Online Geriatrics Curriculum

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Chapter 1: Geriatric Nephrology Has Come of Age: At LastDimitrios G. Oreopoulos* and Jocelyn Wiggins †

*Department of Medicine, University of Toronto, Toronto, Canada; and † University of Michigan, Ann Arbor,Michigan

On May 23–24, 1985, the first International Sym-posium on Geriatric Nephrology was held in To-ronto. In his excellent review of the symposium, 1

Michael Kay commented on the challenges andrisks facing aged individuals and, in view of the in-creased costs of their care, the ethical issues facingthe caregiver. His report stressed the fact that “thedegree of humanity in our healthcare world will bemade evident in the way we treat (or do not treat)our minorities, our underprivileged, our poor, ourmentally infirm, those who have no voice to speak for themselves, and finally, the aged.”

After that successful initial meeting, the Interna-tional Society of Geriatric Nephrology was formed,with its own journal—the International Journal of Geriatric Nephrology and Urology —and five addi-tional international meetings of the InternationalSociety were held at Salamanca, Lisbon, Atlanta,Thessaloniki, and Antalya.

Despite all these efforts and activities, the interestamongnephrologistsconcerninggeriatricnephrology did not increase and, if anything, was decreasing.Membership in the Society and participation to themeetings were small. Also subscriptions to and sub-mission of articles to the Society’s journal were notsufficient to sustain it. As a result, the publisher de-cided to publish the journal as a section in the journal

International Urology and Nephrology .All these regrettable circumstances seem to have

changedbecause of two important factors that havecontributed to a renewed interest in geriatric ne-phrology. First is the amazing increase in the inci-dence of newpatients with ESRD over the age of 65;this segment of our population is the fastest grow-ing group of patients requiring dialysis, and it con-tinues to grow. Thus, nephrologists forced to prac-tice as amateur geriatriciansnowrecognize theneedto master all aspects of geriatrics. Second, the intro-duction and automatic reporting of estimated GFR

(eGFR)usingtheModificationofDiet inRenal Dis-

ease (MDRD) formula has revealed a large numberof patients who have impaired kidney function,most of whom are elderly. Primary care physiciansare inundated with elderly patients with impairedkidneyfunction and, in turn, are flooding theneph-rologists with referrals.

Nephrologists have had to take a serious look atthe plight of elderly, and probably as a result, threeimportant developments have ushered in the new era of Geriatric Nephrology.

1. For the first time, the American Society of Nephrology has in-cluded in its annual Renal Week program a 2-d course on geri-atric nephrology that was sold out and that kept the interest of the participants to the end. All these presentations have beentaped and are available, with the accompanying slides, at http://

asn-online.org/education_and_meetings/media/geriatrics/. Asimilar course has been planned for the 2009 ASN meeting.

2. Recognizing that geriatric nephrology is now essential to ne-phrology training,the Accreditation Council for Graduate Med-ical Education(ACGME),in its program requirements for train-ing in nephrology, has mandated that “fellows must have formalinstruction, clinical experience and demonstrate competence inthe prevention, evaluation and management of geriatric aspectsof nephrology, including disorders of ageing kidney and urinary tract.”In addition,the ACGMEhas mandatedthat “fellowsmustreceive formal instruction in geriatric medicine, including phys-iology and pathology of the ageing kidney, and drug dosing andrenal toxicity in the elderly patient.”

In response to the above, the Chair of the ASNTraining Program Directors Committee (Dr. DonaldKohan) invited a group of individuals to forma com-mittee todesign a curriculum by identifying thetopicsand authors to write the corresponding chapters andwe were honored to be asked to co-chair it. We wereimpressed by the enthusiasm of all members of thecommittee (Table 1). The committee identified 37

Correspondence: Dimitrios G. Oreopoulos, University HealthNetwork, 399 Bathurst Street, 8E-408, Toronto, Ontario M5T 2S8,Canada. E-mail: [email protected]

Copyright 2009 by the American Society of Nephrology

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chapters (Table 2). These chapters are short (5 to 6 pages) andemphasize only knowledge related to geriatric nephrology. They provide keyreferences for further reading with a powerpoint pre-sentation based on the content of each chapter and a number of multiple choice questions at its end.

