The Evolution of Chronic Kidney Disease: Defining a Model for Care

World Congress of Nephrology (ASN/ISN), San Francisco, CA, October, 2001

Correcting the Mild Anemia of Severe, Resistant Congestive Heart Failure (CHF): The Effect on Cardiorenal Function


Donald Silverberg, M.D.
Department of Nephrology
Tel Aviv Medical Center
Tel Aviv, Israel
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CME

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Post-test and evaluation form are at this link, but you must listen to all talks from this symposium prior to completing the test.
CME: The University of Minnesota is accredited by the Accreditation Council for Continuing Medical Education (AACME) to sponsor continuing medical education for physicians.
The University of Minnesota designates this educational activity for up to 1.5 hours in category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit actually spent in the educational activity.

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Posting date: January 15, 2002.
Review date: January 15, 2003
EDUCATIONAL OBJECTIVES :
After participating in this activity, participants should be able to:
Discuss the prevalence of chronic kidney disease (CKD) in the US population and suboptimal treatment of anemia;
Summarize the advances made in defining the stages of CKD and describe current guidelines for anemia correction;
Describe the effects of the correction of anemia on cardiorenal function in patients with congestive heart failure (CHF): and
Summarize knowledge about treatment plans and models of care that are directed at improving CKD treatment and limiting progression of disease.

SPEAKER DISCLOSURE STATEMENT :
Silverberg, Donald: Consultantships: Amgen, Johnson and Johnson

CME POLICY STATEMENTS :
The CME policy statements of The University of Minnesota which is the accrediting organization for this talk, are given in detail on the Symposium Home Page. CME policy and disclosure statements of HDCN are listed on this page.

Moderator: Our next speaker is Dr. Donald Silverberg, who has come all the way from Tel Aviv in Israel. He is a senior member of the Department of the Nephrology in Tel Aviv Medical Center in Israel. He is going to speak about "Correcting the Mild Anemia of Severe, Resistant CHF: The Effect on Cardiorenal Function." Thank you.

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Dr. Donald Silverberg:
Introductory Remarks
Thank you. I think this is the only talk probably in a whole bunch of sessions where half the people on this list are cardiologists. Actually, if you believe Marshall McCluhan that the media is the message, the message is that I think in the future we'll have to be working a great deal more with our cardiologists.

To give you an example, we have been working for years in the field of predialysis anemia using intravenous iron and erythropoietin. One day my cardiologist friend, who is second on this list, Dov Wexler called me and said, "Don, I have this patient Rafi, Rafael, who has had three heart attacks and coronary artery bypass. He is in severe heart failure, has been for months. He has been hospitalized 17 times in the last year. His renal function has been steadily deteriorating. It was 1.5 creatinine a year ago and now it's 3. I have been taking fluid ascites from him every week or two and we have been tapping his lungs because of recurrent pleural effusion. Don, I have thrown the book at this guy. He is on every medicine for heart failure. Nothing works. The only thing is he has a hemoglobin of 10. Now my cardiology textbooks tell me I shouldn't do anything about that, but maybe you can do something with him."

So we started to treat Rafael. Over the period of the next few weeks, he went from a hemoglobin of 10 to 13. Rafael has never seen the inside of a hospital for three years. He lost 10 kilos. His effusions and his ascites disappeared. His ejection fraction doubled, and he was literally a new man. He, in fact, is jogging. We looked at this and we said, "Is this possible? What are we seeing here?"

So we went to the American Heart Association review on heart failure published in the American Journal of Cardiology published by Milton Packer and Jay Cohen and many others. In fact, there were 39 experts and 400 references. Ladies and gentlemen, there wasn't a single word about anemia. Not a word in this huge review of heart failure. So that started us on the adventure I'm going to show you now.

