cleveland clinic journal of medicine-2006-nurko-289-97.pdf

CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 NUMBER 3 MARCH 2006 289

SAUL NURKO, MDDirector, EPO Clinic, Department of Nephrologyand Hypertension, The Cleveland Clinic Foundation

Anemia in chronic kidney disease:Causes, diagnosis, treatment

REVIEW

ABSTRACTMost patients with chronic kidney disease eventuallybecome anemic. We should view the management ofanemia in these patients as part of the overallmanagement of the many clinically relevantmanifestations of chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) are safe and should be used, astreating anemia may forestall some of the target-organdamage of chronic kidney disease.

KEY POINTSAnemia increases in prevalence and severity as renalfunction decreases, becoming much more common whenthe glomerular filtration rate reaches 60 mL/minute orless. It is a risk factor associated with worse prognosis.

Deficiency of erythropoietin is the primary cause ofanemia in chronic renal failure, but it is not the onlycause. A minimal workup is necessary to rule out irondeficiency and other cell-line abnormalities.

Patients with chronic kidney disease should beperiodically checked for anemia by measuring the serumhemoglobin level. If the level is 12.0 g/dL or less in a manor postmenopausal woman or 11.0 g/dL or less in apremenopausal woman, he or she should undergo furtherworkup for anemia.

Patients receiving ESAs should also receive supplementaliron, probably parenterally. The target hemoglobin rangeis lower than the normal range: 11.0 to 12.0 g/dL.

REATMENT WITH RECOMBINANT erythro-poiesis-stimulating agents (ESAs) has

greatly improved the management of anemiain patients with chronic kidney disease, per-mitting better outcomes and a higher qualityof life for most.

See related editorial, page 298

In chronic kidney disease, as nephrons areprogressively lost, the body attempts to main-tain homeostasis via multiple adaptive andmaladaptive processes, including a complexrange of biochemical and physiologic abnor-malities. Almost every organ and systemseems to be affected, but the main complica-tions are cardiovascular, neurologic, hemato-logic, musculoskeletal, and immunologicand all worsen as kidney function declines.

Therefore, patients with chronic kidneydisease, even those with moderate diseasenot yet requiring dialysis, need to be period-ically monitored for anemia. Although mostpatients are anemic when they start dialysis,only about a third are receiving treatmentfor it.

This article offers an update on the patho-genesis of anemia in this disease, diagnostictesting, and treatments, including the datapublished to date regarding the benefits oftreating anemia in chronic kidney disease.

DEFINING ANEMIA

The World Health Organization defines ane-mia as a hemoglobin concentration lowerthan 13.0 g/dL in men and postmenopausalwomen and lower than 12.0 g/dL in otherwomen.

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290 CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 NUMBER 3 MARCH 2006

The European Best Practice Guidelinesfor the management of anemia in patientswith chronic kidney disease propose that thelower limit of normal for hemoglobin be 11.5g/dL in women, 13.5 g/dL in men age 70 andunder, and 12.0 g/dL in men older than age70.1

In the United States, the working defini-tion of anemia in chronic kidney disease hasbeen influenced by government policy, as theMedicare program is the primary payer for itstherapy. The National Kidney FoundationsKidney Dialysis Outcomes Quality Initiative(K/DOQI)2 recommends a workup for anemiain patients with chronic kidney disease if thehemoglobin level is less than 11.0 g/dL (hema-tocrit < 33%) in premenopausal women andprepubertal patients, and when the hemoglo-bin is less than 12.0 g/dL (hematocrit < 37%)in adult men and postmenopausal women.2These levels correspond to a decline toapproximately 80% of the mean level fordefined healthy subgroups.

ANEMIA IS COMMONIN KIDNEY DISEASE

Anemia is very common in patients withchronic kidney disease and probably causesmany of its symptoms.

Physicians should start thinking about ane-mia when their patients glomerular filtrationrate (GFR) declines to 60 mL/minute/1.73 m2or less. In the third National Health and

Nutrition Examination Survey (NHANES),3the prevalence of anemia in stage 3 chronickidney disease (ie, a GFR of 30 to 59 mL/minute/1.73 m2, TABLE 1) was 5.2%, rising to44.1% in stage 4, and becoming almost univer-sal in stage 5. (NHANES defined anemia ashemoglobin < 12.0 g/dL in men and < 11.0g/dL in women.)

