C.K.D.THE JOURNAL OF CHRONIC KIDNEY DISEASE

From the Editors: Welcome to our inaugural issue

Editorial: Why is the anemia of CRI underrecognized and undertreated?

One-on-One: The changing terminology of kidney disease

Dyslipidemia and its ramifications during CRI

Lit Review: Selected papers from the literature

Your Opinion: Preferred approaches to anemia treatment

Mechanisms

of cardiac

remodeling

during

chronic renal

insufficiency

Diagnostic Challenge:

See page 30 to review

this puzzling case.

Volume 1, Number 1June 2001

INAUGURAL ISSUE

INAUGURAL ISSUE

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7

11

22

26

28

30

15

From the Editors: Welcome to our inaugural issue

By Steven Fishbane, MD, and Allen R. Nissenson, MD

Editorial: Why is the anemia of CRI underrecognized

and undertreated? By Steven Fishbane, MD, and

Allen R. Nissenson, MD

One-on-One: An interview with W. Kline Bolton, MD,

and Andrew S. Levey, MD, on the changing

terminology of kidney disease

What’s New: Kidney information on the Web

The RAMP: Left ventricular hypertrophy in chronic renal

insufficiency: mechanisms of cardiac remodeling. By Robert N. Foley, MD

Dyslipidemia and chronic kidney disease:metabolic challenges to treatmentBy Thomas A. Golper, MD

Lit Review: Selected papers from the literature and

commentaries by W. Kline Bolton, MD, and Bradley A. Warady, MD

Your Opinion: Preferred approaches to

anemia treatment during CRI

Diagnostic Challenge: Submitted by Steven Fishbane, MD

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Table of ContentsTable of Contents

C.K.D.Co-Editors

Steven Fishbane, MDMineola, New York

Allen R. Nissenson, MDLos Angeles, California

Editorial Advisory BoardAnatole Besarab, MDMorgantown, West Virginia

W. Kline Bolton, MDCharlottesville, Virginia

David N. Churchill, MDHamilton, Ontario, Canada

Robert N. Foley, MDSalford, United Kingdom

Raymond Hakim, MD, PhDNashville, Tennessee

Annamaria Kausz, MDBoston, Massachusetts

Alan S. Kliger, MDNew Haven, Connecticut

Adeera Levin, MDVancouver, British Columbia, Canada

Jill Lindberg, MDNew Orleans, Louisiana

Roger London, MDWhite Plains, New York

Brian J.G. Pereira, MD, DM, MBABoston, Massachusetts

Richard A. Sherman, MDNew Brunswick, New Jersey

John C. Stivelman, MDSeattle, Washington

Paul Zabetakis, MDOak Park, Illinois

Publishing StaffDavid Dunn

President

Keith J. CroesEditorial Director

Norma Padilla, PhDDirector, Scientific Affairs

Kerry MarianiProject Director

Soleenne DesravinesAssociate Project Director

Sandra SchallerArt Director

Welcome to the inaugural issue of CKD—The Journal of Chronic Kidney Disease. We are proud to have been namedco-editors of the publication, a task we undertake with theassistance of a most distinguished Editorial Advisory Board.

CKD, an educational initiative of Amgen Inc., will be distributed quarterly to all US nephrologists. The journal willpursue its primary emphasis—topics related to the treatmentof chronic kidney disease—with a unique vision. Our goal will be to present salient, highly focused reviews, based onpublished sources, of various aspects of kidney disease and its comorbidities, as well as available therapeutic options. The journal will strive always to remain scientifically credible, clinically relevant, and readily accessible.

In addition to two scientific articles, each issue of CKD will contain a number of departments:

Editorial—Opinion and commentary from the CKDeditors and editorial board;

One-on-One—Interviews with leaders in the field;

Lit Review—Summaries and expert reviews of recent studies in the literature;

What’s New—Brief news items on events and developments of interest to nephrologists;

Your Opinion—Surveys of current clinical practices and preferences; and

Diagnostic Challenge—A provocative, clinical brain-teaser, whose answer is immediately available via an audio file.

We extend our sincere thanks to the authors of this issue’s two featured scientific articles. Robert N. Foley, MD, describes the mechanisms underlying the development of left ventricular hypertrophy in chronic renal insufficiency (page 15), and Thomas A.Golper, MD, reviews the etiology, treatment, and ramifications of dyslipidemia in kidney disease (page 22).

All good publications grow and change with evolving reader interests, and we hopeCKD is no different. We welcome your feedback on the information we present and howwe present it, and your suggestions for future articles, features, and departments. Even as we vow to be responsive, we believe that CKD’s commitment to distill refereed infor-mation to its essence is an element critical to its success, and one you will find increasingly useful in the years ahead. We look forward to the challenge.

Steven Fishbane, MDAllen R. Nissenson, MD

Co-Editors

from the editors

CKD—The Journal of Chronic Kidney Disease (ISSN 1532-4419) is published quarterly by HealthVizion Communications, Inc., and sponsored by Amgen Inc. Copyright 2001 HealthVizion Communications. All rights reserved.

Address correspondence and request for reprints to the Editorial Director, HealthVizion Communications, 20 Waterview Blvd., Parsippany, NJ 07054-1295; fax: 973-263-3952.

[ ]

Steven Fishbane, MD

Allen R. Nissenson, MD

provocative study by Obrador and col-leagues1 attempted to evaluate the qualityof care patients received during chronicrenal insufficiency (CRI) by analyzing

selected health-related parameters recorded immedi-ately before the initiation of dialysis. Investigators hadaccess to the Health Care Financing Administration’sForm 2728 for 155,076 patients who began dialysisbetween April 1, 1995, and June 30, 1997. Among theresults was the finding that, although 51% of patientshad a hematocrit (Hct)<28% prior to starting dialysis,only 20% had been treated with recombinant humanerythropoietin (rHuEPO). These data strongly reflect afailure to meet a basic health need of these patients.Why are we undertreating anemia in patients with CRI?

We need to address three important questions thatinfluence the use of rHuEPO in this patient population:

Is rHuEPO consistently safe and effective in raisingHct in these patients? The answer is yes. The USRecombinant Human Erythropoietin PredialysisStudy Group2 and others have demonstrated thatrHuEPO significantly raises Hct in a dose-dependentfashion in patients, and does so safely. An increasein blood pressure occurs in some patients, but is usually easily amenable to treatment.

Does an increase in Hct hasten the progression ofrenal failure? Garcia et al,3 in a 1988 study of renalablation in rats, found that rHuEPO therapy mightworsen renal injury. However, a number of subse-quent studies in humans,4,5 such as the report fromthe US Recombinant Human ErythropoietinPredialysis Study Group,2 have shown no similarrisk in humans. That is, treatment with rHuEPO in the patient with CRI does not appear to hastenthe progression of renal disease.

Aside from an increase in Hct level, are there otherbenefits of rHuEPO treatment? Again, the answer is affirmative. The CRI patient who is treated withrHuEPO needs fewer blood transfusions (and isexposed to less risks from those blood transfusions)and has improved exercise capacity, cognitive function, possible decreased hospitalizations, betterappetite, activity level, work capacity, and sense ofwell-being.6–9 Of particular interest is the relation-ship between anemia and left ventricular hyper-trophy (LVH). In nonuremic populations there

is an important and independent relationshipbetween LVH and risk of death.10,11 Among patientswith kidney disease, the same relationship holds.12 In a report published in 1999, Levin andcolleagues13 found that in patients with CRI,decreases in serum hemoglobin levels were animportant predictor of progressive LVH. In a studyof 433 dialysis patients, Harnett and colleagues14

showed an association between anemia therapy,with rHuEPO, and beneficial cardiac effects, suchas partial regression of LVH and normalization ofcardiac output. (Twenty-six percent of patients inthe Harnett study had long-standing hypertension;mean systolic blood pressure was 151 mm Hg, andmean diastolic blood pressure was 83 mm Hg.)

Late referralThe benefits and safety of treating CRI patients with

rHuEPO therefore seem to be well demonstrated. Whythen is the approach underutilized? The first answermost nephrologists would likely offer to this questionis the late referral of these patients for consultation. In fact, patients with CRI are often referred late to anephrologist. The general consensus is that most ofthese patients should be seen by a nephrologist for atleast a year, and perhaps longer, prior to the need for dialysis.

Rates of late referral are difficult to summarizebecause of differing definitions in the literature, but the common theme is that the rate is disturbinglyhigh.15-17 A variety of clinical outcome measures areadversely affected by late referral. With regard to anemia, for example, Arora and colleagues15 found that patients referred late were less likely to receiverHuEPO therapy (17% vs 40%), and a greater pro-portion had Hct <28% (55% vs 33%). Earlier referral,therefore, is associated with improved care.

Demographic and medical factorsThe causes of late referral are multifactorial. Ifudu

and colleagues16 found that delayed referral was sixtimes more likely in nonwhite as compared with whitepatients. They also found age to be an important factor;patients older than 55 years were five times more likelyto be referred late.

AWhy is the anemia of CRI underrecognized and undertreated?

Steven Fishbane, MDMineola, New York

Allen R. Nissenson, MDLos Angeles, CaliforniaEditorialEditorial

4

5

One factor of unique interest is the failure to recog-nize that renal insufficiency even exists. Older andsmaller patients can have significant renal insufficiencyin the presence of serum creatinine levels that appearnormal. A frail 80-year-old woman with a serum creati-nine level of 1.4 mg/dL, for example, likely has severekidney disease. A typical laboratory report would classi-fy this creatinine result as normal, which creates aproblem. The busy primary care doctor, who mightreview laboratory results for 40 patients a day, does nothave time to examine every report in detail. Instead,scanning reports for results listed as out of range maybe the only option. This makes it difficult to identifypatients with CRI. We recommend that laboratoriesreport both the raw serum creatinine result and a mod-ified Cockcroft-Gault calculation of creatinine clear-ance.17 The only variable missing from the equationwould be weight; results could therefore be reportedbased on a standard weight, with a notation to thephysician that the calculated clearance should be inter-preted in light of the patient’s actual weight.

Access to nephrologists is an important issue in ruralareas, where the scope of practice for a primary carephysician is often greatly expanded due to the scarcity of specialists. Other factors underlying late referral mayinclude the fear of losing patients to the nephrologist, thefear of disrupting the physician-patient relationship, anda failure to appreciate the depth and complexity of prob-lems that these patients experience. The primary caredoctor may recognize that anemia and renal insufficiencyare present, but may incorrectly attribute the patient’sanemia-related symptoms to the renal disease or othermedical problems. While late referral to the nephrologistis often a problem, it should be recognized that some primary care physicians who have a special interest in kidney disease may be quite competent to treat these patients.

Undertreatment by nephrologistsAlthough late referral is strongly linked to the under-

treatment of anemia, the problem is often seen evenwhen patients are cared for by nephrologists. Arora andcolleagues15 found that, of those CRI patients with latereferral, 33% had Hct <28% at the initiation of dialysis,and 60% had not previously been treated with rHuEPO.Factors that contribute to the undertreatment of anemiaby nephrologists probably include perceived problemswith reimbursement, logistical problems caused by theoffice administration of the drug, and a failure to under-stand the importance of anemia as a cause of morbidity.

Improving nephrologists’ recognition and treatmentof anemia in CRI will probably require enhanced educational efforts. A more rational and standardizedapproach to reimbursement for rHuEPO by payers alsowould be helpful. An important logistical problem now is the need for many patients to visit physicianoffices up to three times weekly to receive rHuEPO.

Predictive variablesThe aforementioned Obrador et al study1 may offer

additional insight into why anemia during CRI isundertreated. The mean Hct of 131,484 patients initiat-ing dialysis was 28%. Values less than 28% were foundmore commonly in younger patients, women, non-Caucasians, unemployed, and those initiatinghemodialysis instead of peritoneal dialysis. In addition,Hct <28% was more likely among patients withoutmedical insurance. Factors associated with an increasedor decreased likelihood of predialysis treatment withrHuEPO were also analyzed, and the results very closelyparalleled those reported for risk of low Hct values.

Taken together, these results reveal certain variablespredictive of the undertreatment of anemia in CRI. It should be noted, however, that although several factors reached statistical significance, none stood outas strongly predictive. Having no medical insurancewas associated with an odds ratio of 1.34 for Hct <28%;as such, the opportunity to improve predialysis anemiamanagement identified by this study exists amongthese uninsured subjects. Improved access to care andreducing late referral would yield the greatest leveragein improving patient care.

In conclusion, the anemia of CRI is underrecognizedand undertreated. A variety of factors, especially latereferral, drive this problem. CRI patients with anemiamay experience a reduction in quality of life and pro-gressive LVH, which is associated with increased morbidity in CRI and ESRD patients and increasedmortality in patients with ESRD. We must act to ensurethat this important aspect of care is moved to the forefront in the training of new nephrology fellows.Nephrologists in practice must increase their recog-nition of the importance of anemia treatment, andreceive more rational support from payers for erythro-poietic protein supplementation. Finally, we mustbuild better bridges to our partners in primary care,helping them recognize the importance of early referral of patients with CRI so that problems such asanemia can be optimally evaluated and treated. CKD

6

References

1. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence of and factors associated with suboptimal care before initiation ofdialysis in the United States. J Am Soc Nephrol. 1999;10:1793-1800.