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Source: Katz AM. et al, Circulation. 1994 Sep;90(3):1572

Reversible and Irreversible Processes
The mechanisms of how anemia cause heart failure is known to you. You get hypoxic vasodilatation causing increased venous return. What really happens is that you get a renal vasoconstriction anemia causes through noradrenaline, a vasoconstriction. This was well shown in 1993 in the British Heart Journal by Poole, Wilson and others. And you also get an elevated renin angiotensin and aldosterone.

You get an increase in plasma volume and a left ventricular dilatation. The key is the left ventricular dilatation goes on to cause, as you see on the other side, increased wall tension. The wall tension is what kills you. That damages the myocytes. You go on to fibrosis. You go on to remodeling, and you go on to LVH and to death.

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Source: Hunter JJ et al, N Engl J Med. 1999 Oct 21;341(17):1276-83. Review. No abstract available.
Source: Frohlich ED et al, J Hypertens 1992 Nov;10(11):1369-78
Source: Gaasch WH et al, Am J Cardiol. 1979 Jun;43(6):1189-94. Review.
Source: Katz AM et al, N Engl J Med. 1990 Jan 11;322(2):100-10. Review. No abstract available.

Plasma Volume Induced Eccentric LVH
So there is a picture of what, on the left side, is a normal heart and the heart of somebody who has had long-standing anemia.

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Source: Hunter JJ et al, N Engl J Med. 1999 Oct 21;341(17):1276-83. Review. No abstract available.
Source: Frohlich ED et al, J Hypertens 1992 Nov;10(11):1369-78
Source: Gaasch WH et al, Am J Cardiol. 1979 Jun;43(6):1189-94. Review.
Source: Katz AM et al, N Engl J Med. 1990 Jan 11;322(2):100-10. Review. No abstract available.

Pressure Induced Concentric LVH
This is in contrast to hypertension, where you actually get a thickening of the ventricle. Here you get, in a long-standing anemia, a ventricular dilation.

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Source: Duke M et al, Circulation. 1969 Apr;39(4):503-15. No abstract available.
Source: Frohlich ED et al, J Hypertens 1992 Nov;10(11):1369-78
Source: Neill WA et al, Am J Physiol. 1969 Sep;217(3):710-4. No abstract available.

Hemodynamic Compensation During Anemia
Of course, you are also stressing the heart, not just with increased volume, but you're stressing that poor little heart with an increase in heart rate and an increase in contractility.

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Source: Silberberg JS et al, Am J Cardiol. 1989 Jul 15;64(3):222-4.

Left Ventricular Mass Index
This is an article not by me, but by Silberberg 10 years ago. He showed that if your hemoglobin, which is the normal hemoglobin is over here, if your hemoglobin is in the normal quartile, you can see your left ventricular mass is here. This is dialysis patients. But as your hemoglobin falls steadily, you can see your left ventricular mass index increases.

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Source: Foley RN et al, J Am Soc Nephrol. 1995 Jun;5(12):2024-31.

Early Anemia: Risk Factor for Late Mortality
So what we know from the studies in Canada and many other studies, that anemia leads to left ventricular hypertrophy. LVH is present in 75% of patients starting dialysis, and LVH at the start of dialysis is an independent risk factor for mortality on dialysis.

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Source: Silverberg DS et al, Clin Nephrol. 2001 Mar;55(3):212-9.

Anemia treatment in CKD associated with decrease of decline of GFR
This just, incidentally, we have just published looking at, as have others, the effect of correction of anemia in chronic renal failure on renal function. We showed that, in fact, as other people have shown, you can actually improve renal function by correcting the anemia, but not everybody has found this.

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Independent Risk of a Fall in Mean Hb of 1 g/dL
But in patients on dialysis, anemia is an independent risk factor. A fall in the hemoglobin of 1 gram percent causes, as we have shown just now, left ventricular dilatation. There is a 42% increase in the risk for that. De novo or new cases of heart failure on dialysis; your chances for every 1-gram fall in hemoglobin are increased by 28%, for recurrent heart failure by 20%, and for mortality by 14%. So that anemia is a cause of death. Anemia is a killer.