African Americans3,4 and patients withdiabetes5 have even higher rates of anemia ateach stage of kidney disease.5

Moreover, chronic kidney disease itself isvery common: nearly 6 million Americans areestimated to have stage 3 chronic kidney dis-ease.4

WHAT CAUSES ANEMIAIN CHRONIC KIDNEY DISEASE?

Factors likely contributing to anemia inchronic kidney disease include blood loss,shortened red cell life span, vitamin deficien-cies, the uremic milieu, erythropoietin(EPO) deficiency, iron deficiency, and inflam-mation. Unfortunately, we know little aboutthe relative contributions of the different fac-tors and conditions in the early stages ofchronic kidney disease.

Blood lossPatients with chronic kidney disease are at riskof blood loss due to platelet dysfunction. Themain cause of blood loss is dialysis, especiallyhemodialysis, and the loss results in absolute

Anemia isalmostuniversalin stage 5chronic kidneydisease

ANEMIA OF KIDNEY DISEASE NURKO

Stages of chronic kidney disease

STAGE DESCRIPTION GLOMERULAR FILTRATION RATE(GFR) (ML/MIN/1.73 M2)

1 Kidney damage with normal or increased GFR > 90

2 Mild decrease in GFR 60 89*

3 Moderate decrease in GFR 30 59

4 Severe decrease in GFR 15 29

5 Kidney failure < 15 or dialysis

*May be normalBASED ON GUIDELINES OF THE NATIONAL KIDNEY FOUNDATION. K/DOQI CLINICAL PRACTICE GUIDELINES FOR CHRONIC KIDNEY DISEASE:

EVALUATION, CLASSIFICATION, AND STRATIFICATION. AM J KIDNEY DIS 2002; 39(2 SUPPL 1):1266.

T A B L E 1


Iron homeostasis is perturbed in chronic kidney disease

FIGURE 1

CCF2006Medical Illustrator: Joseph Pangrace

Iron homeostasis is perturbed in patients with chronic kidney disease. The ability to provideenough iron for erythropoiesis is disrupted at several points in the iron cycle for reasons not yetclear. Thus, patients receiving erythropoiesis-stimulating agents will require iron supplementa-tion, often intravenously, in order to produce additional red blood cells.

Less transferrin. Transferrin lev-els in chronic kidney disease aretwo-thirds of normal levels,decreasing the ability totransport iron to the bonemarrow.

Blocked release of storediron. Macrophages scavengeiron from senescent red bloodcells. Chronic kidney diseaseblocks the release of iron frommacrophages to transferrin.

Iron losses normally total 1 to 2mg/day due to bleeding and desqua-mation, but can be several timeshigher in chronic kidney disease,primarily due to dialysis.

Transferrin

Iron intake

Circulatingerythrocytes

Reticuloendothelialmacrophage


iron deficiency. Hemodialysis patients maylose 3 to 5 g of iron per year.6 Normally, welose 1 to 2 mg per day (FIGURE 1), so the iron lossin dialysis patients is 10 to 20 times higher.Therefore, iron supplementation is a mainstayof anemia management.

Shortened red blood cell life spanThe life span of red cells is reduced byapproximately one third in hemodialysispatients.7

Vitamin deficienciesIt is difficult to determine whether vitamin defi-ciencies play a significant role in causing anemiain chronic kidney disease. Most patients withchronic kidney disease take a multivitamindaily, although there is no strong evidence thatthis is beneficial.8 Therefore, even the preva-lence of vitamin deficiencies in chronic kidneydisease has been hard to establish.

Uremic milieuThe uremic milieu is a term that is overusedin attempts to explain the multiple organ dys-function of chronic kidney disease.

In studies in vitro, the term has beeninvoked when cultured cells were exposed toserum from patients with chronic kidney dis-ease, with results that mimicked some of theclinical observations. For example, uremicserum has been shown to inhibit primary bonemarrow cultures of early erythroid cell lines.9However, the lack of specificity in these stud-ies has been criticized because this serum alsoaffects other cell lines.

In studies in vivo, the concept of a uremicmilieu may explain why the level and preva-lence of anemia correlate with the severity ofthe kidney disease.4 A GFR lower than 60mL/minute/1.73 m2 has been associated with ahigher prevalence of anemia, which reached75% in some studies.10

In addition, in a study in patients who hadbeen receiving hemodialysis,11 the hematocritrose when the intensity of dialysis wasincreased, implying that reducing uremiarestores or improves bone marrow function.However, this study could not distinguish theindependent effects of the increased dialysisdose and the effect of changing to a more per-meable dialysis membrane during the study.