2. The US Recombinant Human Erythropoietin Predialysis StudyGroup. Double-blind, placebo-controlled study of the therapeutic use of recombinant human erythropoietin for anemia associatedwith chronic renal failure in predialysis patients. Am J Kidney Dis. 1991;18:50-59.

3. Garcia DL, Anderson S, Rennke HG, Brenner BM. Anemia lessensand its prevention with recombinant human erythropoietin worsensglomerular injury and hypertension in rats with reduced renal mass.Proc Natl Acad Sci U S A. 1988;85:6142-6146.

4. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW.Correction of anemia of end-stage renal disease with recombinanthuman erythropoietin: results of a combined phase I and II clinicaltrial. N Engl J Med. 1987;316:73-78.

5. Roth D, Smith RD, Schulman G, et al. Effects of recombinant humanerythropoietin on renal function in chronic renal failure predialysispatients. Am J Kidney Dis. 1994;24:777-784.

6. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW.Treatment of the anemia of progressive renal failure with recombi-nant human erythropoietin. N Engl J Med. 1989;321:158-163.

7. Revicki DA, Browne RE, Feeny DH, et al. Health-related quality oflife associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis.1995;25:548-554.

8. Holland DC, Lam M. Predictors of hospitalization and death amongpredialysis patients: a retrospective cohort study. Nephrol DialTransplant. 2000;15:650-658.

9. Canadian Erythropoietin Study Group. Association betweenrecombinant human erythropoietin and quality of life and exercisecapacity of patients receiving haemodialysis. BMJ. 1990;300:573-578.

10. Frohlich ED. Left ventricular hypertrophy as a risk factor. CardiolClin. 1986;4:137-144.

11. Kannel WB, Abbott RD. A prognostic comparison of asymptomaticleft ventricular hypertrophy and unrecognized myocardial infarc-tion: the Framingham Study. Am Heart J. 1986;111:391-397.

12. Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of leftventricular hypertrophy on survival in end-stage renal disease.Kidney Int. 1989;36:286-290.

13. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass indexincrease in early renal disease: impact of decline in hemoglobin.Am J Kidney Dis. 1999;34:125-134.

14. Harnett JD, Kent GM, Foley RN, Parfrey PS. Cardiac function andhematocrit level. Am J Kidney Dis. 1995;25:S3-S7.

15. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, andconsequences of late nephrology referral at a tertiary care center. J Am Soc Nephrol. 1999;10:1281-1286.

16. Ifudu O, Dawood M, Iofel Y, Valcourt JS, Friedman EA. Delayedreferral of black, Hispanic, and older patients with chronic renalfailure. Am J Kidney Dis. 1999;33:728-733.

17. Lamiere N, Van Biesen W. The pattern of referral of patients withend-stage renal disease to the nephrologist--a European survey.Nephrol Dial Transplant. 1999;14:16-23.

18. Cockcroft DW, Gault MH. The pattern of referral of patients withend-stage renal disease to the nephrologist-a European survey.Nephrol Dial Transplant. 1999;14:16-23.

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Clinical practice guidelines developed by the NationalKidney Foundation–Dialysis Outcomes Quality Initiative(NKF-DOQI), popularly called DOQI, were first publishedin 1997,1 and have since been translated into at least 10languages. The work of DOQI’s successor—the KidneyDisease Outcomes Quality Initiative (K/DOQI)—undoubt-edly will receive similar international recognition. But oneof its primary challenges is to help define just one lan-guage—the medical language of kidney disease.

When the original DOQI guidelines were published in1997, the DOQI leadership determined that the guidelinesshould be updated periodically to ensure clinical relevance.Updated guidelines—related to hemodialysis, peritonealdialysis, management of vascular access, and manage-ment of anemia—appear in a supplement to the January2001 issue of the American Journal of Kidney Diseases.

The first guidelines released under the K/DOQI bannerwere Clinical Practice Guidelines for Nutrition in ChronicRenal Failure, published in June 2000.2 Guidelines are alsounder development by three other K/DOQI work groups:Chronic Kidney Disease: Evaluation, Classification, andStratification; Bone Disease and Mineral Metabolism inChronic Kidney Disease; and Atherosclerotic Cardio-vascular Disease.

In contrast to DOQI, which addressed dialysis, K/DOQIwill cover the full range of kidney disease from its earliestdefinable stages. And therein lies a problem. “Reducedglomerular filtration rate (GFR) is the most important com-plication of parenchymal renal disease,” Hsu and Chertowwrote in the August 2000 issue of the American Journalof Kidney Diseases. “The many terms routinely used todescribe states of reduced GFR not requiring dialysis ortransplantation—such as ‘chronic renal failure’ or ‘chronicrenal disease’—are imprecise and poorly defined.” 3

The authors go on to make their own recommendationsregarding terminology and disease staging—recommend-ations that may or may not resemble guidelines from theChronic Kidney Disease: Evaluation, Classification, andStratification work group, chaired by Andrew S. Levey, MD.Those guidelines are expected to be published before theend of the year.

Various nephrology organizations—such as the RenalPhysicians Association (RPA)—are closely following the

group’s efforts. CKD—The Journal of Chronic KidneyDisease interviewed Dr Levey and RPA representative W.Kline Bolton, MD, on the process and progress of this formi-dable challenge.

CKD: Dr Bolton, how are you involved in the K/DOQI effort?

W. KLINE BOLTON, MD: As a representative of the RPA, I am observing the K/DOQI effort and thework of Dr Levey and his group. I chair an RPA groupthat is developing a Clinical Practice Guideline for theAppropriate Preparation of Patients for RenalReplacement Therapy (RRT). There has been a closeinteraction between the RPA and the NKF so that the guidelines that overlap will be consistent.

We’re handling only the phase of kidney diseaserepresented by a GFR of 30 (mL/min) down to theneed for RRT. K/DOQI is involved in the entire spec-trum of disease. But where the two areas overlap, weneed to end up having exactly the same guidelines sothat there won’t be confusion for the providers whoare going to use the guidelines.

CKD: Dr Levey, you have a much broadermandate than the original NKF-DOQI effort.

ANDREW S. LEVEY, MD: Yes. As background, I think we’d all agree—both the NKF and the RPA—that chronic kidney disease is a public health problem. The rising incidence and prevalence of end-stage renaldisease is a testament to that. Its high mortality, highmorbidity, and high cost put kidney disease in thepublic’s eye as well.

We also know there’s a high prevalence of earlierstages of chronic kidney disease, and that these earlierstages can be detected through routine laboratory test-ing. We know that treatment of these earlier stages iseffective in slowing the worsening of kidney disease toits end-stage and that the outcome of chronic kidneydisease includes cardiovascular disease as well as theend-stage of kidney disease. The treatment of thesecardiovascular risk factors in the earlier stages ofchronic kidney disease would be effective in reducing

One-on-OneOne-on-One

Defining kidney disease: in search of a common language

W. Kline Bolton, MDAndrew S. Levey, MD

8

cardiovascular disease events. But currently, chronickidney disease is underdiagnosed and undertreated inthe United States. And this leads to lost opportunitiesfor prevention of complications of chronic kidney disease and worse outcomes for patients.

CKD: What is the main challenge facing this effort?

DR LEVEY: To begin with, there is no uniform agree-ment on three things: the methods for clinical assess-ment of kidney disease, a description of those stagesalong the progression of kidney disease, and the riskof progression of kidney disease and development ofcardiovascular disease. So the goals of the K/DOQIteam are three: to evaluate the laboratory measure-ments for clinical assessment of chronic kidney dis-ease; to develop a classification system of the severityof chronic kidney disease; and to stratify the risk forloss of kidney function, the development of cardiovas-cular disease, and death. We call this first project ofthe K/DOQI work group Chronic Kidney Disease:Evaluation, Classification, and Stratification because those are the three goals.

CKD: When will the guidelines be finalizedand published?

DR LEVEY: We plan to publish them by the end ofthis year.

CKD: Obviously, the guidelines will have the imprimatur of the National KidneyFoundation, and presumably the RPAhas a role in their development, as evidenced by Dr Bolton’s involvement.Is there any kind of formal sign-off onthe part of other organizations as tothe final form of the guidelines?

DR LEVEY: The Advisory Board to K/DOQI has abroad representation, including patients and profes-sionals in all areas that touch the diagnosis and treat-ment of kidney disease. I believe that whatever ourwork group comes up with will go to the AdvisoryBoard for its input and refinement, and then will besent to a number of individuals outside the AdvisoryBoard. We will ask these organizations for review andcomment. The process of “sign-off” varies from organi-zation to organization. Our intention is to get input

from a wide group of professionals in the field.

CKD: I’m sure both of you are familiar withthe editorial by Hsu and Chertow in the August 2000 issue of the American Journal of Kidney Diseases.The authors searched for the termchronic renal failure in the literatureand came up with 21,091 citations.The term chronic renal insufficiency, on the other hand, brought up only2,253 articles. Yet they advocate theuse of chronic renal insufficiency overchronic renal failure. Has your workgroup looked at these terms? Has apreference emerged?

DR LEVEY: Our committee will look at objective evi-dence for evaluation, classification, and stratification,and will certainly come to a classification of kidneydisease that emphasizes different ranges of severity. I think we would all agree that failure is a term thatimplies greater severity than insufficiency.

Our concern has been that words like failure shouldbe reserved for patients who are doing the worst, andthat a term like insufficiency is a complicated conceptthat is not well understood by patients. We need tolook at these terms anew and try to decide which termbest approximates a certain level of severity of illness.We must also keep in mind that the choice of terms isan issue that has ramifications beyond the realm ofscientific evidence. The choice must also be consistentwith the efforts by the NKF, RPA, and other organiza-tions to get the best message across to providers ofhealth care as well as patients and other consumers.

We have to be able to speak simply to each other.This cannot be just a matter of scientific discourse. It relates to basic questions—for example, whetherhere in the United States we should use kidney, thenoun, or renal, the adjectival Latin root. At theNational Institutes of Health, they’ve chosen to nameall their institutes using the English words. So we havethe National Institute of Diabetes and Digestive andKidney Diseases. They’ve chosen specifically not touse other roots from different languages.

I don’t think that’s a scientific question. I thinkthat’s a policy question, which those in charge of theNKF and the RPA and other professional societiesneed to address before we can buy into a common

W. Kline Bolton, MD,

is professor of internal

medicine and chief

of the Division of

Nephrology at the

University of Virginia

Health System in

Charlottesville, Va.

A member of the

Renal Physicians

Association, he chairs

a work group that is

developing Clinical

Practice Guidelines

for the Appropriate

Preparation of

Patients for Renal

Replacement Therapy.

W. Kline Bolton, MD

]

[

9

terminology. We will help by proposing what we think would make sense, but I think it’s beyond thepurview of our individual work group to make a decision like that.

DR BOLTON: I agree. I think that in nephrologyand indeed throughout medicine, terms become com-monly used to the point where they are almost impos-sible to change, even if other terms are more appropri-ate or accurate. Change can occur through some majornational effort, but it’s not a trivial matter to change a term like chronic renal failure to chronic renal insufficiency or ESRD to ESKD. Those terms in particular will require great consideration.

DR LEVEY: Right. ESRD is so strongly embedded inour administration of health care for these patientsthat it probably would not be worthwhile to attempt to change that term.

DR BOLTON: I think ESRD would be one of thehardest to change. CRI and CRF reflect new attitudesthat have emerged just over the past few years.

CKD: Is it possible to make staging distinctions within that portion of kidney disease we think of as chronic renal insufficiency?

DR LEVEY: The Chertow editorial you mentionedpoints out that the term chronic renal failure is usedvery frequently, but the term does imply a severestage of the disease. Perhaps it should be restricted to that smaller number of people who are at the stagethat we often refer to as end-stage renal disease. Theterm renal insufficiency seems to be a more appropriateterm for those many, many more people who havereduced kidney function.

Kidney function is measured on a continuous basis.Only in recent years have public health officials adopt-ed the use of discontinuous stages to define what isreally a continuum of function. For example, for yearsthe National High Blood Pressure CoordinatingCouncil has issued reports from the Joint NationalCommittee (JNC), but it’s only in the past couple ofreports that the JNC has developed definitions forstages of hypertension. They did so specifically toenhance communication—so that we could better talkto patients and among ourselves, the health careproviders and scientists, and so that we could betterstratify the risk.