3. In 1998, ASN agreed to create a process to develop geriatric nephrologists. Aworkshop was held to review the process and, in conjunction with the Associ-ation of Specialty Professors (ASP), a program of career development awardsfor geriatric nephrologists was initiated. One or two awards are made on acompetitive basis each year to a junior faculty nephrologist who commits todevelop a career in some aspect of geriatric nephrology. Applications are re-viewedby theASN,and successful candidates arereferredto ASP. ASPmanagesa fund provided by Atlantic Philanthropies and the Hartford Foundation andmakes the T. Franklin Williams Scholarship Award each year. The scholarshipprovides2 yr of funding forcareer development ina combination of nephrology and geriatric skills. The first scholarships were awarded in 2003, and a total of ninescholarshipswereawarded through 2008.It is anticipated that theseschol-ars will form a group that will become leaders in this area and train others toprovide age-sensitive nephrology care in the future. Several of these scholarshave contributed to the writing of the curriculum initiative discussed above.

In collaboration with various geriatric groups, our committeewilldevelop teaching tools in thediagnosisandmanagement of various geriatric entities.

The curriculum will be available at the ASN s website. We areconfident that it will strengthen the teaching of geriatric nephrol-ogynot only intheUnitedStatesbutalsothroughouttheworld. Anumberofcolleagues fromothercountries havealreadyexpressedgreat interest suggesting that, at last, geriatric nephrology hascome of age. We look forward to its rapid growth.

Table 1. Geriatric Nephrology Curriculum CommitteeMembers (in alphabetical order)Abrass, Christine O’Hare, AnnAbdel-Rahman, Emaad Oliver, MatthewCampbell, Kellie Oreopoulos, DimitriosDanziger, John Owens, Suzan

Dubeau, Catherine Patel, Sanjeevkumar Dubose, Tom Quinn, RobertFeinfeld, Don Reckelhoff, JaneFerrucci, Luigi Rosner, MitchellFriedman, Eli Sands, Jeff Gambert, Steven Schlanger, LynnHartman, Erica Shim, RosemareHollander, Jay Singh, HarmeetJassal, Vanita Stankus, NicoleKuchel, George Striker, GaryKujubu, Dean Swartz, RichardLeinau, Lisa Swidler, MarkMehta, Manisha Juthani Tamura, ManjuMichelis, Michael Unruh, MarkMiller, Myron Vijil, JulioMiyawaki, Bill Wiggins, JocelynMohamed, Maha Williams, MarkMorley, John Winkelmayer, WolfgangMunikrishnappa, Devraj Wright, Seth

Table 2. Geriatric Nephrology Curriculum chaptersTable of Contents Author(s)

Geriatric Nephrology Has Come of Age: At Last Dimitrios Oreopoulos and Jocelyn WigginsWhy Do We Need a Geriatric Nephrology Curriculum? Jocelyn Wiggins and Dimitrios OreopoulosThe Coming Pandemic of Chronic Kidney Disease/ESKD and the Aging

PopulationJocelyn Wiggins and Sanjeet Kumar Patel

Kidney Senescence Lynn Schlanger Rate of Decline in eGFR and Clinical Evaluation of the Elderly With a Low eGFR Ann O’Hare and Rose ShimLimitations of Various Formulae and Other Ways of Assessing GFR in the Elderly:

Is There a Role for Cystatin C?Devraj Munikrishnappa

Decline of Renal Function in Normal Aging, Role of Oxidants/Inflammation: WhenDoes It Begin, Is It Inevitable, Preventable, Treatable?

Helen Vlassara, Luigi Ferrucci, James Post andGary Striker

Diabetic CKD in the Elderly Mark WilliamsDrug Dosing and Renal Toxicity in Elderly Patients William BennettGlomerular Disease in the Elderly Christine AbrassHypertension, Chronic Kidney Disease, and the Elderly Ann O’HareCardiovascular Disease in the Elderly With Kidney Disease Wolfgang Winkelmayer Vascular Disease in the Elderly Nobuyuki Miyawaki and Paula Lester Bone Disease and Calcium Abnormalities in the Elderly With CKD Harmeet SinghAnemia in the Geriatric Population With CKD Julio VijilDisorders of Serum Sodium Concentration in the Elderly Michael MichelisFluid Balance Disorders in the Elderly Myron Miller Acute Kidney Injury in the Elderly Mitchell Rosner Nocturia in the Elderly Persons and Nocturnal Polyuria Dean KujubuHemodialysis in the Elderly Seth Wright Vascular Access for Hemodialysis in the Elderly Seth Wright and John Danziger Peritoneal Dialysis in the Elderly Seth Wright and John Danziger Assisted Home Dialysis in the Elderly Matthew Oliver and Robert Quinn

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Table 2. ContinuedTable of Contents Author(s)

Renal Transplantation in the Older Adult Erica HartmanInteraction of Dialysis Teams With Geriatricians Nicole Stankus and Kellie CampbellComprehensive Geriatric Assessment: A Multidimensional Process Designed to