EPO deficiencyEPO deficiency is considered the most impor-tant cause of anemia in chronic kidney dis-ease. Researchers postulate that the special-ized peritubular cells that produce EPO arepartially or completely depleted or injured asrenal disease progresses, so that EPO produc-tion is inappropriately low relative to thedegree of anemia. Thus, measuring EPO levelsin this population is of no use and should notbe ordered: in fact, it can even be misleadingif the value is normal when it ought to behigh. However, the reason for this inappropri-ately low EPO production is not well under-stood.

EPO is produced when its gene is tran-scribed, in a process that depends on the bind-ing of a molecule called hypoxia-induciblefactor 1 alpha to the hypoxia-responsive ele-ment on the erythropoietin gene. Productionof this factor increases in states of relative oxy-gen deficiency. Therefore, the balancebetween oxygen supply and consumptiondetermines the production of hypoxia-inducible factor 1 alpha and, in turn, produc-tion of EPO.

Donnelly12 proposed that the relativeEPO deficiency in chronic kidney diseasecould be a functional response to a decreasedglomerular filtration rate. The theory is thatthe EPO-producing kidney cells themselvesmay not be hypoxic: if the glomerular filtra-tion rate is low, there is less sodium reabsorp-tionand sodium reabsorption is the maindeterminant of oxygen consumption in thekidney. In this situation there may be a localrelative excess of oxygen that could down-reg-ulate EPO production.12

Moreover, dialysis patients in one studymaintained the ability to increase EPO pro-duction when exposed to high altitude.13

However, the best example that nativekidneys have the potential for restoring EPOproduction is seen in some patients whodeveloped erythrocytosis after receiving kid-ney transplants,14 a situation in which the ure-mic milieu is eliminated.

Iron deficiencyHuman iron metabolism is unique because noexcretory route exists: it is mostly regulatedvia uptake. Iron homeostasis depends on iron

Hemodialysispatients maylose 35 gof ironper year,so ironsupplementsare essential


being absorbed in the duodenum and alsorecycled from senescent red blood cells. Mostof the iron is bound to hemoglobin and isstored in hepatocytes and macrophages of thereticuloendothelial system (FIGURE 1).15

Iron is delivered to the maturing erythro-cytes by a protein called transferrin, whichtransports both the iron absorbed and the ironreleased from macrophages (mainly from recy-cled senescent red blood cells).

Iron homeostasis appears to be altered inchronic kidney disease. For reasons not yetknown (perhaps malnutrition), transferrinlevels in chronic kidney disease are one half toone third of normal levels, diminishing thecapacity of the iron-transporting system.16This situation is then aggravated by the well-known inability to release stored iron frommacrophages and hepatocytes in chronic kid-ney disease.

Clinically, diminished iron transport andaccumulated iron stores are manifested as lowtransferrin saturation and elevated serum fer-ritin levels. These characteristics suggest thatthe interorgan iron transport pathways may berate-limiting factors in erythropoiesis in thesepatients. Interplay between increased ironlosses (as discussed previously) and abnormalinterorgan iron transport results in an absoluteor functional iron deficiency that can be cor-rected only by aggressive iron replacementtherapy.17

InflammationInterestingly, the anemia of inflammation isalso characterized by low serum iron, lowtransferrin saturation, and impaired release ofstored iron, manifested as high serum ferritin.Chronic kidney disease shares several featuresof the inflammatory state. Elevated circulat-ing levels of inflammatory cytokines such asinterleukin 6 have been associated with poorresponse to EPO treatment in end-stage renaldisease.18 These cytokines can impair bonemarrow function and can significantly alteriron metabolism. The molecular mechanismsinvolved in the altered interorgan iron com-munication in both inflammation and chron-ic kidney disease are yet to be elucidated.

Newly discovered molecules haveincreased our understanding of iron metabo-lism. For example, hepcidin, a 25-amino-acid

peptide secreted by the liver, profoundly influ-ences iron metabolism. Recent studies indi-cate that hepcidin inhibits iron absorption,placental iron transfer, and iron release fromthe reticuloendothelial macrophages, and itmediates the anemia of inflammation.19,20However, hepcidins role in the anemia ofchronic kidney disease still needs to be eluci-dated.