Similarly, the National Cholesterol Education

Program has defined stages of severity for elevation inblood cholesterol. We all need to communicate witheach other better, and the delineation of stages of evena continuous variable like levels of kidney functioncould help. So I think we’re behind the blood pressureand cholesterol initiatives—but not too far behind.

CKD: The Chertow paper points out that itdoesn’t make much sense to categorizeif you don’t have data suggesting thatthere’s a difference among segments.In other words, if you don’t have datathat indicate there’s a differencebetween stage A and stage B, it doesn’t make much sense to draw the distinction.

DR LEVEY: That’s just what our work group isdoing—developing the evidence basis for creatingthose stages. We will certainly be able to come up withbroad strokes that categorize the severity of kidney disease. It’s easy to look at patients whose kidneyshave failed and who require treatment with dialysis or transplantation, and to say that they have a moresevere stage of disease than patients whose kidneyshaven’t failed. I believe also that we will succeed indeveloping the evidence basis for finer cut points. Ofcourse, your point is well taken: creating categoriesbased on finer and finer distinctions will become moreand more arbitrary. We hope to find the evidence basisfor whatever categories are created, but in the endthose divisions must be based on a certain amount ofarbitrariness, which nonetheless should reflect ourbest judgment. I hope there will be enough evidencebasis to convince our colleagues, first in science andlater in policy, of the validity of what is developed.

CKD: The Chertow article proposed aban-donment of the terms pre-dialysis andpre-ESRD, asking whether the termspre-amputation or pre-blind wouldever be used to describe individualswith advanced diabetes mellitus. Do you share that opinion, Dr Bolton?

DR BOLTON: Yes, I think that we need to revampthe way we educate our patients and incorporate theminto the process so that they become empowered tomake their own decisions and maintain positive atti-tudes. Having nihilistic terminology or negative con-

Andrew S. Levey, MD,

is chair of the Kidney

Disease Outcomes

Quality Initiative

(K/DOQI) Clinical

Practice Guidelines

Work Group on

Chronic Kidney

Disease: Evaluation,

Classification, and

Stratification. He is

chief of the Division

of Nephrology at the

New England Medical

Center in Boston,

and professor of medi-

cine at Tufts University

School of Medicine

in Boston.

Andrew S. Levey, MD

]

[

10

notations in the terminology benefits no one. I’m verymuch in favor of changing terminology that itself mayexert a negative influence on patients.

I think that staging—such as what the ChronicKidney Disease work group is developing—will lenditself well to our communication with patients. Just aswhat has been done with blood pressure or choles-terol, we can show patients where they are in terms ofstages in the continuum, and help them begin to thinkabout RRT and their options. The usual educationalfunctions will still be necessary, but the goal will beserved much better by using staging terminology.

CKD: When does chronic renal insufficiencystart? And how do you go about con-veying that starting point to primarycare physicians, who are most likely tobe faced with having to identify it?

DR LEVEY: We recognize that, long before GFRdeclines, patients can show signs of injury to their kidneys. For some diseases, such as diabetes andglomerular disease, injury is demonstrated by a posi-tive test for protein in the urine. For patients withpolycystic kidney disease, renal cysts are present longbefore GFR declines. Unfortunately, we do not havedefinite markers for injury due to other diseases. The stage of injury is a time when patients alreadyhave chronic kidney disease, and are at risk of losingkidney function and of developing heart disease. Andthese patients need care at that time. We need moreresearch to develop markers of injury for other diseases, and screening programs to detect injury in people at risk of chronic kidney disease.

This is certainly a message that needs to gobeyond kidney doctors to primary care physicians andto others who are at the front lines of medical care. We could even argue that the stage of reduced kidneyfunction, which Dr Chertow referred to as renal insuffi-ciency, would be a late stage to detect kidney disease

in patients at high risk. The American DiabetesAssociation, for example, recommends that patientswith diabetes be screened for the presence of proteinin their urine long before GFR declines. And we’veknown for a number of years that the stage of injury,manifested by microalbuminuria, precedes the GFRdecline in diabetic kidney disease by 5 to 10 years,during which time patients could be treated withmeasures that are known to prevent the progression of kidney disease.

DR BOLTON: The current definition of chronicrenal insufficiency provides a good example of howguidelines can be established nationally and also howthey can change. A National Institutes of Health (NIH)consensus panel in 1993-1994 placed the “warningflag” for chronic renal disease at a serum creatininelevel of 2 (mg/dL) or greater in men and 1.5 (mg/dL)or greater in women. The recent Healthy People 2010initiative4 puts the beginning of chronic renal insuf-ficiency at creatinine levels of 1.5 (mg/dL) or greater in men and 1.2 (mg/dL) or greater in women. Thatchange was driven by the recent Third National Healthand Nutrition Examination Survey (NHANES III) data,5

which revealed the huge problem of underdiagnosisand undertreatment of CRI that Dr Levey referred to earlier. CKD

References1. NKF-DOQI Work Group. NFK-DOQI clinical practice guidelines for

the treatment of anemia of chronic renal failure. Am J Kidney Dis.1997;30(suppl 3):S192-S240.

2. K/DOQI, National Kidney Foundation. Clinical practice guidelinesfor nutrition in chronic renal failure. Am J Kidney Dis. 2000;35:S1-S140.

3. Hsu CY, Chertow GM. Chronic renal confusion: insufficiency, fail-ure, dysfunction, or disease. Am J Kidney Dis. 2000;36:415-418.

4. National Institute of Diabetes and Digestive and Kidney Diseases.Healthy People 2010: Chronic Kidney Disease. 2000.

5. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levelsin the US population: Third National Health and NutritionExamination Survey (published erratum appears in Am J KidneyDis 2000 Jan;35:178)1998;32:992-999.

11

National multispecialty anemia initiative formed

Leading experts in various therapeutic areas have been selected to guide the National Anemia ActionCampaign (NAAC), an educational initiative sponsoredby Amgen Inc. L. Tim Goodnough, MD, of St. Louis, and Allen R. Nissenson, MD, of Los Angeles, cochairedthe NAAC kick-off meeting in November 2000.According to the cochairs, NAAC will work across specialties—in nephrology, oncology, gastroenterology,rheumatology, infectious disease, and primary care—toraise awareness of the latest developments in the diagnosis and treatment of anemia.

More than 5 million Americans each year are diag-nosed with anemia, and millions more go undiagnosed,according to industry estimates. NAAC hopes thatgreater anemia awareness and education among practitioners will result in earlier and more effectivecare for patients who need it.

Educated patient more likely to choose PDA study called “the largest education study of pre-

dialysis patients ever conducted” suggests that, ifpatients were better informed, more would chooseperitoneal dialysis (PD) over hemodialysis (HD) than is currently the case. Thomas A. Golper, MD, ofVanderbilt University Medical Center, Nashville, Tenn,reported the study’s findings at the annual meeting of the American Society of Nephrology.

After receiving extensive education, 45% of the11,363 study patients chose PD and 55% opted for HD,Golper said. Yet only 12% of Americans on dialysis usePD, according to government figures.

“This study reinforces that a person’s preferred treat-ment option for kidney failure is largely influenced bythe scope of education they receive prior to startingdialysis,” Golper said. “People need more educationthan they’re receiving now to make an informed treat-ment decision that may have an impact on their suc-cess with the therapy and on their quality of life.”

RenalAdvances Web site offers nephrology resources

Amgen Inc. has launched a new Web site,RenalAdvances.com, designed to cater specifically tothe clinical and informational needs of the nephrologyhealth care community. In addition to a comprehen-sive meeting and events calendar, the site featuresweekly nephrology news, a library of informationalmaterial, and a variety of clinical tools. Site visitors

can access an easy-to-use summary of the clinicalguidelines issued by the National Kidney Foundation’sKidney Disease Outcomes Quality Initiative, reprintsof relevant journal articles, and dialysis patient materi-als. The site allows nephrology health care professionalsto simultaneously search health care databases such asPubMed, Medscape, Medinex, and FDA.

Other features of the site include:

“Contact Amgen”—another way to communicatewith nephrology experts for the purpose of askingclinical questions and requesting materials andinformation.

An anemia management assistant to help profes-sionals develop customized anemia managementprotocols.

A “Reimbursement Advisor” designed to help dialysisproviders understand the complex reimbursementenvironment of Medicare’s End-Stage Renal DiseaseProgram and allow quick access to reimbursementand indigent patient program information.

Links to nephrology publications and journals, rele-vant societies, associations and foundations, govern-ment agencies, and community bulletin boards.

BMI a poor predictor in dialysis chart studyThe results of a retrospective chart review, reported

at the annual meeting of the American Society ofNephrology, challenge the idea that larger people withend-stage renal disease on average have better out-comes with dialysis than those with normal body mass index (BMI).

The study, conducted by Rita Suri, MD, of theUniversity of Alberta, included 168 dialysis patientswhose records covered a 3-year period. Patients weredivided into three groups by BMI: <21, 22-25, and >25(standard divisions used by insurance companies).

what’s newwhat’s new

12

The analysis found no difference in mortality or inthe number of hospital visits among the BMI groups, aresult that contradicts other studies. Overall, a 26% mor-tality rate was found over 3 years.

Suri noted that the lowest rates of cardiovascular dis-ease were seen in the group with the lowest BMI, a find-ing, she suggested, that might have protected them fromhaving a higher mortality rate. The group with the low-est BMI also had a higher Kt/V score.

Suri concluded that BMI, while an important measureto follow, should not be used as an absolute marker ofmortality or morbidity risk in dialysis patients. Mortalityand morbidity, she said, are multifactorial, not related toany one patient characteristic.

Cases of kidney rejection linked to St. John’s wort

St. John’s wort may be related to the acute rejection of transplanted kidneys in two patients, according toArkansas physician Sameh Abul-Ezz, who described thecases at the annual meeting of the American Society ofNephrology. The herb apparently interferes with theantirejection properties of cyclosporine.

The first case, a 44-year-old woman who received akidney transplant in February 1996, experienced acuterejection in December 1999. She had been taking cyclo-sporine, but blood levels of the drug suddenly dropped.Doctors increased the dose of cyclosporine, thenlearned that she had started taking daily doses of St.John’s wort. Within 2 weeks of discontinuing the herb,her blood levels of cyclosporine increased to normal.

The second case, a 29-year-old woman who under-went a combined kidney-pancreas transplant in July1994, experienced a sudden drop in blood levels ofcyclosporine in November 1998. Two months later,doctors discovered she was taking St. John’s wort andasked her to stop. Within weeks, her blood levels ofcyclosporine were back to normal; however, she even-tually needed another kidney transplant, which wasperformed in January 2000.

Number of ESRD cases up 78% in next decade

By 2010, the number of Americans with end-stagerenal disease (ESRD) will increase by 78%, according tothe United States Renal Data System (USRDS) 2000annual report. About 372,000 Americans currently haveESRD (including patients with kidney transplants). The

USRDS estimates that 661,000 will have ESRD a decadefrom now. Total costs are expected tosurpass $28 billionin 2010, up from $16.7 billion in 1998.

The complete USRDS 2000 annual report is avail-able at www.usrds.org.

Study predicts epidemic of type 2 diabetesA national epidemic of type 2 diabetes likely will

follow the current epidemic of obesity in US children,a study of 688 children suggests.

The study, conducted by researchers at theUniversity of North Carolina at Chapel Hill (UNC-CH)schools of nursing, medicine, and public health,showed that 7% of the randomly selected, apparentlyhealthy schoolchildren already had three of the leadingrisk factors for heart disease and eventual type 2 dia-betes: high insulin levels, high blood pressure, andeither elevated levels of triglycerides or not enoughhigh-density lipoproteins.

“That 7% doesn’t sound like a lot, but when you con-sider that these children very probably will go on todevelop type 2 diabetes within 10 years, it’s frighten-ing,” said Joanne S. Harrell, MD, professor of nursingat UNC-CH and director of the Center for Research onPreventing and Managing Chronic Illness in VulnerablePeople. “Because we studied healthy, normal kids infive different schools, we think this is a national prob-lem that needs to be addressed on a national level.”

Harrell presented the findings at the AmericanHeart Association’s 73rd Scientific Session in New Orleans.

Hemodialyzer reuse may not lead toincreased mortality risk

A recent analysis of data from the United StatesRenal Data System (USRDS) Dialysis Morbidity andMortality Study (DMMS) suggests that mortality forpatients treated in facilities that reuse dialyzers is simi-lar to that for patients treated in facilities that do notpractice reuse. (Port F et al. Am J Kidney Dis.2001;37:276-286).

In the study, researchers evaluated a representativesample of 12,791 chronic hemodialysis patients fromthe DMMS to determine the relationship betweenpatient mortality and (1) reuse vs no reuse, (2) reuseagent, and (3) membrane type, with and without theuse of bleach.