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Treatment of Anemia with Erythropoietin Induces LVH Regression
We also know that when you treat the anemia, you can improve the cardiac output, cardiac index, left ventricular end-diastolic diameter, intraventricular septum, left ventricular posterior wall index, and left ventricular mass index. All of this is known on dialysis.

But what about before dialysis? As I said, we were appalled when we realized that at least the American Heart Association didn't think there was really an importance to anemia at all. So as a matter of fact, we have just seen the data from Dr. McClellan. It's the first time I've seen that data, by the way. I almost fell out of my seat -- I didn't see it before -- that the lower the hemoglobin, the higher the mortality in these patients. This isn't dialysis, it's just heart failure.

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Epoetin alfa and IV Iron for Anemia in Patients with CHF
In the current issue, which came out today, of the Journal of American Cardiology, the SOLVD group, which is a study from Boston, a huge study of 7,000 patients with heart failure, they have demonstrated, as you can see, that during a mean followup of 33 months in heart failure, the mortality was 22% for those with a normal hematocrit of 140, 27% for those with a mild reduction in hemoglobin and 34% for those with a hematocrit of less than 35. This and Dr. McClellan's data are practically the only data in the world on that subject.

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Epoetin alfa and IV Iron for anemia in patients with CHF
When we saw this one case of Rafi that I told you about, this really dramatic case, we said, "Hey, is anemia common in heart failure? Nobody is talking about it. Certainly, it's not listed in the American Heart Association Journal." So we went and pulled the records from 142 patients in our outpatient cardiac department. We have a heart failure department.

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Source: Silverberg DS et al, J Am Coll Cardiol. 2000 Jun;35(7):1737-44.

Relationship between severity of anemia, CKD and CHF
Sure enough, what we found, as you can see on this slide, as you go from mild heart failure, New York Heart Association 1, to severe heart failure, obviously the left ventricular ejection fraction falls. That's known. But what really knocked us for a loop was, in fact, we found that the hemoglobin fell steadily from 14 down to 10, as you go from mild to severe heart failure. That was not in the literature. We couldn't find anything about that. Dr. McClellan has shown it now, but this was not in the literature. We found, of course, which is in the literature, that as you go from mild to severe heart failure, your serum creatinine -- in the blue -- went up. Well, that wasn't new. But the anemia was. We thought we were crazy.

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Prevalence of HB <12 gr % by NYHA Class
Then I was very pleased. I kept looking through the internet and we finally found this paper which came out a month ago from Liverpool, Wisniacki, which looked at over 200 patients, 201 patients, with heart failure in the community. He found just what we found. We found that 55.6% of all our patients with heart failure were anemic, steadily increasing as the heart failure got worse, from 9.1% in the mild cases to 79% of the patients with severe heart failure had a hemoglobin of less than 12. He found almost exactly the same. So we felt that maybe we weren't crazy after all. Today we heard from Dr. McClellan the same thing.

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Anyway, in the British study, by multivariate analysis, the severity of congestive failure was independently related. This was an independent risk factor to the level of hemoglobin independent of hypertension, sex, atrial fibrillation and medications taken.

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Clinical Picture of IHD With and Without Anemia
In a study that was done in a hospital just outside Tel Aviv, where they looked at another group, patients with just cardiac coronary ischemia. Not heart failure. Patients who came into the hospital with angina. Heart attack. What they found is that those who were anemic did much worse than those who weren't. This is just the preliminary data. They show that acute ischemia, as you see, was found in 44% of the patients who were anemic, but only 26% of the patients who weren't. Myocardial infarction was twice as common in those with anemia, heart failure twice as common. Arrhythmias, almost three times as common, and the mortality rate more than three times. So not only in heart failure, but in patients with ischemic heart disease, the cardiologist is quite content for him to go along with a hemoglobin of 10. A hemoglobin of 10 is a killer. That's the message that we somehow have got to get to our cardiologists.