BENEFITS OF TREATING ANEMIA

Although no randomized trial has fullyassessed the consequences of not treating ane-mia in chronic kidney disease, the consensusis that untreated anemia contributes to thelarge cardiovascular disease burden in thispopulation.

Most information comes from studies inpatients who already had stage 5 chronic kid-ney disease and were on dialysis. Most of thedata are epidemiologic, showing associationbut not causality. Nevertheless, these studiessuggest that treating anemia with a goal of rais-ing the hematocrit to at least 36% improvesquality of life,20 decreases the need for transfu-sions,21,22 improves muscle strength23 and cog-nitive function,24 and decreases rates of hospi-talization and death.25,26

In patients with nephropathy due to type2 diabetes who were not on dialysis, anemiawas identified as an independent risk factorfor progression of chronic kidney disease afterblood pressure control.27 Other independentrisk factors include the degree of renal dys-function, the serum albumin level, and pro-teinuria.

Studies of patients with chronic kidneydisease not on dialysis have been designed toanswer two fundamental questions: Does treating anemia influence the rate ofprogression of chronic kidney disease? Does treating anemia affect the presenceor regression of left ventricular abnormalities,especially left ventricular hypertrophy?

Three recent papers address the effects oftreating anemia with epoietin alfa on the pro-gression of kidney disease.2830 However, onlyone30 used progression of renal disease as theprimary end point. The total number ofpatients treated in this triad of studies was246, of which 167 were women and 58 had


Treatinganemia appearssafe inpatients withstage 3 or 4kidney disease


diabetes. All patients were white. The approx-imate average GFR was 27 mL/minute/1.73m2 (this was measured by creatinine clearanceusing the Cockroft-Gault formula in onestudy30 and by nuclear estimates in the othertwo28,29). Follow-up time after anemia treat-ment was 1 to 2 years. None of the studiesshowed progression of renal disease (measuredas a change in creatinine clearance) associat-ed with the anemia treatment, and one study30was able to detect even a slight decrease inprogression of disease.

Moreover, an epidemiological study31showed that the use of and response to epoi-etin alfa in predialysis patients offers a modestearly survival benefit after starting dialysis.

Based on these studies, treating anemiaappears safe in patients with stage 3 or 4chronic kidney disease. However, we have nospecific data yet for African Americans.

If treating anemia slows the progression ofchronic kidney disease, the mechanism is stilla matter of speculation. Some of the currentlyproposed mechanisms are that treatmentreduces oxidative stress, ameliorates the effectsof hypoxia at the tubular level (thus protectingagainst nephron loss), lowers the accumulationof extracellular matrix, promotes angiogenesis,and prevents apoptosis.32

Does treating anemiareduce left ventricular hypertrophy?Left ventricular hypertrophy is closely linkedto chronic kidney disease. The estimatedprevalence in stage 3 and 4 is 39%, and it iseven higher in patients with lower renalfunction.33,34 At the start of dialysis nearly74% of patients have left ventricular hyper-trophy.35

A multivariate prospective study of 246patients showed that a declining hemoglobinlevel was an independent contributor to thedevelopment of left ventricular hypertrophy(odds ratio 1.32 for each 0.5-g/dL decrease; P= 004).33

In a recent 2-year randomized controlledtrial,29 Roger et al randomized 155 patientswith stage 3 or 4 chronic kidney disease andhemoglobin levels of 11.0 to 12.0 g/dL (inwomen) or 11.0 to 13.0 g/dL (in men) toreceive epoietin alfa as necessary to maintaintheir hemoglobin levels between either 12.0

and 13.0 g/dL or 9.0 and 10.0 g/dL. Usingintention-to-treat analysis, the authors foundno statistical differences in the left ventricularmass index between the two study groups at 2years, suggesting that normalizing hemoglobinhad no advantages. However, the difference inhemoglobin concentration between thegroups was narrow and may have had a con-founding effect on the results. In spite of thenegative results, anemia was identified as anindependent predictor of left ventricularhypertrophy in patients achieving the proto-col targets.

In a subsequent nested analysis of thesame study,36 McMahon et al described theeffects of change in hemoglobin level onleft ventricular mass in patients with orwithout left ventricular hypertrophy atbaseline.36 Among patients without hyper-trophy at baseline, 68% showed no changeat 2 years, and 32% developed hypertrophy.Among those with hypertrophy at baseline,50% showed no change, and 22% had someevidence of regression. The factors associ-ated with left ventricular hypertrophy wereage, elevated systolic blood pressure, ele-vated pulse pressure, anemia, and a lowerGFR.