The authors found no difference in mortality risk forpatients in reuse vs no-reuse facilities. For the disinfec-tants peracetic acid mixture vs formalin, mortality riskvaried significantly by membrane type and use ofbleach, achieving borderline significance for syntheticmembranes. A comparison of all membrane typesrevealed that mortality rates were lowest when patientswere treated with high-flux synthetic membranes, par-ticularly when bleach was used in reprocessing. After 2 years of follow-up, these findings remained robust.

Warning against deriving a “false sense of security”from their findings, and calling for further research to clarify the role of reuse agents, the researchers con-cluded that “reuse of hemodialyzers as presently prac-ticed does not appear to measurably modify the averagemortality risk compared with nonreuse in the UnitedStates when applying various levels of adjustment.”

Serum creatinine levels predict cardiovascular events

Elevated serum creatinine (SCr) levels and a reduc-tion in estimated creatinine clearance are powerfulpredictors of cardiovascular events and death, accord-ing to an analysis of data from the HypertensionOptimal Treatment (HOT) study (Ruilope L et al. J AmSoc Nephrol. 2001;12:218-225).

Previous research has shown that baseline SCr ispredictive of 8-year all-cause mortality among patientswith essential hypertension and that there is a relation-ship between renal insufficiency and cardiovascularmortality. Investigators from the HOT study consideredthese findings in an effort to determine (1) whetherbaseline SCr and its clearance were predictors of car-diovascular events, and (2) the effects of intensiveblood pressure (BP) reduction on cardiovascular eventsin patients with reduced renal function.

The risk of cardiovascular events was significantlyincreased in patients with elevated baseline SCr andreduced creatinine clearance. Conversely, patients withreduced renal function were able to achieve BP control,and there was no difference in the incidence of majorcardiovascular events in the three diastolic BP targetgroups of patients with mild renal insufficiency com-pared with healthy controls.

At the end of the 3.8-year treatment period, SCr lev-els were not significantly changed in the majority ofpatients. However, despite reduction of diastolic BP, a

small group of patients (0.58% of the total study popu-lation) experienced deterioration of renal function. The researchers found that adding acetylsalicylic acidto antihypertensive therapy could benefit patients with reduced renal function.

The researchers concluded that “an elevation in SCris a very powerful predictor of cardiovascular eventsand death. Reduced renal function does not precludethat the diastolic BP target is achieved. There is, however, a small group of patients whose renal func-tion deteriorates despite satisfactory reduction of diastolic BP.”

Environmental lead exposure may exacerbate renal insufficiency

There may be a link between progressive renalinsufficiency and long-term exposure to low levels ofenvironmental lead pollution, according to an inves-tigative team led by J-L Lin at Chang Gung MemorialHospital in Taiwan (Lin J-L et al. Arch Intern Med.2001;161:264-271).

Over a 2-year period, the investigators trackedincreases in serum creatinine (SCr) levels and changesin SCr clearance in 110 patients with chronic renalinsufficiency who were divided into high-normal orlow body lead burden (BLB) groups. To further definethe role of environmental lead exposure in progressiverenal insufficiency, patients with high-normal BLBunderwent chelation therapy for 3 months at the endof follow-up.

At the conclusion of the study, initial SCr levels hadincreased 1.5-fold in 15 patients, only one of whom wasin the low BLB group. Patients with high-normal BLBalso demonstrated a higher rate of renal insufficiencyin the second year of the study. Adjustment for severalcommon risk factors showed that BLB was the mostimportant risk factor for determining the progression ofrenal insufficiency. Significant improvements in renalfunction that lasted more than 12 months were seenafter the patients underwent chelation therapy.Basedon their findings and previous epidemiologic studies ofthe relationship between environmental low-level leadexposure and renal function, the researchers suggestedthat environmental lead exposure might contribute tothe progression of renal insufficiency in the generalpopulation. CKD

13

14

Upcoming MeetingsJune

The 38th European Renal Association-EDTA Congress will be held on June 24-27,2001, in Vienna, Austria. The ERA-EDTA is a European Medical Association thatencourages and reports advances in the field of clinical nephrology, dialysis, renaltransplantation, and related subjects. The ERA-EDTA Congress office can bereached at 39-0521-989-078 or e-mail congress@euromeetings.it for more details.

OctoberRenal Week 2001 October 10-17, 2001

The National Kidney Foundation’s Professional Councils Conference will be held in San Francisco October 11-14, 2001. Innovative program sessions developed bythe Council of Nephrology Nurses and Technicians (CNNT), Council of NephrologySocial Workers (CNSW), and Council on Renal Nutrition (CRN) will be featured. The sessions will include a variety of educational activities for allied health profes-sionals in the renal and transplant fields. All sessions will be held at The Hilton San Francisco. For more information visit www.kidney.org.

The World Congress of Nephrology, a joint meeting of the American Societyof Nephrology and the International Society of Nephrology, will be heldOctober 14-17 at the Moscone Convention Center in San Francisco. Abstractforms were sent to current members in January 2001. If you are not a member of the ASN/ISN and would like to receive the abstract form, call the number provided. Information is available at 202-367-1190 or online at www.asn-online.com.

15

eft ventricular hypertrophy (LVH) repre-sents one of the most important predictorsof cardiovascular morbidity and mortality.1,2

In hypertensive patients, LVH occurs com-monly with a prevalence ranging from 19% to 41% andvaries by race.3 In patients with chronic renal insuffi-ciency (CRI) or end-stage renal disease (ESRD), LVHappears to develop early, and becomes more prevalentwith declining renal function,4 reaching a prevalence ofapproximately 74% in patients just starting dialysis.5 Thehigh prevalence of LVH in this patient population is like-ly to contribute to the high cardiovascular disease (CVD)mortality rate of ESRD patients. Cardiovascular mortalityrates are known to be significantly higher than in thegeneral population, and CVD is the leading cause ofdeath in patients who progress from CRI to ESRD.6–8

In patients with chronic kidney disease who havenot reached ESRD, risk factors for LVH include hyper-tension, male sex, body mass index (BMI), and degreeof anemia.4,9,10 Two modifiable factors among these, ane-mia and hypertension, are similar to those seen in dial-ysis patients.4,10–12 LVH leads to diastolic dysfunction,increased oxygen consumption due to enhanced walltension, and diminished coronary reserve in states ofhigh cardiac output demand. Sustained exposure to theinciting stresses can lead to changes that are clearlymaladaptive, especially fibrous tissue deposition andhigher rates of cardiac myocyte apoptosis. The clinicalconsequences can include poor tolerance to ultrafiltra-tion on hemodialysis, congestive heart failure, arrhyth-mias, angina pectoris, and myocardial infarction.13

What is LVH?Left ventricular (LV) remodeling or LVH is a struc-

tural adaptation of the heart to compensate forincreased wall stress (Figure 1, next page). Althoughthe molecular basis of LVH is just beginning to beunderstood, it is clear that LVH is a heterogeneous disorder in which genetic, hormonal, and metabolicfactors are likely to be important in its pathogenesis.

There are two general patterns of structural re-modeling in LVH: concentric and eccentric (Figure 2).Classically, anemia has been associated with eccentric

growth, whereas hypertension has been associatedwith concentric growth.13 After the postnatal period,myocytes lose their ability to proliferate, and subse-quent growth occurs when preexisting cells enlarge.

On a cellular level, cardiac myocytes tend to elon-gate in cases of eccentric LVH and expand laterally inconcentric LVH.13 In animal models, cardiac myocyteenlargement is usually accompanied by increased ratesof fibrous tissue and collagen deposition and myocyteapoptosis.14,15 As a result, diastolic relaxation becomesimpaired relatively early. Later, cardiac reserves maybe decreased, and eventually the heart is unable tomeet the circulatory needs of the body at rest.

Eccentric LVHEccentric LVH, defined as LVH with a normal ratio

of LV diameter to wall thickness, is seen in processes ofLV dilatation. Volume overload results primarily in theaddition of new sarcomeres in series and secondarily in the addition of sarcomeres in parallel, resulting in

Left ventricular hypertrophy in chronic renal insufficiency

the rampthe ramp Robert N. Foley, MDSalford, United Kingdom

Author information: Robert N. Foley, MD, is Consultant Renal Physician at Hope Hospital, Salford Royal Hospitals NHS Trust, Stott Lane, Salford M6 8WH, United Kingdom.

Renal Anemia Management Period

]

[ How LVH is measuredLVH is measured by

using echocardiography

to determine LV mass.

Measures of cardiac

function include stroke

volume (a measure of

volume load), stress-

corrected midwall short-

ening (a measure of

myocardial contractility),

isovolumic relaxation

time (a measure of early

myocardial relaxation),

and the ratio of pulse

pressure to the stroke

index (an estimate of

large artery compliance).

Other standard

measures of systolic

and diastolic function

are also used.

L

Figure 2: Patterns of structural remodeling during LVH:Concentric LVH, characterized by lateral expansion of myocytes,results in an increase in relative wall thickness (RWT) and a higherratio of wall thickness to cavity diameter. Eccentric LVH, character-ized by myocyte elongation, results in a normal ratio of RWT tocavity diameter.

1616

Figure 1:

1. The normal heart: Hypertension and anemia are common conditions that have been associated with anincreased risk of developing left ventricular hypertrophy (LVH). LVH is a structural adaptation of the heart to compensate for increased wall stress. There are two general patterns of structural remodeling in LVH: concentricand eccentric. Anemia is associated with eccentric growth whereas hypertension is associated with concentricventricular hypertrophy.

2. The diseased kidney: Hypertension is a critical risk factor for the progression of kidney disease. Furthermore,chronic renal insufficiency (CRI) has been correlated with decreased production of erythropoietin and clinically relevant anemia. The kidney in early CRI may display normal morphology. Progressive disease may be associatedwith reduced renal size, thinned cortex, and an irregular surface.

3. Reduced red blood cell count: The decreased production of erythropoietin in CRI leads to a decline in theproduction of erythrocytes and shortened erythrocyte survival. These abnormalities result in anemia, which maylead to reduced tissue oxygenation. Compensatory vasodilation, a result of relative hypoxia, increases venous

Cardiac Remodeling in Chronic Renal Insufficiency

1. The normal heart

2. The diseased kidney

1717

return to the heart. This increased preload results in LV dilatation and increased heart rate, the two critical factorsthat contribute to increased cardiac output. Thus, peripheral vasodilation, increased venous return, LV dilatation,and augmented heart rate are clinical sequelae of the progressive anemia associated with CRI.

4. Development of eccentric LVH: Eccentric LVH, defined as LVH with a normal ratio of LV diameter to wallthickness, occurs in the setting of LV dilatation. LV dilatation may result in increased ventricular wall tension. LVH is a compensatory adaptation that develops in response to this increased wall tension. Often, the result is a hypertrophied and noncompliant ventricle.

5. Development of concentric LVH: Concentric LVH is classically associated with hypertension. In the setting ofincreased afterload, a hallmark of systemic hypertension, cellular remodeling occurs. Cardiac myocytes tend toexpand laterally in this setting, resulting in concentric LVH. As a result, diastolic relaxation may become impairedrelatively early in this process. These hearts are predisposed to diastolic dysfunction as well as subendocardialischemia and overt systolic impairment, whereby the heart is unable to meet adequate circulatory needs.

3. Reduced red blood cell count

4. Development ofeccentric LVH

5. Development ofconcentric LVH

18

an enlargement of the left ventricular chamber with anincreased wall thickness sufficient to counterbalancethe increased radius (eccentric hypertropy).16,17 LV dilat-ation may first occur alone, which implies a state ofincreased ventricular wall tension, according to the lawof Laplace, a state that is opposed by wall thickening.Thus, in LV dilatation, LVH is a compensatory adapta-tion that reduces wall tension. In the absence of hyper-tension and coronary artery disease, LV dilatation iscommon in CRI patients and appears to be the mostcharacteristic morphology among uremic patients.18

LV dilatation increases wall tension, metabolic fuelrequirements, and oxygen consumption. This type ofLVH is thought to be a result of cardiac adaptation tothe volume overload that can result from aortic incom-petence, the peripheral vasodilation that occurs withanemia, or an arteriovenous fistula.

Anemia and LVHFunctional and absolute iron deficiency, aluminum

intoxication, bone marrow fibrosis, and reduced ery-throcyte survival are some of the factors that contributeto anemia in renal patients.19 The primary factor, how-ever, is insufficient production of erythropoietin, whichleads to a decline in the production of erythrocytes.20

Uncompensated anemia leads to reduced tissue oxy-genation.2,21,22 Vasodilation, thought to be triggered byhypoxia, compensates for this, resulting in enhancedvenous return to the heart, which itself mandates anincrease in cardiac output. LV dilation and increasedheart rates are major adaptations facilitating thisincrease in cardiac output. Thus, peripheral vasodila-tion, increased rates of venous return, and LV dilationare expected findings in moderate to severe anemia.