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Anemia is Associated with Increased Cardiac Events and Mortality
Nephrologists don't have any trouble with that anymore. All this was known from the animal studies. Patients with ischemic heart disease and congestive failure are more sensitive to lower levels of hemoglobin than those without ischemic heart disease. The data from Carson, from Nelson, from Hebert, there are so much data in the literature from animal studies that the ischemic heart is sensitive to anemia.

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Animal Studies
One, artificially induced coronary stenosis in dogs and reduced coronary blood flow causes myocardial ischemia and heart failure to a greater extent with anemia. You can take a dog and bleed him down to a hemoglobin of 2 before he'll get heart failure. But if you block off his coronaries, he'll go into heart failure with a hemoglobin of 9. When you treat the anemia, his heart failure will improve.

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Epoetin alfa and IV Iron for Anemia in Patients with CHF
So anyway, with this in mind we then performed our prospective, uncontrolled intervention study where we took 26 anemic patients, hemoglobin 10-11.9 -- mildly anemic, not a big deal -- with severe congestive failure, despite being treated with maximally tolerated medications. These were people that were treated by cardiologists. They threw the works at these patients. This was not under-treated heart failure. These were patients in whom the cardiologist had failed. The only thing that they had left was to send them to us for treatment of the anemia. We tried to raise the hemoglobin to above 12 by erythropoietin and intravenous iron.

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Prospective Intervention Study in 26 Patients
The study lasted 7.2 months. They were given about 5,000 units a week of subcutaneous erythropoietin and about 180 mg per month of iron intravenous.

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Source: Silverberg DS et al, J Am Coll Cardiol. 2000 Jun;35(7):1737-44.

Anemia Treatment Improves CHF
In the yellow on top, you see the hemoglobin which rose from 10 to 12. The iron saturation went up. The New York Heart Association, in yellow, 4 being the worst, they were on death's door, these patients, and it improved remarkably. The dose of oral furosemide fell dramatically. The dose of intravenous furosemide on the bottom, in the blue, it just disappeared. They didn't need any more intravenous furosemide.

Most dramatically was the fall in hospitalizations. These patients were spending all their time in hospital. The one thing that happened when you treated their anemia, as Allan Collins just showed with his slides and his group, the hospitalizations in these patients fell to practically zero. These are the most grateful patients I have seen in all my 40 years of medicine.

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Epoetin alfa and IV Iron for Anemia in Patients with CHF: Ejection Fraction
The ejection fraction increased from 27% to 35%. That's the kind of response you get from a coronary artery bypass. Here we were doing the same by an injection every week.

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Epoetin alfa and IV Iron for Anemia Patients with CHF: Renal Function
The other point, as nephrologists -- and I spoke to Barry Brenner about this the other day -- these patients were losing renal function at the rate of about 1 mL per month with their heart failure. I don't see where it's written in any textbook that heart failure is a common cause of progressive renal failure. I think it's a very common cause of progressive renal failure. A group in Rotterdam have shown the same. They have exactly the same data. Patients with uncontrolled heart failure are losing renal function at the rate of .95 or the rate of 1 mL per minute per month. Once you control them with all these medicines and control their anemia, this deterioration stops or slows down dramatically. We now have a new form of therapy for preventing progression of chronic renal disease. Treat their heart failure.

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Epoetin alfa and IV Iron for Anemia in Patients with CHF: Controlled Clinical Trial
To verify this, we then performed a prospective, randomized, controlled study. 32 anemic patients, hemoglobin 9-11.5 with severe heart failure, despite being treated with maximally tolerated medication for more than six months. We gave 16 of them the same therapy, subcutaneous erythropoietin, IV iron and 16 patients that we did not treat.

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Source: Silverberg DS et al, J Am Coll Cardiol. 2001 Jun 1;37(7):1775-80.

Treatment of Anemia in Patients with CHF: Controlled Study in 32 Patients
They were treated for an average of 8.2 months. The average dose of erythropoietin was the same, of iron the same. The first paper was published in the Journal of the American College of Cardiology last June and a second one this June if you want to read it.