From these two studies one can concludethat there is some association between anemiaand left ventricular hypertrophy, but keepingthe hemoglobin level in the normal rangeoffers no significant advantage over a lowerstable hemoglobin level. The authors advocat-ed aggressive treatment of the clinically rele-vant manifestations of the chronic kidney dis-ease (ie, high blood pressure, anemia) in theprevention and reversal of left ventricularhypertrophy, as hypertrophy either did notprogress or regressed in close to 70% of thepatients with hypertrophy.

Moreover, a decrease in left ventricularmass index at 6 months was recently reportedin an open-label interventional trial.37 In thisstudy, patients who had stage 4 chronic kidneydisease and a hemoglobin level less than 10g/dL were treated with epoietin alfa with a tar-get hemoglobin of 12 g/dL.

However, whether treatment lowers thedeath rate is not yet known. This questionmay be answered when several ongoing multi-center trials are completed.

No proofyet thatnormalizingthe hemoglobinlevel offerssignificantclinicaladvantage


DIAGNOSIS:DONT ASSUME RENAL DISEASEIS THE ONLY CAUSE

In chronic kidney disease, anemia may not beentirely attributable to the kidney disease.Anemia of chronic kidney disease should bealmost a diagnosis of exclusion after ruling outiron deficiency and nonerythroid cell-lineabnormalities.

A minimal workup is recommendedbefore starting therapy with an ESA (FIGURE 2).It should include: A complete blood cell count

Red blood cell indices A reticulocyte count Iron measurements (serum iron, totaliron-binding capacity, percent transferrin sat-uration, serum ferritin) Testing for occult blood in the stool.

Depending on clinical and laboratory cir-cumstances, a more extensive workup may beindicated, ie: Serum vitamin B12 level Parathyroid hormone level Serum or urine protein electrophoresis A hemolysis panel.1,2


Anemia workup for patients with chronic kidney disease

Check hemoglobin periodically

No

No workup

Iron deficiency

Yes

Treat with ironsupplementation

Anemia corrected:Periodic follow-up

Otherwise abnormal

Refer for hematologyworkup

Yes

Workup:Complete blood cell countRed blood cell indicesReticulocyte countIron measurements

Serum ironTotal iron-binding capacityPercent transferrin saturationSerum ferritinStool for occult blood

Normal

Treat witherythropoiesis-stimulating agent (ESA)if indicated

Anemianot corrected

For men and postmenopausal women: 12.5 mg/dLFor other patients: 11.0 mg/dL

FIGURE 2

ADAPTED FROM GUIDELINES OF THE NATIONAL KIDNEY FOUNDATION. K/DOQI CLINICAL PRACTICE GUIDELINES FOR CHRONIC KIDNEY DISEASE: EVALUATION,CLASSIFICATION, AND STRATIFICATION. AM J KIDNEY DIS 2002; 39(2 SUPPL 1):1266.

No

REFERENCES1. Locatelli F, Aljama P, Barany P, et al. Revised European best practice

guidelines for the management of anaemia in patients with chronicrenal failure. Nephrol Dial Transplant 2004; 19(suppl 2):147.

2. National Kidney Foundation. IV. NKF-K/DOQI Clinical PracticeGuidelines for Anemia of Chronic Kidney Disease: update 2000. Am JKidney Dis 2001; 37(suppl 1):182238.

3. Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associat-ed with chronic renal insufficiency among adults in the UnitedStates: results from the Third National Health and NutritionExamination Survey. J Am Soc Nephrol 2002; 13:504510.

4. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kid-ney function with anemia: the Third National Health and NutritionExamination Survey (19881994). Arch Intern Med 2002; 162:14011408.

5. El-Achkar TM, Ohmit SE, McCullough PA, et al. Higher prevalence ofanemia with diabetes mellitus in moderate kidney insufficiency: theKidney Early Evaluation Program. Kidney Int 2005; 67:14831488.

6. Tong EM, Nissenson AR. Erythropoietin and anemia. Semin Nephrol2001; 21:190203.

7. Ly J, Marticorena R, Donnelly S. Red blood cell survival in chronicrenal failure. Am J Kidney Dis 2004; 44:715719.

8. Descombes E, Hanck AB, Fellay G. Water soluble vitamins in chronichemodialysis patients and need for supplementation. Kidney Int1993; 43:13191328.