The role of genetic phenotypes in the pathogenesisof uremic cardiomyopathy remains undefined. Somestudies have suggested that a certain angiotensin-con-verting enzyme (ACE) genotype (insertion/deletionpolymorphism of intron 16 of the ACE enzyme gene)might have an effect on the development of LVH inhemodialysis patients. However, Yildiz et al23 recentlyconcluded that LVH in hemodialysis patients was main-ly related to hypertension, anemia, and time spent ondialysis. In this study, the ACE polymorphism geno-type was not associated with the extent of LVH.23

Concentric LVHConcentric LVH is characterized by an increase in

ventricular wall thickness and a higher ratio of wallthickness to cavity diameter.16 As in essential hyper-tension, blood pressure level appears to be the princi-pal modifiable risk factor for concentric LVH, which

is common in patients with CRI, with a prevalence of approximately 42% in those starting dialysis ther-apy.16 It usually develops as an adaptation to pressureoverload, typically from hypertension or aortic steno-sis. To compensate, systolic intraventricular pressuremay be augmented by arraying myocytes in parallel.24

The characteristic trade-offs for such an adaptationinclude enhanced ventricular stiffness or diastolic dysfunction and increased perfusion requirements,especially during exercise.

Hypertension and LVHBoth hypoxia, as influenced by anemia, and hyper-

tension can stimulate the angiotensin system, which in turn stimulates myocyte growth.25 Associations havebeen found between persistently reduced diurnal bloodpressure rhythms and the development of progressivelydilated left ventricle and left atrium and worse LV func-tion, even in patients with relatively good overall bloodpressure.26 In an observational study of 65 patients, a correlation was found between change in LV mass indexand change in mean ambulatory blood pressure para-meters for 24-hour systolic, mean arterial pressure, daytime systolic, nocturnal systolic, and nocturnal diastolic blood pressure.8

Volume overloadIn CRI patients, hypervolemia may be poorly con-

trolled, which may lead to increased cardiac preloadand potentially serving as another mechanism con-tributing to the development of LVH.8 Dialysis patientsmay retain salt and water, which not only plays a rolein dialysis hypertension but also may have a directhemodynamic effect of increasing the cardiac pre-load.27-29 Interdialytic weight gain may cause a rise inLV end diastolic diameter and, thus, with echocardiog-raphy, may be shown as an increase in LV mass index.

Other factors that contribute to LVHIn patients without CRI, other factors that have been

associated with LVH include obesity,30 age, dietary sodi-um intake,31 arterial hypertrophy and stiffening,32 andinsulin resistance.33 In normotensive, nondiabetic obeseindividuals, LV mass is mediated by the degree ofinsulin resistance and hyperinsulinemia, regardless of BMI and blood pressure.34 In addition to anemia andhypertension, a number of other mechanisms con-tribute to LVH in CRI patients. Other potentially rever-sible factors such as volume overload, secondary hyper-parathyroidism, and malnutrition may also be ofimportance in the pathogenesis of LVH in patients with CRI.13

19

Hyperparathyroidism, a common complication inpatients with chronic renal failure, can be present veryearly in the course of renal disease. The pathogenesisof LVH in hyperparathyroidism is complex and notcompletely understood. Some, but not all, studies havesuggested a relationship between parathyroid hormone(PTH) values and LV mass index. In experimentalmodels, PTH has been shown to lead to cardiac fibrosisby binding to cardiac receptors for PTH in cardiacfibroblasts and myocardiocytes. In addition, PTH canincrease cytosolic free calcium levels. Together, thesefactors may also contribute to LVH.13

Some evidence suggests that the dialysis dose isdirectly related to improvements in cardiac structuralabnormalities and dysfunction.13 Hypoalbuminemiahas also been independently related to LV dilation indialysis patients and appears to predispose patients tothe development of both de novo congestive heart fail-ure and ischemic heart disease.13 The relative contribu-tion of fluid overload, malnutrition, and even inflam-mation to these relationships remains to be elucidated.

Treatment approaches to prevent orreverse the development of LVH

Treatment of existing LVH is directed at correctingthe underlying cause. Surgical repair or replacement ofa narrowed aortic valve can provide benefit in cases ofvalve disorders.

In patients with hypertension, early, adequate, andsustained control of elevated blood pressure is of primeimportance in preventing progression and possiblyreversing structural remodeling. In addition to its effecton the progression of LVH, hypertension can result inthe development of impaired tolerance to dialysis.13 Toavoid these treatment-confounding factors, adequatecontrol of hypertension is an essential part of any com-prehensive management plan.

Strict blood pressure control with achievement ofeuvolia, with ACE inhibitors, and if necessary, calciumchannel blockers and beta blockers, appears not onlyto halt LVH progression, but also induce LVH regres-sion in many patients.9 In some studies, ACE inhibitorshave shown the greatest ability to reduce LV mass inpatients with LVH at baseline.9 ACE inhibitors reduceangiotensin II levels and appear to have both hyper-tension-dependent and -independent effects on LVH.Angiotensin II not only raises blood pressure but hasbeen shown to have direct, trophic effects on the fibro-blasts and cardiomyocytes.35, 36 Intuitively, then, lower-ing angiotensin II should lower blood pressure and pre-vent this trophic effect on cardiomyocytes. SignificantLVH regression has been achieved with ACE inhibitorseven when given at doses not affecting blood pressure,

providing further support of a blood pressure-indep-endent mechanism.37

A number of reports19,38-40 have documented de-creases in LV mass associated with partial anemia correction in dialysis patients treated rHuEPO. Each ofthese studies included normotensive and controlledhypertensive patients in whom LV mass decreaseswere noted, as described below.

Silberberg and colleagues38 studied a 22-patientcohort of 118 patients in the Canadian ErythropoietinStudy. Seven of the 22 patients required antihyperten-sive agents (the agents are not identified in the pub-lished report). All 22 patients showed decreased LVmass over the 6-month course of the study. In fact, astatistically significant decrease in LV mass (P=0.0004)was seen despite a statistically significant increase indiastolic blood pressure (P=0.01) (the change in sys-tolic blood pressure was not significant).

Massimetti and colleagues39 reported a study of 11hemodialysis patients, 2 of whom were taking antihy-pertensive drugs (enalapril and nifedipine, respective-ly) and another 2 who started on enalapril during thecourse of the study. The investigators found a statisti-cally significant decrease (P<0.05) in LV mass in thosestudy patients who had greater LVH at baseline.

Pascual and colleagues40 studied 15 hemodialysispatients, 7 of whom were taking antihypertensiveagents prior to starting rHuEPO therapy (3 receivedpropranolol and hydralazine, 2 celiprolol and captopril,and 2 alpha-methyldopa); and 1 who required low-dosecaptopril several weeks into the study (group 1, n=8).Seven patients were normotensive throughout thestudy (group 2, n=7). All patients had normal bloodpressure at the beginning of the study. LV mass prior tothe start of rHuEPO therapy was higher in group 1than in group 2 (P<0.05), and decreased by 28.5% ingroup 1 and 41.4% in group 2 after a year. The contin-ued higher LV mass in group 1 patients throughout thestudy, according to the authors, confirmed “the relativeimportance of hypertension in the genesis and mainte-nance of LVH.”

Jeren-Strujic et al19 reported the results of rHuEPOtherapy in 22 hemodialysis patients, 7 of whomreceived calcium channel blockers and ACE inhibitorsfor hypertension. LV mass decreased 30% (P<0.001) in the study.

Finally, a review of 15 published studies41 found thata partial correction of anemia to steady-state Hct of32.9%, using rHuEPO, was associated with a decline ofapproximately 18% in the LV mass index, although thistrend was not statistically significant. (These studiesapproached hypertension in various ways; readers arereferred to the original papers for details.)

20

The question remains as to whether complete cor-rection of renal anemia could result in more completeregression.42 Certainly, the relationship between LVHand anemia has been documented in a number of stud-ies of CRI patients. Levin and colleagues,4 for example,reported that for every 1-g/dL decrease in hemoglobin,the risk of LVH was increased by 6%. In a later study,Levin and colleagues reported that for every 0.5-g/dLdecrease in hemoglobin, the relative risk of LV growth increased by 32% (P=0.004).10

In the Canadian Normalization of HemoglobinStudy,43 normalization of hemoglobin did not lead toregression of established concentric LVH or LV dilation.rHuEPO was used to treat 146 hemodialysis patients for48 weeks using regimens designed to achieve hemoglo-bin levels of 10 g/dL or 13.5 g/dL. Neither group exhib-ited changes in LV mass index (for those with concen-tric LVH) or in cavity volume index (for those with LVdilation). Normalization of hemoglobin levels, howev-er, appeared to prevent the development of new LVdilation. In addition, normalization of hemoglobin significantly improved fatigue (P=0.009), depression(P=0.02), and relationship indicators of quality of life (P=0.004).

The benefit of anemia treatment, as observed withrHuEPO as previously described, on LVH developmentmay not be achieved if hemoglobin is partially correct-ed without adequate blood pressure control.44 Both ane-mia and hypertension must be adequately treated.10

Similarly, treatment of hypertension alone, without cor-recting anemia, may significantly decrease the degreeof LVH regression that can be achieved. Additionally,the role of other factors such as hyperparathyroidismand hypoalbuminemia must also be taken into accountin any management strategy.

Primary prevention of LVH: a betteroption than LVH regression?

Intuitively, primary prevention of LV dilation and/orhypertrophy may be a better approach than treatmentafter restructuring has begun. If primary prevention isnot possible, early intervention may result in slowingof the progression of LVH and, perhaps, a betterchance of regression. The management of aortic regur-gitation from primary valvular disease is a paradigmat-ic illustration of the risk-benefit ratio of early and lateintervention. In uremia, LVH is associated with sub-stantial myocardial fibrosis that occurs independentlyof hypertension.13 The degree of fibrosis would likelylimit the amount of LVH regression possible to achieve.

There are limited clinical data supporting thehypothesis that timing of intervention plays a role thatis independent of the overall cumulative burden ofhemodynamic stress. In a prospective study, 433 dialy-sis patients were followed for a mean of 44 months. Of these, 29 patients had four yearly echocardiograms.Progressive LV dilation with compensatory hypertro-phy was characteristic. Most of the additional cardiacenlargement occurred within the first year of dialysistherapy, and associations for enlargement could onlybe identified during this period. The LV growth seenafter 1 year was autonomous of standard hemodynam-ic parameters like anemia and hypertension.45 Thisstudy suggests that the therapeutic window for inter-vention to prevent progressive cardiac enlargementnarrows with the passage of time. The CanadianNormalization of Hemoglobin Trial43 also suggested that timing was important: primary outcome analysis suggested that normalization of hemoglobin could notreverse established LV dilatation, while secondary outcome analysis generated a clear hypothesis thatnormalization of hemoglobin could prevent the development of LV dilation. Studies to date are incon-clusive as to the risks and benefits of hemoglobin nor-malization in patients with CKD.46 Several trials usingrHuEPO currently under way are investigating therisks and benefits of early intervention and/or normalization of hemoglobin in earlier disease phases.

Taken together, LV dilation and hypertrophy occurearly in the course of CRI, and progress rapidly withdeclining kidney function. This process occurs in paral-lel with declining hemoglobin and rising blood pres-sure levels, which appear to be the principal modifiablerisk associations. If hypertension and anemia remainuntreated or insufficiently treated, LVH continues toprogress, especially during the early years of dialysis.To reduce the mortality and morbidity associated withLVH-related cardiovascular events, management ofhypertension, anemia, and other potential contributorsto LVH progression may achieve more than practicesthat favor late intervention. CKD

References1. Portolés J, Torralbo A, Martin P, et al. Cardiovascular effects of

recombinant human erythropoietin in predialysis patients. Am JKidney Dis. 1997;29:541-548.

2. Eckardt KU. Cardiovascular consequences of renal anemia and ery-thropoietin therapy. Nephrol Dial Transplant. 1999;14:1317-1323.

3. Koren MJ, Mensah GA, Blake J, et al. Comparison of left ventricularmass and geometry in black and white patients with essentialhypertension. Am J Hypertens. 1993;6:815-823.

4. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricularhypertrophy in the predialysis population: identifying opportunitiesfor intervention. Am J Kidney Dis. 1996;27:347-354.

5. Harnett JD, Kent GM, Foley RN, Parfrey PS. Cardiac function andhematocrit level. Am J Kidney Dis. 1995;25:S3-S7.

21

6. NIH Consensus Statement: Morbidity and Mortality of Dialysis.Bethesda, Md: National Institutes of Health; NIH ConsensusDevelopment Conference. 1993;11:1-34.

7. United States Renal Data System. Patient characteristics at start ofESRD: Data from the HCFA medical evidence form. Am J KidneyDis. 1999;34:S63-S73.

8. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis. 2000;35:S117-S131.

9. Tucker B, Fabbian F, Giles M, et al. Reduction of left ventricularmass index with blood pressure reduction in chronic renal failure.Clin Nephrol. 1999;52:377-382.

10. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass indexincrease in early renal disease: impact of decline in hemoglobin.Am J Kidney Dis. 1999;34:125-134.

