcome may be mediated by decreased cardiovascular event.

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Goals
How should we treat anemia in the CKD patients? We all know about erythropoietin. The question is, is there any benefit to IV iron? What is the role for IV iron and is it safe?

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Source: Silverberg DS. Kidney Int 55 (suppl 69):S-79-S-85,1999.
Iron deficiency in CKD
It turns out that in many patients with chronic kidney disease, despite having reasonable iron indices, that is, what most hematologists would consider not iron deficiency, do have iron depletion in the bone marrow and the reason is severalfold. Patients with chronic kidney disease have decreased oral iron intake, they have decreased iron absorption, they have low-grade GI bleeds, and phosphate binders interfere with the absorption of iron. But what I think is more impressive is that about 30% of patients who are anemic with chronic kidney disease can attain hematocrit levels of 35% with therapy of iron only, and I would like to show you just one study to that effect.

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Source: Silverberg DS, et al: Clin Nephrol 55(3):212-219,2001.
I.V. iron alone corrects hemoglobin in CKD
On the left hand side of the slide you can see patients treated with IV iron sucrose and EPO. They received 2000 units subcutaneously weekly of EPO, as well as iron sucrose, at a dose of 200 mg a week for 5 weeks. You can see, as you would expect, they had a dramatic increase of the hemoglobin level from about 9.7 to 11. On the right hand side are patients treated with IV iron only. They received 200 mg of the IV iron sucrose weekly for 5 doses, and they had a dramatic increase in the hemoglobin level from 9.8 to 10.7. There is clearly a role for iron therapy in patients with chronic kidney disease. If you are treating patients with erythropoietin, you may not get the response you want unless you give them IV iron, but equally important is a relatively cheap way of correcting anemia; to treat them with IV iron, get a good response, and if you still need more, you can add erythropoietin to their regimen.

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Safety results of an iron sucrose clinical trial
We can give IV iron sucrose to treat anemia. The question is, is it a safe and effective way of treating?

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Oral iron compared to iv iron sucrose in patients with CKD: A feasibility and safety study
I would like to review with you a study that looked at iron sucrose therapy in patients with chronic kidney disease. The background is simple. Patients who are anemic have some iron deficiency, and the hypothesis was that iron sucrose given at 200-mg doses relatively rapidly in terms of sequence could improve hemoglobin levels and avoid any adverse events that you might see with oral iron.

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Experimental design: Randomized, parallel, short term
This study protocol was quite simple. There were about 100 patients randomized into 2 groups. One group received ferrous sulfate at a dose of 325 mg 3 times a day, the other group received iron sucrose 200 mg weekly for 5 doses, and then their labs were evaluated. Each group got erythropoietin at a dose of 2000 units weekly.

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Criteria for assigning iron deficiency, anemia and CKD
To be included in the study, you had to have iron sats less than 25%, ferritin levels less than 300 ng/mL, which is not a low level, you had to be anemic with a hemoglobin of less than 10.5 g/dL, and you had to have chronic kidney disease, as evidenced by creatinine clearance less than 40 mL/min/1.73 M2. Patients with severe concurrent medical illnesses such as malignancy, chronic infection etc., were excluded from the study.

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Administration of iron sucrose
Iron sucrose was administered intravenously, either as a 200-mg dose, undiluted, over 5 minutes without a test dose. If patients did not tolerate that or if the investigator was uncomfortable with that regimen, they could receive 200 mg diluted in saline over a 30- to 60-minute period. What did we find?

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Only 36% of patients in oral iron group adhered to prescribed therapy
First, we found, as you all know, that patients are noncompliant with their oral iron therapy. Only about 35% or 40% of patients took all their iron pills, majority did not. There were a couple of overzealous patients - on the right side - who took more iron than prescribed.

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Drug-Related adverse events
If we look at adverse events, in oral iron group there were no deaths, there were no serious related adverse events, and there were no withdrawals. In the iron sucrose group, there were no deaths, there were no serious related adverse events, and the only withdrawal was to one minor non-serious related event, which I believe was constipation or something like that.