Assess an Elderly Person’s Functional Ability, Physical Health, Cognitive andMental Health, and Socio-Environmental Situation

Stephen Gambert

Rehabilitation Services for Elderly Dialysis Patients Vanita JassalIntegrated Care of the Elderly With ESRD Jocelyn WigginsNutrition and the Kidney in the Elderly Patient John MorleyUrinary Incontinence in the Elderly George Kuchel and Catherine DuBeauLower Urinary Tract Conditions in the Elderly Population Damon Dyche and Jay Hollander Urinary Tract Infections in Elderly Persons Manisha Juthani-MehtaFalls in Elderly Patients With Kidney Disease John MorleyAssociation Between CKD and Frailty and Prevention of Functional Losses Emaad Abdel-RahmanMethods to Assess Quality of Life and Functional Status and Their Applications in

Clinical CareTara Chang and Manjula Tamura

Recognizing Delirium, Dementia, and Depression Manjula TamuraDialysis Decisions in the Elderly Patient With Advanced CKD and the Role of

Nondialytic therapy

Mark Swidler

End of Life and Decision-Making in Elderly Patients With ESRD Richard Swartz and Erica Perry

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Chapter 2: Why Do We Need a Geriatric NephrologyCurriculum?Jocelyn Wiggins

University of Michigan, Ann Arbor, Michigan

In 2005, ACGME (Accreditation Council for Grad-uate Medical Education) issued the following state-ment with respect to nephrology fellowship train-ing:

“Fellows must have formal instruction, clinicalexperience and demonstrate competence in theprevention, evaluation and management of geriat-ricaspects of nephrology, includingdisordersof theaging kidney and urinary tract.” In addition, theACGME mandated that “fellows must receive for-mal instruction in geriatric medicine, includingphysiology and pathology of the aging kidney; anddrug dosing and renal toxicity in the elderly pa-tient.”

The following curriculum is an attempt to fulfillthis mandate and prepare the next generation of

nephrologists for the comprehensive care of theolder population with kidney disease.

The over 65 population in the United States israpidly growing. During the next 20 yr, it is ex-pected to double (Figure 1).This means that duringthe professional lives of current fellows, they canexpect to see an increasing number of older patientsin their practice. Average life expectancy in 2004was 75.2yr for men and 80.4yr for women;by 2015,it is expected to be 76.2 and 82.2 yr, respectively,and to continue growing. During the 1990s, theover 85-yr-old population was the fastest growing

group at 38% growth. This older age group is thelargest consumer of healthcare services. In 2005,only 5% of the over 75-yr population had no healthvisits, whereas fully 30% of those with 10 or morevisits were in this age group, although they consti-tute 10% of the population. 1

Why should the aging of the population impactnephrologists? There are currently about 35 millionpeople over 65 yr of age in the United States. Forty percentof this population has some level of disabil-ity: sensory, physical, mental, or self-care. 1 Once aseniordevelops disability, it greatly impacts on their

ability to follow a complex medical regimen. Pa-

tients with chronic kidney disease (CKD) usually require complicated medication routines, complex dietary restrictions, and frequent medical visits.Many patients in this age group have lost the ability to administer their own pills, to buy and cook theirown groceries, or to drive themselves to office visitsor dialysis units. Many patients, particularly in thediabetic population, have difficulties with basicmobility. It is essential that the nephrologist be fa-miliar with and able to perform routine functionalassessments of their older patients. This includesevaluating cognitive, affective, functional, social,economic, and environmental status. This enablesthemtocustomize a regimen ordirect the patienttoa living environment where such supportive care isavailable. In a busy practice, some aspects of this

assessment can be allocated to other providers suchas social workers, nurses, nurse practitioners, orphysician assistants. The management of those el-derly who require chronic dialysis is even morecomplex. They frequentlyhave more difficulty withvascular access; they have more cardiovascular dis-ease that leads to arrhythmias and hypotensionwhile on dialysis. Furthermore, traveling to andfrom the unit is a greater burden to them. Furtherimprovements in assisteddialysis athome willallow themto enjoy the benefits of treatment athome andis an area that needs further exploration.