9. Eschbach JW. The anemia of chronic renal failure: pathophysiologyand the effects of recombinant erythropoietin. Kidney Int 1989;35:134148.


As already mentioned, measuring EPOlevels is not useful.1

TREATMENT

ESAs should be given to achieve and main-tain a target hemoglobin concentration of11.0 to 12.0 g/dL.38 There is currently no evi-dence that raising the hemoglobin to normallevels offers any significant clinical advantageover this target goal.

Two ESAs:Epoietin alfa and darbepoetin alfaIn the United States, the two agents availablefor treating anemia in chronic kidney diseaseare recombinant epoietin alfa (Epogen,Procrit) and darbepoetin alfa (Aranesp). Inmy opinion, both are effective and safe.Patients on dialysis can receive them intra-venously; those not on dialysis can receivethem subcutaneously.

According to the manufacturers, theseproducts differ in pharmacodynamic and phar-macokinetic properties, affinity for the EPOreceptor,39 and half-life.38,40 These differentcharacteristics could be used to apply differentdosing regimens.

Iron supplementationPatients should receive iron supplementationwhile on ESA therapy, because pharmacologi-cally induced erythropoiesis is limited by theiron supply,17 as shown by lower ESA require-ments after iron supplementation.

In addition, as patients make more redblood cells they use up more iron, which canlead to iron deficiency. Serum ferritin and per-cent transferrin saturation have been shownto drop after 1 week of ESA therapy in both

healthy people and iron-replete patients withchronic kidney disease on dialysis.41

Because patients with kidney disease havealtered iron metabolism, their serum ferritinlevels and percent transferrin saturation shouldbe maintained at levels higher than in the nor-mal population.16 Recommended mainte-nance levels for serum ferritin are at least 200ng/mL; for percent transferrin saturation atleast 20%.2

Most patients with chronic kidney diseaseneed parenteral iron supplementation toachieve the recommended iron levels.2Possible explanations for the failure of oraliron supplementation include a diminishedability of the oral mucosa to absorb iron andpoor patient compliance (due to difficult dos-ing, side effects, and cost).

Monitoring and controlling side effectsSide effects of treatment with ESAs (mainlywith recombinant epoietin alfa because it hasbeen studied more thoroughly) include wors-ening of hypertension and problems at the siteof injection. The K/DOQI panel reviewed 47reports that included a total 3,428 patients.About 23% of patients had a new onset ofhypertension or an increase in blood pressure,or both. If hypertension worsens, one shouldadjust the antihypertensive regimen ratherthan withhold the ESA treatment.

At The Cleveland Clinic Foundation,nearly all patients with chronic kidney diseasewho receive ESAs are seen in a special EPOclinic in the Department of Nephrology andHypertension. More than 80% of the patientsenrolled reach their hemoglobin target.Because this therapy requires frequent moni-toring, such centralized care with algorithm-based management works well.

Side effectsof ESAsincludehypertensionand injectionsite problems



10. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemiain patients with chronic kidney disease. Curr Med Res Opin 2004;20:15011510.

11. Ifudu O, Feldman J, Friedman EA. The intensity of hemodialysis andthe response to erythropoietin in patients with end-stage renal dis-ease. N Engl J Med 1996; 334:420425.

12. Donnelly S. Why is erythropoietin made in the kidney? The kidneyfunctions as a critmeter. Am J Kidney Dis 2001; 38:415425.

13. Blumberg A, Keller H, Marti HR. Effect of altitude on erythropoiesisand oxygen affinity in anaemic patients on maintenance dialysis. EurJ Clin Invest 1973; 3:9397.

14. Martino R, Oliver A, Ballarin JM, Remacha AF. Postrenal transplanterythrocytosis: further evidence implicating erythropoietin produc-tion by the native kidneys. Ann Hematol 1994; 68:201203.

15. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:19861995.

16. Besarab A, Frinak S, Yee J. An indistinct balance: the safety and effi-cacy of parenteral iron therapy. J Am Soc Nephrol 1999;10:20292043.

17. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and eryth-ropoiesis. Blood 2000; 96:823833.

18. Macdougall IC, Cooper AC. Erythropoietin resistance: the role ofinflammation and pro-inflammatory cytokines. Nephrol DialTransplant 2002; 17(suppl 11):3943.