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Treatment of Anemia in Patients with CHF: Controlled Study in 32 Patients
4 of the 16 patients in the control group died. We felt terrible. We stopped the study. Their deaths were considered to be at least partially related to the unrelenting heart failure. This was in the control group. There were no deaths in the 16 patients in whom we treated the anemia.

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The effect of treatment of anemia on the Hb level
On the left, this is the anemia, the first one. You can see the hemoglobin went up in the treated group and remained the same in the untreated group. That's hemoglobin.

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The effect of treatment of anemia on the serum creatinine
The second one is serum creatinine. In the treated group, the serum creatinine did not change, whereas in the control group the serum creatinine worsened. Again, we had evidence that progressive uncontrolled heart failure causes progressive renal failure.

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The effect of treatment of anemia on the LVEF
The third of those slides is the ejection fraction, which improved in the treatment group and deteriorated in the control group.

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The effect of treatment of anemia on the NYHA class

The fourth was the New York Heart Association class, which again, as in the uncontrolled study, showed an improvement in the treated group and no change in the control group.

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The effect of treatment of anemia on the daily dose of oral furosemide
The fifth was the dose of oral furosemide, which practically dropped out of site. We had to reduce the dose. If we hadn't reduced the dose of furosemide, they would have fainted from volume depletion. In the control group, the need for oral furosemide went up.

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The effect of treatment of anemia on the weekly dose of I.V. furosemide
And the same thing with the I.V. furosemide. It went down to practically zero in the treated group, but you have to do that. You have to reduce the dose, or you're going to be in big trouble. It went up in the other group.

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The effect of treatment of anemia on the number of days of hospitalizations
The number of hospitalizations, as in the controlled study, just fell dramatically in the treated group and worsened in the untreated group.

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Long Term Follow-Up of 126 Anemic CHF Patients
We have followed now 150 patients with renal failure and anemia in our department. Ladies and gentleman, 83% of these patients have heart failure. I don't know what you're seeing with anemia, but what we're seeing with patients with renal failure and anemia are patients with heart failure. Maybe that's because our cardiologists all over Israel are sending their patients to us because they have seen the rather dramatic effects. Or maybe this is, in fact, true. Maybe the majority of patients with anemia and renal failure are patients with heart failure, and you never know because you don't get echocardiograms. You don't really evaluate their cardiac status. Maybe if you did, you'd find it's not the 20% or 30% that some people think, but that the majority of patients with chronic renal failure and anemia, in fact, have heart failure and need intensive -- first of all, need a diagnosis and need intensive therapy. The majority had systolic dysfunction.

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Long Term Follow-Up of 126 Anemic CHF Patients
The cause of it. 86% of them had ischemic heart disease. Half of them were hypertensive. Half of them hyperlipidemic, half of them diabetic. I'm not saying that diabetes doesn't contribute, but I'm saying that diabetes contributes through the damage to the heart.

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Long Term Follow-Up of 126 Anemic CHF Patients
In fact, as in all heart failure, the majority of the patients with heart failure in the community have ischemic heart disease. 78.6%. Every study shows that. Hypertension by itself without ischemia is responsible for about 10%. That's also in the literature. Valvular heart disease 7% and idiopathic cardiomyopathy 4%.

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Long Term Follow-Up of 126 Anemic CHF Patients After Correction of Their Anemia
As I said, the hemoglobin went up, the hematocrit went up, the creatinine stayed the same.

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Long Term Follow-Up of 126 Anemic CHF Patients After Correction of Their Anemia
We are, again, shown the same slowing of fall of the renal failure. In fact, an improvement in renal function. 28% of the patients, in fact, there was a fall in creatinine. In 51.6% it stayed the same. The creatinine only increased in 19%.