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IV iron proves more effective in correcting both anemia and depleted iron stores
If we look at outcomes and if the outcome is a composite outcome, that is, an increase in hemoglobin level of 0.8 with an increase in the ferritin level of 160, we can see that the oral iron group was unable to increase their ferritin levels, but the IV iron sucrose group had increase in hemoglobin levels, as well as increase in ferritin levels. To be fair, the oral iron group did have increase in their hemoglobin levels, but they were not able to restore their iron deficit by increasing the ferritin levels.

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Safety experience with iron sucrose in current clinical trial: Summary
In summary, iron sucrose can be administered safely in a dose of 200 mg over 5 minutes. There were no serious events with either oral iron or IV iron, and non-serious GI effects were common after oral iron.

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Safety experience with iron sucrose in all 5 U.S. clinical trials: Summary
If you look at some other safety studies with iron sucrose, almost 1300 patients, almost 10,000 doses of 100-200 mg at a time, given at 20-50 mg per minute, no serious adverse reactions at all.

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Source Charytan C et al. Nephron Clin Pract 2004; 96:c63-c66.
Safety of IV iron sucrose in patients with a prior history of sensitivity to other IV iron agents
What do you do if your patients were intolerant of one iron product? We all know patients who are intolerant of iron dextran or iron gluconate. What can you do with those patients? As a subanalysis of the previous studies I showed you, they then analyzed about 130 patients who were intolerant to either iron dextran, iron gluconate, or both. They were treated with iron sucrose. It tuns out that there were no withdrawals, no serious adverse events, 8 minor non-serious reactions as you can see, taste disturbance, nausea, hypotension, etc. All the iron products are not the same, if the patient is intolerant to one product, they may benefit from another. If you have patients with chronic kidney disease who need IV iron, you have several options available to you.

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Morbidity of anemia in patients with CKD and CVD: Conclusions
In summary, anemia is a significant risk factor for cardiovascular disease and progressive renal insufficiency. Therapy of anemia improves renal outcomes. Therapy of anemia in chronic kidney disease may improve outcomes in the end-stage renal disease. Therapy of anemia requires not just erythropoietin, but IV iron also, and you can administer IV iron in the form of IV sucrose in a very safe and effective manner.

References
  1. Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM, Toto R; RENAAL Study Investigators. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int. 2003 Apr;63(4):1499-507.

  2. Rossert J, Fouqueray B, Boffa JJ. Anemia management and the delay of chronic renal failure progression. J Am Soc Nephrol. 2003 Jul;14(7 Suppl 2):S173-7. Review.

  3. Jungers P, Choukroun G, Oualim Z, Robino C, Nguyen AT, Man NK.Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients. Nephrol Dial Transplant. 2001 Feb;16(2):307-12.

  4. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 2004 Aug;66(2):753-60.

  5. Xue JL, St Peter WL, Ebben JP, Everson SE, Collins AJ. Anemia treatment in the pre-ESRD period and associated mortality in elderly patients. Am J Kidney Dis. 2002 Dec;40(6):1153-61.

  6. Levin A, Thompson CR, Ethier J, Carlisle EJ, Tobe S, Mendelssohn D, Burgess E, Jindal K, Barrett B, Singer J, Djurdjev O. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999 Jul;34(1):125-34.

  7. Silverberg DS, Blum M, Agbaria Z, Schwartz D, Zubkov A, Yachnin T, Iaina A. Intravenous iron for the treatment of predialysis anemia. Kidney Int Suppl. 1999 Mar;69:S79-85. Review.

  8. Silverberg DS, Blum M, Agbaria Z, Deutsch V, Irony M, Schwartz D, Baruch R, Yachnin T, Steinbruch S, Iaina A. The effect of i.v. iron alone or in combination with low-dose erythropoietin in the rapid correction of anemia of chronic renal failure in the predialysis period. Clin Nephrol. 2001 Mar;55(3):212-9.

  9. Charytan C, Schwenk MH, Al-Saloum MM, Spinowitz BS. Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products. Nephron Clin Pract. 2004;96(2):c63-6.




Next Talk (David B. Van Wyck)


This satellite symposium is sponsored by an unrestricted educational grant from American Regent Laboratories, Inc.
This activity has been planned and produced in accordance with CE guidelines and policies. From a CE symposium held on October 17, 2004 at the American Nephrology Nurses' Association (ANNA) Fall Meeting in New Orleans, LA.
This symposium was approved by ANNA. It was not part of the official ANNA Annual Meeting.


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