19. Ganz T. Hepcidin, a key regulator of iron metabolism and mediatorof anemia of inflammation. Blood 2003; 102:783788.

20. Moreno F, Sanz-Guajardo D, Lopez-Gomez JM, Jofre R, ValderrabanoF. Increasing the hematocrit has a beneficial effect on quality of lifeand is safe in selected hemodialysis patients. Spanish CooperativeRenal Patients Quality of Life Study Group of the Spanish Society ofNephrology. J Am Soc Nephrol 2000; 11:335342.

21. Eschbach JW, Adamson JW. Iron overload in renal failure patients:changes since the introduction of erythropoietin therapy. Kidney Int1999; 69(suppl 1):S35S43.

22. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant humanerythropoietin in anemic patients with end-stage renal disease.Results of a phase III multicenter clinical trial. Ann Intern Med 1989;111:9921000.

23. Robertson HT, Haley NR, Guthrie M, Cardenas D, Eschbach JW,Adamson JW. Recombinant erythropoietin improves exercise capacityin anemic hemodialysis patients. Am J Kidney Dis 1990; 15:325332.

24. Marsh JT, Brown WS, Wolcott D, et al. rHuEPO treatment improvesbrain and cognitive function of anemic dialysis patients. Kidney Int1991; 39:155163.

25. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associatedmortality in hemodialysis patients. J Am Soc Nephrol 1999;10:610619.

26. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitaliza-tion risks in hemodialysis patients. J Am Soc Nephrol 1999;10:13091316.

27. Keane WF, Brenner BM, de Zeeuw D, et al. The risk of developing

end-stage renal disease in patients with type 2 diabetes andnephropathy: the RENAAL study. Kidney Int 2003; 63:14991507.

28. Furuland H, Linde T, Ahlmen J, Christensson A, Strombom U,Danielson BG. A randomized controlled trial of haemoglobin nor-malization with epoetin alfa in pre-dialysis and dialysis patients.Nephrol Dial Transplant 2003; 18:353361.

29. Roger SD, McMahon LP, Clarkson A, et al. Effects of early and lateintervention with epoetin alpha on left ventricular mass amongpatients with chronic kidney disease (stage 3 or 4): results of a ran-domized clinical trial. J Am Soc Nephrol 2004; 15:148156.

30. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating ane-mia early in renal failure patients slows the decline of renal function:a randomized controlled trial. Kidney Int 2004; 66:753760.

31. Canadian Erythropoietin Study Group. Association between recombi-nant human erythropoietin and quality of life and exercise capacityof patients receiving haemodialysis. BMJ 1990; 300:573578.

32. Rossert J, Fouqueray B, Boffa JJ. Anemia management and the delayof chronic renal failure progression. J Am Soc Nephrol 2003; 14(7suppl 2):173177.

33. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass indexincrease in early renal disease: impact of decline in hemoglobin. AmJ Kidney Dis 1999; 34:125134.

34. Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ven-tricular hypertrophy in the predialysis population: identifying oppor-tunities for intervention. Am J Kidney Dis 1996; 27:347354.

35. Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiograph-ic disease in patients starting end-stage renal disease therapy. KidneyInt 1995; 47:186192.

36. McMahon LP, Roger SD, Levin A, Slimheart Investigators Group.Development, prevention, and potential reversal of left ventricularhypertrophy in chronic kidney disease. J Am Soc Nephrol 2004;15:16401647.

37. Ayus JC, Go AS, Valderrabano F, et al. Effects of erythropoietin onleft ventricular hypertrophy in adults with severe chronic renal fail-ure and hemoglobin < 10 g/dL. Kidney Int 2005; 68:788795.

38. National Kidney Foundation. K/DOQI clinical practice guidelines forchronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis 2002; 39(2 suppl 1):1266.

39. Egrie JC, Browne JK. Development and characterization of novel ery-thropoiesis stimulating protein (NESP). Br J Cancer 2001; 84(suppl1):310.

40. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulat-ing protein for treatment of anemia in chronic renal insufficiency.Kidney Int 2001; 60:741747.

41. Eschbach JW, Haley NR, Egrie JC, Adamson JW. A comparison of theresponses to recombinant human erythropoietin in normal uremicsubjects. Kidney Int 1992; 42:407416.

ADDRESS: Saul Nurko, MD, Department of Nephrology and Hypertension,A51, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH44195.

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