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Long Term Follow-Up of 126 Anemic CHF Patients After Correction of Their Anemia
The New York Heart Association in all of our patients -- in the majority of patients -- has improved. The ejection fraction has improved. The number of hospitalizations has fallen. 5% require dialysis, and 7.9% died.

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Mechanisms for the Anemia in CHF
Why do patients with heart failure get anemia? Part of it may be something with the cytokines. We know that heart failure causes an increase in TNF-alpha, interleukin-1, interleukin-6. These things interfere with erythropoietin. You may have erythropoietin levels that are quite high, but they don't work because all these cytokines released by the damaged heart don't allow the erythropoietin to work.

This is the anemia of chronic disease. You see the same in rheumatoid arthritis. You see the same in ulcerative colitis. You see the same in Crohn's disease; any chronic inflammatory state. Heart failure acts like a chronic inflammatory state.

ACE inhibitors also may cause an interference with erythropoietin. Part of it is just renal failure. Of course, aspirin may cause GI blood loss. The last thing is that, with proteinuria you can lose a lot of erythropoietin in the urine.

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Conclusions
I'm on my last slide, so conclusions. Preliminary evidence suggests that erythropoietin and IV iron in patients with heart failure improves anemia, improves iron status, improves congestive failure, improves the left ventricular ejection fraction and New York Heart Association class, decreases hospital utilization, lowers diuretic doses and slows deterioration of renal function.

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Cardiorenal Anemia (CRA) Syndrome
Basically, we have triangle of heart failure, renal failure and anemia. What people didn't realize is that heart failure itself can cause anemia. The treatment of the heart failure can improve the renal function as well.

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Closing Thoughts
The fate of the dialysis patient is cast in the predialysis period. Congestive failure is a common and crucial contributor to the progression of renal failure. Treatment of anemia in patients with congestive failure may improve both the cardiac and renal function. To save the heart and the kidney, treat the anemia. Thank you.


References

1. Katz AM. Health care reform. A threat to research and education in the academic health center. Circulation. 1994 Sep;90(3):1572

2. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med. 1999 Oct 21;341(17):1276-83. Review. No abstract available.

3. Frohlich ED, Sasaki O, Chien Y, Arita M. Changes in cardiovascular mass, left ventricular pumping ability and aortic distensibility after calcium antagonists in Wistar-Kyoto and spontaneously hypertensive rats J Hypertens 1992 Nov;10(11):1369-78

4. Gaasch WH. Left ventricular radius to wall thickness ratio. Am J Cardiol. 1979 Jun;43(6):1189-94. Review.

5. Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med. 1990 Jan 11;322(2):100-10. Review. No abstract available.

6. Frohlich ED, Sasaki O, Chien Y, Arita M. Changes in cardiovascular mass, left ventricular pumping ability and aortic distensibility after calcium antagonists in Wistar-Kyoto and spontaneously hypertensive rats J Hypertens 1992 Nov;10(11):1369-78.

7. Neill WA, Oxendine JM, Moore SC. Acute and chronic cardiovascular adjustments to induced anemia in dogs. Am J Physiol. 1969 Sep;217(3):710-4. No abstract available.

8. Silberberg JS, Rahal DP, Patton DR, Sniderman AD. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Am J Cardiol. 1989 Jul 15;64(3):222-4.

9. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The prognostic importance of left ventricular geometry in uremic cardiomyopathy. J Am Soc Nephrol. 1995 Jun;5(12):2024-31.

10. 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.

11. Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, Brosh D, Laniado S, Schwartz D, Yachnin T, Shapira I, Gavish D, Baruch R, Koifman B, Kaplan C, Steinbruch S, Iaina A. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000 Jun;35(7):1737-44.

12. Silverberg DS, Wexler D, Sheps D, Blum M, Keren G, Baruch R, Schwartz D, Yachnin T, Steinbruch S, Shapira I, Laniado S, Iaina A. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001 Jun 1;37(7):1775-80.


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This educational activity is based on an ASN/ISN evening symposium which was
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