11. Silberberg JS, Rahal DP, Patton DR, Sniderman AD. Role of anemiain the pathogenesis of left ventricular hypertrophy in end-stagerenal disease. Am J Cardiol. 1989;64:222-224.

12. Harnett JD, Parfrey PS, Griffiths SM, et al. Left ventricular hyper-trophy in end-stage renal disease. Nephron. 1988;48:107-115.

13. Lopez-Gomez JM, Verde E, Perez-Garcia R. Blood pressure, left ven-tricular hypertrophy and long-term prognosis in hemodialysispatients. Kidney Int. 1998;54:S92-S98.

14. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophyand failure. N Engl J Med. 1999;341:1276-1283.

15. Mall G, Rambansek M, Neumeister A, et al. Myocardial interstitialfibrosis in experimental uremia: implications for cardiac compli-ance. Kidney Int. 1988;33:804-811.

16. London GM, Parfrey PS. Cardiac disease in chronic uremia: patho-genesis. Adv Ren Replace Ther. 1997;4:194-211.

17. London GM, Guérin AP, Marchais SJ. Pressure-overload cardiomy-opathy in end-stage renal disease. Curr Opinion NephrolHypertens. 1999;8:179-186.

18. Levin A, Foley RN. Cardiovascular disease in chronic renal insuffi-ciency. Am J Kidney Dis. 2000;36:S24-S30.

19. Jeren-Strujic B, Raos V, Jeren T, Horvatin-Godler S. Morphologicand functional changes of left ventricle in dialyzed patients aftertreatment with recombinant human erythropoietin (r-HuEPO).Angiology. 2000;51:131-139.

20. Cotes PM, Pippard MJ, Reid CD, et al. Characterization of the ane-mia of chronic renal failure and mode of its correction by a prepara-tion of human erythropoietin (r-HuEPO): an investigation of thepharmacokinetics of intravenous erythropoietin and its effects onerythrokinetics. Q J Med. 1989;70:113-137.

21. Erslev AJ. Erythropoietin. N Engl J Med. 1991;32:1339-1344.

22. Roger SD, Grasty MS, Baker LRI, et al. Effects of oxygen breathingand eythropoietin on hypoxic vasodilatation in uremic anemia.Kidney Int. 1992;42:975-980.

23. Yildiz A, Akkaya V, Hatemi AC, et al. No association between dele-tion-type angiotensin-converting enzyme gene polymorphism andleft ventricular hypertrophy in hemodialysis patients. Nephron.2000;84:130-135.

24. Foley RN, Parfrey PS, Harnett JD, et al. Impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney Int. 1996;49:1379-1385.

25. Sen S. Factors regulating myocardial hypertrophy in hypertension.Circulation. 1987;75:181-184.

26. Covic A, Goldsmith DJA, Covic M. Reduced blood pressure diurnalvariability as a risk factor for progressive left ventricular dilatationin hemodialysis patients. Am J Kidney Dis. 2000;35:617-623.

27. London GM, Marchais SJ, Guérin AP, et al. Cardiac hypertrophyand arterial alterations in end-stage renal disease: hemodynamicfactors. Kidney Int. 1993;43:S42-S49.

28. Ifudu O, Dawood M, Homel P, Friedman EA. Excess interdialyticweight gain provokes antihypertensive drug therapy in patients onmaintenance hemodialysis. Dial Transplant. 1997;26:541-547.

29. Mitsnefes MM, Daniels SR, Schwartz SM, Meyer RA, Khoury P,Strife CF. Severe left ventricular hypertrophy in pediatric dialysis:prevalence and predictors. Pediatr Nephrol. 2000;14:898-902.

30. Lauer MS, Anderson KM, Kannel WB, Levy D. The impact of obesity on left ventricular mass and geometry: the FraminghamHeart study. JAMA. 1991;266:231-236.

31. De Simone G, Devereux RB, Camargo MJF, et al. Influence of sodium intake on in vivo left ventricular anatomy in one-kidneyone clip and two-kidney one clip Goldblatt rats. Am J Physiol.1993;264:H2103-H2120.

32. Saba PS, Roman MJ, Pini R, et al. Relation of carotid pressure wave-form to left ventricular anatomy in normotensive subjects. J AmColl Cardiol. 1993;22:1873-1880.

33. Lind L, Andersson PE, Andren B, et al. Left ventricular hypertro-phy is associated with the insulin resistance metabolic syndrome. J Hypertens. 1995;13:433-438.

34. Sasson Z, Rasooly Y, Bhesania T, Rasooly I. Insulin resistance is animportant determinant of left ventricular mass in the obese.Circulation. 1993;88:1431-1436.

35. Crabos M, Roth M, Hahn AWA, Erne P. Characterization ofangiotensin II receptors in cultured adult rat cardiac fibroblasts. J Clin Invest. 1994;93:2372-2378.

36. Vlahakos DV, Hahalis G, Vassilakos P, et al. Relationship betweenleft ventricular hypertrophy and plasma renin activity in chronichemodialysis patients. J Am Soc Nephrol. 1997;8:11764-11770.

37. Cannella G, Paoletti E, Delfino R, et al. Prolonged therapy with ACEinhibitors induces a regression of left ventricular hypertrophy ofdialyzed uremic patients independently from hypotensive effects.Am J Kidney Dis. 1997;30:659-664.

38. Silberberg J, Racine N, Barre P, Sniderman AD. Regression of leftventricular hypertrophy in dialysis patients following correction ofanemia with recombinant human erythropoietin. Can J Cardiol.1990;6:1-4.

39. Massimetti C, Pontillo D, Feriozzi S, et al. Impact of recombinanthuman erythropoietin treatment on left ventricular hypertrophyand cardiac function in dialysis patients. Blood Purif. 1998;16:317-324.

40. Pascual J, Teruel JL, Moya JL, et al. Regression of left ventricularhypertrophy after partial correction of anemia with erythropoietinin patients on hemodialysis: a prospective study. Clin Nephrol.1991;35:280-287.

41. Radermacher J, Koch KM. Treatment of renal anemia by erythro-poietin substitution: the effects on the cardiovascular system. ClinNephrol. 1995;44:S56-S60.

42. Berweck S, Hennig L, Sternberg C, et al. Cardiac mortality prevent-ion in uremic patients: therapeutic strategies with particular attent-ion to complete correction of renal anemia. Clin Nephrol.2000;53:S80-S85.

43. Foley RN, Parfrey PS, Morgan J, et al. Effect of hemoglobin levels inhemodialysis patients with asymptomatic cardiomyopathy. KidneyInt. 2000;58:1325-1335.

44. Zehnder C, Zuber M, Sulzer M, et al. Influence of long-term amelio-ration of anemia and blood pressure control on left ventricularhypertrophy in hemodialyzed patients. Nephron. 1992;61:21-25.

45. Foley RN, Parfrey PS, Kent GM, et al. Long-term evolution of car-diomyopathy in dialysis patients. Kidney Int. 1998;54:1720-1725.

46. Besarab A, Bolton WK, Browne JK, et al. The effects of normal ascompared with low hematocrits values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med.1998;339:584-590.

22

Dyslipidemia and chronic kidney disease: metabolic challenges to treatment

Author information: Thomas A. Golper, MD, is Professor of Medicine and Medical Director of the Patient Care Center for Nephrology, Diabetes, Hypertension, and Vascular Diseases,Vanderbilt University, Nashville, Tenn. He can be reached at Vanderbilt University Medical Center, S-3303 Medical Center North, Nashville, TN 37232.

idney disease can affect anyone, especiallypeople with diabetes and high blood pres-sure, the two principal causes of end-stagerenal disease (ESRD).1 The United States

(US) incidence rate for ESRD—311 per million people—is the highest in the world.2

According to Healthy People 2010, chronic renal insuf-ficiency (CRI) appears to have reached epidemic pro-portions as well.3 Using data collected between 1988and 1994 by the Third National Health and NutritionExamination Survey (NHANES III),4 Healthy People 2010estimated that 0.4% of the total US population older than 12 years have serum creatinine (SCr) levels ≥ 2.0mg/dL and 1.6% have SCr levels ≥ 1.6 mg/dL. It isimportant to note that small changes in SCr levels canreflect large decreases in glomerular filtration rates(GFRs),4 signifying the need for careful evaluation of any suspect renal function changes.

In patients with reduced renal function, abnormalalterations in the levels and composition of lipoproteinsare common.5–7 Such dyslipidemia, along with hyper-tension and proteinuria, is now considered to be anindependent risk factor for the progression of renal disease.5,8 There appears to be a biologic link between dyslipidemia in CRI and cardiovascular disease (CVD),as elevated total and low-density lipoprotein (LDL) cholesterol levels are associated with CVD in patients with CRI.9,10

Although data from human clinical trials are scarce,the recent prospective Atherosclerosis Risk inCommunities (ARIC) study of 12,728 participants(baseline SCr <2.0 mg/dL for men and <1.8 mg/dLfor women) found that abnormal high-density lipopro-tein (HDL), HDL-2, and triglyceride (TG) levels wereall significant predictors of an increase in SCr levels,used as a measure of diminishing renal function.6

Moreover, TG levels exhibited the most statistically sig-nificant association with future renal dysfunction.6

Separate 3-year observational data from a study of 73patients with chronic renal disease and GFRs rangingfrom 15 to 75 mL/min/1.73 m2 body surface arearevealed that increased concentrations of apolipopro-

tein (apo) B-containing lipoproteins may be linked tomore rapidly progressing CRI. While the cause-and-effect relationship between renal disease progressionand lipid abnormalities remains to be elucidated, thestudy authors noted that the lipid alterations caused byrenal insufficiency could also enhance the progressionof chronic renal disease.11 Muntner and colleagues6

have postulated that, like hypertension, dyslipidemiamight hasten renal disease progression and renal dis-ease might heighten dyslipidemia, suggesting a patho-logic synergy. Thus, CRI patients with abnormal lipidprofiles are at risk for CVD, and lipid-lowering therapyshould be initiated.

Lipid abnormalities and renal disease: the specifics

A growing body of evidence now supports the con-tention that dyslipidemia is involved in the pathogene-sis of both diabetes mellitus and essential hypertensionwith microalbuminemia, although the underlyingmechanisms are not understood. Moreover, patientswith diabetes or essential hypertension are at higherrisk for CVD and have an increased cardiovascularmortality rate.5 These patients are also at a greater riskfor progressive renal damage.5 A number of recentreports have implicated lipids and their oxidative by-products as key players in CRI and progressive kidneydisease.8,10–12 Although controlled clinical trials are cur-rently lacking, experimental data suggest that lipidscontribute directly to renal injury, such as glomeru-losclerosis and tubulointerstitial damage, and whenlipid abnormalities are corrected, the progression ofrenal disease is slowed.13

Collectively, abnormal levels of specific lipoproteinmoieties are central to the dyslipidemia associated withCRI. Among CRI patients, hypertriglyceridemia with-out hypercholesterolemia is the most common lipidabnormality.14 CRI patients also demonstrate increasedlevels of apo B-containing LDL and very low-densitylipoproteins (VLDL), and reduced levels of HDL apo A-containing lipid moieties. Further, an abnormal composition (eg, apoprotein and lipid content) of theselipid particles is also evident. Defective catabolism of

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By Thomas A. Golper, MDNashville, Tennessee

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the apo B-containing lipids by lipoprotein lipase andhepatic lipase is thought to be responsible for thisabnormality.7,13

The TG enrichment of apo B-containing lipids is alsoa risk factor that correlates with renal disease progres-sion.5 According to Muntner and colleagues,6 higher TGlevels at baseline were associated with a significantlyhigher risk of creatinine elevations at follow-up. In theARIC study, when a ≥25% drop in creatinine clearancewas used as an outcome measure, higher TG levels pre-dicted a loss in renal function regardless of insulin lev-els, raising the possibility that insulin resistance mayalso be involved in lipid-associated renal impairment.6

In vitro data have led Ginsberg15 to characterize insulinresistance as a decreased ability of adipose cells to takeup or store fatty acids and/or the increased release offatty acids. This inability to store TG is likely to be thefirst step leading to the dyslipidemia characteristic ofinsulin resistance.