Patients in this older age group are likely to havemultiple comorbidities. The average 75 yr old suf-fers from 3.5 chronic diseases. 1 Many symptoms inolder patients are caused by multiple deficits andnot by a single disease. These diseases and theirtreatments are likely to interact and complicate oneanother. Murray 2 has reported that up to 70% of dialysis patients 55 yr of age and older have chronic

Correspondence: Jocelyn Wiggins, University of Michigan, 1150W. Medical Center Drive, 1560 MSRB II, Ann Arbor, MI 48109.E-mail: [email protected]




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cognitive impairment of a level severe enough to impact on theircompliance andability to make informeddecisions. 3,4 Prevalenceof depression is reported to beas high as 45% in the older dialysispopulation. 5–7 Metabolic bone disease is complicated by age-re-lated osteoporosis. The cardiovascular consequences of CKD are

complicated by structural heart disease such as valvular insuffi-ciency and atrial fibrillation. Neurodegenerative disease impactson the patient’s mobility and cognitive function. Osteoarthritisand neuropathy limit their physical activity. As age and diseaseadvance, frailty becomes an issue. All of these things combine tomake their care much more complex than that of a younger pa-tient. Druginteractionsand inappropriate dosing becomesan in-creasing issue as the number of comorbidities and medicationsincreases (Table 1).

In 1992, Nespor and Holley 8 did a small study of in-centerhemodialysis patients in Pittsburgh. Eighty percent of thesepatients did not have a family physician and relied on their

nephrologist for all of their medical care. Ninety-one percentsought treatment from their nephrologist for minor acute ill-ness. Nephrologists werealsoproviding ongoing treatment forcomorbid chronic illnesses such as diabetes and heart disease.In 1993, they went on to confirm similar statistics in theirchronic peritoneal dialysis patients. 9 This would suggest thatthe nephrologist needs to be prepared to take on the full com-plexity of care for their older patients, particularly theirchronic dialysis population. In older patients, this would in-clude health maintenance screening and immunizations. Al-though malignancies are more common in both the dialysispopulation and in the posttransplantation population than in

the general population, life expectancy, age, and cost effective-ness need to be considered by the nephrologists before order-ing screening tests.

Patients with possible CKD are being referred to nephrolo-gists in greater numbers since the introduction of formulae forestimating GFR. Most clinical laboratories supply an eGFR when a serum creatinine is ordered. NHANES data estimatesthat approximately 11% of the US population has CKD, andthis may be as high as 30% in the older population. 10 A recentAustralian study showed that monthly referrals overall in-creased by 40% after the introduction of eGFR reporting, andthis was most marked for the tertiary renal service (52% abovebaseline). 11 Patients referred after the introduction of eGFR

were significantly more likely to be older (median, 63.2 versus59.3 yr; P 0.05),because serum creatinine is a poor predictorof renal function in the elderly. GFR declines with age in nor-

mal individuals; therefore, it canbe difficult to distinguish age-related decrease in GFR from CKD in the elderly. Older pa-tients with mild decreased GFR and low risk for progressivedecline in GFR need to be distinguished from those with pro-gressive disease, because once identified, they probably do notneed to be followed by a nephrologist.

In conclusion, older patients will make up a growing pro-portion of the nephrologist’s practice. Thus, nephrologistsneed to become comfortable with shouldering the full care of this segment of their patient population or work closely with ageriatrician and family physicians. As we become more willingto offer life-prolonging technologies in the older age groups,

we need to be willing to deal with the consequences of thisdecision. Finally, with their elderly patients, nephrologists facechallenging ethical problems, such as whether to withhold orwithdraw dialysis. Unless addressed promptly and effectively,these ethical issues will greatly increase the stress on both thehealthcare provider and family members.

TAKE HOME POINTS• A knowledge of geriatric medicine is required by ACGME for training in

nephrology• The population over 65 yr of age will double in the next 20 yr• This older population will bring their problems with them to the neph-

rologists• Dialysis patients rely on their nephrologists for most or all of their care

DISCLOSURESNone.

REFERENCES

*Key References1. US Census Bureau: www.census.gov/2. Murray AM: Cognitive impairment in the aging dialysis and chronic

Number of Persons over 65 in Milli ons

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Table 1. Common geriatric conditions that impact onnephrology care

Visual impairmentHearing impairmentMalnutrition/weight lossUrinary incontinence

Balance/gait impairment/fallsPolypharmacyCognitive impairmentAffective disordersFunctional limitationsLack of social supportEconomic hardshipHome environment/safety



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kidney disease populations: an occult burden. Adv Chronic Kidney Disease 15: 123–132, 2008

3. Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, LiS, Smith GE, Hochhalter AK, Collins AJ, Kane RL: Cognitive impair-ment in hemodialysis patients is common. Neurology 67: 216–223,2006*

4. Madero M, Gul A, Sarnak MJ: Cognitive function in chronic kidney

disease. Semin Dial 21: 29–37, 20085. Kimmel PL: Depression in patients with chronic renal disease: whatwe know and what we need to know. J Psychosom Res 53: 951–956,2002