Data from ESRD patients describe a dyslipidemiawith increased small, dense lipid particle levels (eg,LDLIII, VLDL).7 Both predialysis and dialysis patientsexhibited abnormal LDL particle composition consist-ing of TG-rich and cholesterol-deficient moieties, lipids also associated with a greater risk of CVD.7

Lipoprotein(a) (Lp(a)) is similarly linked to atheroscle-rotic vascular disease.14 Lp(a), which resembles LDL instructure except for the additional protein, apolipopro-tein(a), is also a small, dense lipoprotein. Lp(a) levelswere found to be elevated in the ARIC study patients.6

Extending these data, Samuelsson et al11 reportedthat renal dyslipidemia is predominantly a defect ofapolipoprotein distribution rather than of overalllipoprotein levels. They proposed that this apolipopro-tein profile is more clinically useful, having found thatrenal dyslipoproteinemia has, as a main component,the accumulation of apo B-containing lipoproteins.Notably, the authors showed that cholesterol, LDL cho-lesterol, and apo B accumulate in both sclerotic andnonsclerotic glomeruli of patients with various renaldiseases. Glomerular cells have been shown to possessthe LDL receptor, and mesangial cells and glomerularepithelial cells can internalize intermediate-densitylipoproteins by both receptor-mediated and non–recep-tor-mediated mechanisms.11 Deighan et al7 reportedthat TG levels, which are biologically linked to LDLIIIproduction, may serve as a surrogate marker foratherogenic levels of LDLIII, and noted that, whileexcess LDLIII levels were prominent in patients receiv-ing peritoneal dialysis, elevated concentrations ofLDLIII were also present in both hemodialysis and pre-dialysis patients (vs controls).

The prevalence of hyperlipidemia is known to gen-erally increase with deteriorating kidney function, butthe point at which increased lipid levels become morecommon than in normal patients is not clearly de-fined.10 Despite the seemingly diffuse clinical and bio-logical data surrounding renal failure dyslipidemia,however, new data are emerging that outline a frame-work resembling a molecular mechanism for lipid-based renal injury.

A possible mechanism for lipid–derived renal injury

A number of recent in vitro studies reviewed byKeane,5 along with a detailed pathologic report byKamanna and coworkers,12 now point toward an emerg-ing paradigm for renal glomerular damage akin to thevascular effects of atherosclerosis.13

Interestingly, Kamanna and coworkers12 observed aseries of cellular events occurring similarly in both ath-erosclerosis and glomerulosclerosis: (1) lipid, LDL, andoxidized-LDL deposition, (2) monocyte influx, (3) foam-cell formation, (4) smooth muscle cell or mesangialcell proliferation, and (5) extracellular matrix expan-sion. The authors reported that the infiltration ofatherogenic lipoproteins into glomerular endotheliumand mesangial cells initiates a cascade of events thatincludes adhesion molecule expression and monocytechemoattractant production.12 Such cellular activation,by either lipoproteins or cytokines, appears to alterglomerular epithelial structure, allowing leakage oflipoproteins into the mesangium, similar to eventsnoted in atherosclerosis. The LDL in the mesangialspace can then become oxidized (ox-LDL), taking on amore atherogenic character, releasing reactive oxygenspecies (ROS), and resulting in the activation of other-wise quiescent endothelial cells. ROS further increasesthe formation of ox-LDL, resulting in a cyclic pattern ofoxidative damage.5,12 These activated cells can thenrelease cytokines purported to be involved in earlyglomerular injury.12

As described in a review by Keane,5 ox-LDL stimu-lates the production of endothelin, thromboxane, andrenin, leading to an ultimate imbalance in the levels ofvasoactive substances within the renal tissue.Ultimately, the deposition of lipids within renal tissueowing to reduced enzymatic clearance is likely to pro-mote this sequence of “atherogenic” events that dam-ages the renal endothelium, mesangial cells, and vascu-lature and leads to irreversible scarring.13 As illustratedin the Figure, the glomerular capillary endotheliumand the renal mesangial cells are targets for oxidativedamage from circulating monocytes, LDL, and ox-LDL.

Management of dyslipidemiaTo combat the complex lipid abnormalities associated

with CRI, the HMG-CoA reductase inhibitors, or statins,have gained a prominent place in clinical medicine.Clearly able to favorably alter many cellular changeswithin the vascular inflammatory response, statinshave been shown to inhibit the proliferation of mesan-gial cells, vascular smooth muscle cells, and tubularepithelial cells and, most important, to reduce theglomerular infiltration of macrophages.13 In addition,statins may block early response genes involved bothin cholesterol metabolism as well as cell cycle regula-tion of mesangial and smooth muscle vasculature.5

Statins are, therefore, the most widely used drugs inthe treatment of hyperlipidemia associated with renal disease.13

Dyslipidemia treatment in CRIIt is well known that hypercholesterolemia leads to

serious cardiovascular sequelae in the general popula-tion; however, no definitive data are available to estab-lish whether dyslipidemia furthers the risk of athero-sclerosis in patients with CRI.13 Although ample evi-dence now implicates an array of lipid abnormalities inthe progression of renal dysfunction,5,11,13 intervention

with lipid-lowering therapies, while a logical choice,has not proved to slow the progression of renaldisease.8,10,11,13

Despite the need for accurate data from large-scale,controlled, lipid-lowering studies of patients with CRIand dyslipidemia, the dyslipidemic CRI patient shouldbe considered to be at high risk for lipid-related comor-bidity and treated accordingly, based on the document-ed benefits of aggressive lipid-lowering therapy in CVDpatients.10 Current clinical recommendations outlinethe following approach for CRI patients with hyperlipidemia10:

Patients with a total cholesterol level ≥ 200 mg/dLor an HDL level ≤ 35 mg/dL should undergo a fast-ing lipid profile.

An LDL cholesterol level ≥ 100 mg/dL is the threshold for dietary modification, while an LDLlevel ≥ 130 mg/dL is the threshold for drug therapy.

Target LDL levels should be ≤ 100 mg/dL for bothdiet and drug therapies.

Statins are generally the first-line drug therapy;myositis can occur, and lower doses are indicated in24

Figure:Proposed mechanism for the role of atherogenic lipoproteins in renal injury. As shown, atherogenic lipoproteins activate glomerularcapillary endothelial and mesangial cells, causing mononuclear cells to be attracted, adhere, and migrate into the mesangium. Thisprocess is mediated by the expression of adhesion molecules and monocyte chemoattractant peptides. Once within the mesangium,the atherogenic lipoproteins may be further oxidized, thereby activating glomerular cells and resulting in foam cell production. Theseevents may then stimulate the production of cytokines (eg, macrophage-colony stimulating factor [M-CSF], macrophage chemoat-tractant protein-1 [MCP-1]), growth factors (eg, platelet-derived growth factor [PDGF], transforming growth factor-β [TGF-β), andextracellular matrix (ECM) proteins and affect the proliferation of mesangial cells. (Reprinted with permission from Kamanna et al.12)

25

renal transplant patients being given immunosup-pressive agents such as tacrolimus or cyclosporine.

Fibric acid derivatives are also effective.

In addition, the National Cholesterol EducationProgram (NCEP) Guidelines do not recommend treat-ing elevated TG and/or diminished HDL levels unlessLDL levels are also increased.10 However, changes indiet and increased physical activity are recommendedfor patients in this category.

The current clinical recommendations for treatinghyperlipidemic CRI patients are summarized in theTable, and, as with all clinical recommendations, theymust be applied to CRI patients on an individual basis.10

Overall, the dietary effects of reducing cholesterol andTG levels are limited and statin-based therapy remainsthe most effective treatment.

Table. Clinical Recommendations forDyslipidemic Patients With CRI

Recommendation Specific Intervention

Dietary modifications NCEP Step I diet, usually in combination with drug therapy10

Low-saturated fat diet; fish oil supplements13

Lifestyle modifications Regular exercise13

Lipid-lowering drug Statins: most widely used; safeand effective; may modulate vas-cular and renal cell-cycle regula-tion and proliferation and maylower lipid levels8,10,16,17

Fenofibrate: safe and effective;good TG-lowering effects18

Gemfibrozil: safe and effective;good TG-rich lipoprotein clearance19

NCEP, National Cholesterol Education Program; TG, triglyceride.

ConclusionsEmerging preclinical and clinical data suggest a

pathophysiologic link between CRI and dyslipidemia; however, the involvement of abnormal lipid levels and altered composition of lipoprotein particles in progressive renal disease remains to be elucidated.Cardiovascular risks are evident, but whether theserisks also enhance the progression of renal disease isunproven. Although statins appear most favorable aslipid-lowering interventions and their use is clearlyadvocated, further rigorous evaluation through large-

scale clinical trials is needed to ascertain whether suchtherapy slows the progression of renal dysfunctionand/or decreases the frequency of cardiovascular complications and death. CKD

References1. American Society of Nephrology. Kidney disease facts & figures.

Available at: http://www.asn-online.com/facts/faqs.html. AccessedOctober 17, 2000.

2. USRDS. Atlas of end-stage renal disease in the United States. 2000annual data report of the United States Renal Data System.Minneapolis, Minn: National Institutes of Health; 2000:18.

3. Healthy People 2010 - Chronic kidney disease. National Institutes of Health. National Institute of Diabetes and Digestive and KidneyDiseases, 2000 Web site. Available at: http://www.ep.niddk.nih.gov/divisions/kuh/kidneyHP2010.html. Accessed July 25, 2000.

4. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levelsin the US population: Third National Health and NutritionExamination Survey (published erratum appears in Am J KidneyDis 2000 Jan;35:178)1998;32:992-999.

5. Keane WF. The role of lipids in renal disease: future challenges.Kidney Int. 2000;57(suppl 75):S27-S31.

6. Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ. Plasma lipidsand risk of developing renal dysfunction: the Atherosclerosis Risk in Communities Study. Kidney Int. 2000;58:293-301.

7. Deighan CJ, Caslake MJ, McConnell M, et al. Atherogenic lipopro-tein phenotype in end-stage renal failure: origin and extent of smalldense low-density lipoprotein formation. Am J Kidney Dis.2000;35:852-862.

8. Keane WF. Lipids and progressive renal disease: the cardio-renal link.Am J Kidney Dis. 1999;34:xliii-xlvi.

9. Levey AS, Beto JA, Coronado BE, et al for the National KidneyFoundation Task Force on Cardiovascular Disease. Controlling theepidemic of cardiovascular disease in chronic renal disease: What dowe know? What do we need to learn? Where do we go from here?Am J Kidney Dis. 1998;32:853-906.

10. Kasiske BL. Hyperlipidemia in patients with chronic renal disease.Am J Kidney Dis. 1998;32(5 suppl 3):S142-S156.

11. Samuelsson O, Mulec H, Knight-Gibson C, et al. Lipoprotein abnor-malities are associated with increased rate of progression of humanchronic renal insufficiency. Nephrol Dial Transplant. 1997;12:1908-1915.

12. Kamanna VS, Roh DD, Kirschenbaum MA. Hyperlipidemia and kid-ney disease: concepts derived from histopathology and cell biologyof the glomerulus. Histol Histopathol. 1998;13:169-179.

13. Majumdar A, Wheeler DC. Lipid abnormalities in renal disease. J RSoc Med. 2000;93:178-182.

14. Rader DJ, Rosas S. Management of selected lipid abnormalities.Hypertriglyceridemia, low HDL cholesterol, lipoprotein(a), in thy-roid and renal diseases, and post-transplantation. Med Clin NorthAm. 2000;84:43-61.

15. Ginsberg HN. Insulin resistance and cardiovascular disease. J ClinInvest. 2000;106:453-458.

16. Oda H, Keane WF. Recent advances in statins and the kidney.Kidney Int Suppl. 1999;71:S2-S5.

17. Guijarro C, Blanco-Colio LM, Massy ZA, et al. Lipophilic statinsinduce apoptosis of human vascular smooth muscle cells. KidneyInt Suppl. 1999;71:S88-S91.

18. Levin A, Duncan L, Djurdjev O, et al. A randomized placebo-con-trolled double-blind trial of lipid-lowering strategies in patients withrenal insufficiency: diet modification with or without fenofibrate.Clin Nephrol. 2000;53:140-146.

19. Samuelsson O, Attman PO, Knight-Gibson C, et al. Effect of gemfi-brozil on lipoprotein abnormalities in chronic renal insufficiency: a controlled study in human chronic renal disease. Nephron.1997;75:286-294.

therapies

26

n order to evaluate the risk of nephropathyin diabetics and devise prophylactic strate-gies, it is essential to know the relative con-tribution to risk of each type of diabetes.

The high incidence of type 2 diabetes in young Japanesepatients provides an opportunity to compare the twotypes of diabetes in populations of the same age. A dia-betes center in Tokyo compiled data from 1,578 male andfemale Japanese patients who were diagnosed with dia-betes between ages 10 and 30, and who lacked preexist-ing nephropathy or nondiabetic causes of nephropathy.

The investigators found that the incidence ofnephropathy in patients with type 2 diabetes was twicethat of type 1 patients. In type 2 patients, the rate ratioper postpubertal years of diabetes was 2.04 times thatof the type 1 patients (95% CI, 1.50 to 2.78), a differ-ence unlikely to result from the delay in diagnosisoften seen in type 2 diabetes. The incidence ofnephropathy was independent of differences in sex,referral bias, or family history of diabetes.

Interestingly, the incidence of nephropathy per 20years of postpubertal diabetes declined significantlyfrom 1965 to 1980 in type 1 diabetics (rate ratio 0.34,P=0.002), but remained the same in type 2 diabetics.One possible explanation for this phenomenon is bettermetabolic and blood pressure control in type 1 diabet-ics in recent years because of mandatory clinic visits.When the rate ratios were stratified according to levelof glycosylated hemoglobin and blood pressure, thetype 2 diabetics had significantly more nephropathy inevery stratum of glycosylated hemoglobin, but signifi-cantly less within the highest blood pressure stratum.

Further investigation is warranted to elucidate thefactors underlying the complex relationship betweenblood pressure, type of diabetes, and nephropathy.Importantly, the risk of nephropathy due to type 2 diabetes varies with ethnicity. The results of this studysupport increased vigilance in the prevention ofnephropathy in type 2 diabetics, especially in high-risk populations.

CommentaryThis is an important and interesting study that

confirms a number of observations, adds new find-ings, and raises areas for additional investigation indiabetic nephropathy.

Among the study’s strengths was the large and homo-geneous study population, comprising 620 type 1 and958 type 2 diabetic patients <30 years old. In addition,patients received long-term follow-up and frequent eval-uations conducted at the same site.

The study’s weaknesses included proteinuria measure-ment with an albumin dipstick, which is a less sensitivemethod than other assays and could have led to theunderdiagnosis of diabetic nephropathy toward the endof the study. The study also excluded patients with non-diabetic nephropathy, but no renal biopsies were done.Immunoglobulin A nephropathy, focal sclerosis, andmembranous nephropathy, therefore, could have beenmissed, especially in this population. In addition, thepopulation was metropolitan; conclusions drawn fromthe study may not be applicable to populations in ruralareas. Similarly, information regarding income and edu-cation was not provided; these factors can bias outcomes.

For the most part, the paper offers careful anddetailed analysis of data accumulated over the course ofthe study. It lacks, however, an analysis of body massindex by cohort, year of diagnosis, and age, whichwould be useful. The homogeneous population—allJapanese—is both a strength and weakness of the study,as conclusions may not apply to other ethnic groups.

The study confirms and extends observations that:

after correction for comorbidities, diabetic nephro-pathy incidence and prevalence in type 1 and 2 diabetics are similar;

the incidence of type 1 diabetic nephropathy isdecreasing while the incidence of type 2 diabeticnephropathy is increasing; and

blood pressure and diabetes control are key factorsin preventing diabetic nephropathy.

The study also illustrates that, during the first 10 years of life, essentially all diabetic nephropathy is related to type 1 diabetes. During the second 10 years, however, nearly 30% of patients have type 2 diabetes, and in the third decade, two thirds of patientshave type 2 diabetes. This is important because manystudies use age 30 as a cutoff for distinguishingbetween type 1 and 2 diabetes.

Review and commentary on the recent literature

lit reviewlit review

Article title: Higher incidence of diabetic nephropathy in type 2 than intype 1 diabetes in early-onset diabetes in Japan

Authors: Yokoyama H, Okudaira M, Otani T, et al

Journal: Kidney Int. 2000;58:302-311

I

27

This study should raise alarms regarding the progres-sive emergence of type 2 diabetic patients in our end-stage renal disease population. Americans and othermodern peoples may be eating themselves into anearly grave due to the impact of diet on the occurrenceof diabetes and the need for dialysis. A number of com-mon-sense interventions, related to lifestyle and educa-tion, could be efficacious “medicines” in this setting.This study provides a basis for further examination ofthese issues and the potential for designing interven-tions and analyzing outcomes.

W. Kline Bolton, MDCharlottesville, Va

Article title: Alterations of protein metabolism bymetabolic acidosis in children withchronic renal failure

Authors: Boirie Y, Broyer M, Gagnadoux MF, et al

Journal: Kidney Int. 2000;58:236-241

hildren with chronic renal failure (CRF)tend to exhibit growth retardation and protein malnutrition. It has been suspectedthat the malnutrition is caused by meta-

bolic acidosis, but the relationship between these twoparameters has not been studied in children with CRF.This was the subject of a French study of 10 childrenwith CRF, ages 1 to 4 years. The subjects were allgrowth-retarded, and did not exhibit end-stage renalfailure or infectious disease. The investigators assessedprotein breakdown and branched-chain amino acid oxidation in the postabsorptive state by infusing thesubjects with radioactive leucine and monitoring thelevel of the labeled leucine in plasma and excreted air.Five of the subjects did not have acidosis (mean values22.6 ± 3.0 mmol · L-1 HCO3-, 7.42 ± 0.11 pH), mostlydue to receiving bicarbonate treatment. The other five,who exhibited acidosis (15.8 ± 1.5 mmol · L-1 HCO3-,7.33 ± 0.06 pH), had significantly higher postabsorp-tive protein breakdown per fat-free mass than the firstgroup. In addition, regression analysis revealed a stronginverse correlation between plasma bicarbonate andboth leucine oxidation per kilogram of body weight andprotein breakdown.

The results indicate that acidosis profoundly affectsprotein metabolism. This may be due to decreasedresponse to anabolic hormones such as growth hormone.The study was unable to link abnormally high proteinbreakdown to growth retardation; this would haverequired a larger study in which the data could be strati-

fied for origin and duration of CRF. Nevertheless, it isquite plausible that the link exists, as suggested byseveral human and nonhuman studies. The authorssuggest that growth retardation may be preventable bybicarbonate treatment and shortening the postabsorp-tive state. However, a better understanding of postpran-dial protein metabolism in children with CRF is neces-sary in order to properly evaluate the latter hypothesis.

CommentaryGrowth retardation is a prominent complication of

CRF during childhood and is multifactorial in origin.Experimental data support the contention that thegrowth retardation that occurs in association with meta-bolic acidosis is in part related to the effect of acidosison the growth hormone (GH)/insulin growth factor(IGF) access, in which acidosis alters the pattern of GHsecretion. Although the beneficial effect of the correct-ion of acidosis on growth retardation is well substantiat-ed in children with renal tubular acidosis and normalrenal function, there have been no published studiesthat specifically address how acidosis might contributeto the growth delay seen in children with CRF.

In an attempt to fill that void, Boirie and colleagueshave demonstrated a correlation between whole-bodyprotein breakdown and the plasma bicarbonate concen-tration in children with renal insufficiency. Patientswith a low mean plasma bicarbonate level experiencedsignificantly greater protein breakdown than patientswith a normal mean plasma bicarbonate in this short-term evaluation.

The study suffers from a very small number ofpatients and the lack of a control population. One alsowonders how the investigators were able to continuous-ly measure the CO2 content of expired air in theseyoung children, all less than 5 years of age.

Nevertheless, these preliminary data suggest thatmetabolic acidosis is a risk factor for protein malnutri-tion and possibly growth delay in children with renalinsufficiency and help substantiate the recommenda-tion for the maintenance of a normal serum bicarbon-ate level made in the recent Pediatric Clinical PracticeGuidelines for Nutrition in Chronic Renal Failure fromthe National Kidney Foundation’s Kidney DiseaseOutcomes Quality Initiative (K/DOQI).

Bradley A. Warady, MDKansas City, Mo

CKD

C

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Anemia treatment during chronic renal insufficiencyIn each issue, Your Opinion will present the results of a reader survey that welcomes the participation of all nephrologists (see next issue’s survey on page 29). For our debut issue, 13 members of our Editorial Advisory Board responded to questions related to the treatment of anemia during chronic renal insufficiency (CRI). Here are their aggregate responses.

your opinionyour opinion

Is it necessary to consider gender when treating anemia in CRI patients?

What percentage of your CRI patients receivetreatment with recombinant human erythropoietin(rHuEPO) for anemia?

What percentage of your CRI patients receiveany type of treatment for anemia?

In a CRI patient who is a good candidate for anemia therapy, at what hemoglobin level do you initiate treatment?

The survey asked participants to number the followingstatements 1 through 4 in order of their importance (1=most important, 4=least important) in explainingwhy CRI patients do not receive anemia treatment:Why does anemia during CRI often go untreated?

Average response

Late referral to nephrologist 1.23Unable to pay for anemia therapy 1.82Patients are noncompliant with needfor weekly injections 2.77

Lack of evidence of medical benefit 3.77

Comment for publicationThe survey included questions related to the hemo-

globin levels at which oral and parenteral iron treat-ments are initiated. A number of respondents tookissue with the questions, noting that the initiation oforal or parenteral iron depends on iron stores, not hemoglobin levels.

One respondent provided the following comment for publication:

Oral iron is useful only if an iron deficiency, by tradi-tional criteria, is present. Iron deficiency in all malesand nonmenstruating females should be evaluated diagnostically for blood loss (for example, colonoscopy). A negative stool for occult blood is not a satisfactorymeans of excluding gastrointestinal blood loss.

The use of parenteral iron for CRI patients will evolveover the coming 1 to 2 years. Currently, it is infrequent,but with the greater safety of newer nondextran ironpreparations and a greater sensitivity of physicians toanemia in CRI, its use will increase.

Richard A. Sherman, MDNew Brunswick, NJ

The survey also queried participants as to hemoglobinlevels at which blood transfusions and androgen therapyare considered. Of the respondents, 54% indicated thatthey did not prescribe blood transfusions; none of therespondents used androgens. Of those who prescribedblood transfusions, all responded that they do so only ifhemoglobin levels fall below 9 g/dL.

We want your opinion for our next issue!

Fax or mail us your responses to the following questionsregarding the management of hemodialysis patients:

Which blood pressure reading do you use to adjust blood pressure medications (check one):

__ Predialysis__ Postdialysis__ 24-h ambulatory__ Other

Which of the following do you suggest when malepatients complain of sexual dysfunction (check all that apply):

__ Androgens__ Higher hemoglobin/more rHuEPO__ Endocrinology evaluation__ Bromocriptine__ Viagra__ Other

Your comment for publication:__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Name:____________________________Phone: ____________City:__________________________State: ______________

Fax the completed survey to 973-263-3952 or send to: CKD Survey, HealthVizion Communications, 20 Waterview Blvd, Parsippany, NJ 07054-1295. 29

Note—“Your Opinion” is an informal poll that makes no claims of statistical significance.

3030

INITIAL VISIT: DECEMBER 1996Case description: A 54-year-old female patient was

referred to the nephrologist in December 1996 due toproteinuria and edema. In September 1996, she hadnoted swelling that she attributed to an abscessed tooth.She had a 3-year history of hypertension, and diabetesthat had been controlled by diet for 6 months.

History: Her mother had diabetes. The patient did notdrink or smoke cigarettes.

Medications: She was taking 80 mg of Lasix (furosemide,Aventis Pharmaceuticals) once a day and K-Dur (potas-sium chloride, Key) 20 mEq three times a day.

Test results: On physical examination, blood pressure

was 150/85 mm Hg; lungs were clear; heart rate andrhythm were regular; abdomen was soft and nontender;patient had 3+ peripheral edema of her extremities(Table 1).

The blood urea nitrogen (BUN) was 26 mg/dL; serumcreatinine level was 0.8 mg/dL; serum albumin was 1.7 g/dL; cholesterol was 510 mg/dL; urine protein was 6.7 g/d (Table 2).

Treatment adjustments: Her dose of the diureticLasix was increased to 80 mg twice a day. She alsowas started on 10 mg of Lipitor (atorvastatin calcium,Pfizer) a day for her high cholesterol. Ten milligramsof Accupril (quinapril HCl, Pfizer) a day also wasadded to her regimen.

diagnosticchallenge

diagnosticchallenge

Table 1: Physical Examination Test Results

Table 2: Laboratory Test Results

NA = Not available

BUN = Blood urea nitrogen, NA = Not available

Submitted by

Steven Fishbane, MDMineola, New York

31

Diagnostic Challenge: What is the most likely cause of this patient’s acute renal failure?

FOLLOW-UP: JANUARY 1997Test results: In January 1997, a renal biopsy was per-

formed, which showed findings of minimal change disease. The BUN and creatinine levels rose with the use of diuretics (Table 2). The serum potassium leveldropped to 3.6 mEq/L.

Physical examination showed that blood pressure haddecreased to 100/70 mm Hg with positive orthostasis.Her weight was 150 lb (Table 1).

Treatment adjustments: The patient had becomedehydrated; her creatinine level rose to 1.3 mg/dL andher blood pressure dropped. The dose of Lasix wasdecreased to 80 mg a day, and a dose of 60 mg a day of prednisone was started. Her creatinine level thencame back to 0.7 mg/dL (Table 2).

FOLLOW-UP: MARCH 1997Complaints: In March 1997, the patient came in com-

plaining of worsening swelling.

Test results: On physical examination, blood pres-sure was 140/100 mm Hg and she had 4+ peripheraledema (Table 1).

The BUN level had increased to 63 mg/dL; the creatinine level had increased to 2.3 mg/dL; 24-hour pro-tein excretion was 18 g/d; serum albumin was 1.5 g/dL, and cholesterol was 386 mg/dL (Table 2).

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