6. Watnick S, Kirwin P, Mahnensmith R, Concato J: The prevalence andtreatment of depression among patients starting dialysis. Am J Kidney Dis 41: 105–110, 2003*

7. Kimmel PL, Cohen SD, Peterson RA: Depression in patients with

chronic renal disease: where are we going? J Ren Nutr 18: 99–103,2008

8. Nespor SL, Holley JL: Patients on hemodialysis rely on nephrologistsand dialysis units for maintenance health care. ASAIO J 38: M279–M281, 1992*

9. Holley JL, Nespor SL: Nephrologist-directed primary health care inchronic dialysis patients. Am J Kidney Dis 21: 628–631, 1993*

10. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult USpopulation: Third National health and Nutrition Examination Survey.Am J Kidney Dis 41: 1–12, 2003*

11. Noble E, Johnson DW, Gray N, Hollett P, Hawley CM, Campbell SB,Mudge DW, Isbel NM: The impact of automated eGFR reporting andeducation on nephrology service referrals. Nephrol Dial Transplant 23:3845–3850, 2008



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REVIEW QUESTIONS: WHY DO WE NEED AGERIATRIC NEPHROLOGY CURRICULUM?

1. The 85-yr-old population is growing at what rate per year?a. 10%b. 45%

c. 25%d. 38%

2. The average 75-yr-old suffers from how many chronic dis-eases?a. 0b. 5c. 3.5d. 10e. 2

3. The prevalence of depression in the dialysis population isa. 5%b. 25%c. 33%d. 45%e. 80%

4. What percent of dialysis patients receive all their medical carefrom their nephologist?a. 10%b. 20%c. 30%d. 50%e. 80%



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Chapter 3: The Coming Pandemic of CKD/ESKD andthe Aging PopulationJocelyn Wiggins and Sanjeevkumar Patel

University of Michigan, Ann Arbor, Michigan

In chapter 1, data were presented about the growthof the older US population and their special needs.In this chapter, we will discuss the epidemiology of the elderly patients with chronic kidney disease

(CKD) and end-stage kidney disease (ESKD).

CHRONIC KIDNEY DISEASE

There is much debate in the literature aboutwhether the incidence of CKD is actually increas-ing or whether we are measuring changes in theway we detect and define CKD. In 1998, a reportusing NHANES data estimated the prevalence of CKD as about 11% in the US adult population. 1

This estimate was based on routine creatinine

measurements in a subset of the study popula-tion. Since that data were published, several de-velopments have altered the way we define CKD.The Modification of Diet in Renal Disease(MDRD) formula was developed and validated. 2

The National Kidney Foundation created a panelof experts, who redefined how CKD was classifiedand staged. 3 There has been a change in way cre-atinine is measured. Automated reporting of eGFR based on MDRD formula was initiated inmost clinical laboratories across the country.These changes resulted in an apparent “pan-

demic” of CKD. A study from an academic de-partment in Australia tracked the level of ne-phrology referrals after the implementation of automated eGFR reporting. 4 General referrals in-creased by 40%, whereas referrals to the tertiary renal service were 52% above baseline. The pa-tients newly referred were significantly older:63.2 versus 59.3 yr. However, the quality of thereferrals declined with as many as 35% being in-appropriate. It seems likely with the increases inthe incidence of diabetes, vascular disease, andthe general aging of the population that the true

prevalence of CKD has increased, but it is very

hard to get an accurate measure of the extent of the increase. 5,6 Coresh et al.7 have estimated thatthe overall prevalence of CKD has increased from10 to 13% of the US adult population since 1988.

Because 50% of patients in the United States startdialysis with no previous nephrology care, over-referral is probably preferable to underreferral. 8

Another contentious area of debate is thedeclineof renal function with age. It is generally acceptedthat renal function declines about 1 ml/min per year after the fourth decade of life, even in the ab-sence of comorbidities such as diabetes and hyper-tension. Many nephrologists regard this as “normalaging” and do not feel that this constitutes a reasonfor referral. It is certainly true that only a very smallfraction of these older patients will progress to end

stage or die from renal failure. It is likely that they are at greater risk from vascular disease becausethere is a very robust association betweendecline inGFR and vascular deaths. 9

So, which older patients should the busy neph-rologists follow and which should be returned tothe care of their primary care physician after an ini-tial evaluation? Clearlysigns of ongoing active renaldisease such as an active urine sediment or signifi-cant proteinuria are reason for a nephrologist’scare. eGFR values between 45 and 59 ml/min per1.73 m2 in those 70 yr of age and older should beinterpreted with caution. If other signs of kidney damage ( e.g., proteinuria, hematuria) are notpresent, a stable eGFR in this range may be consis-tent with typical GFR for this age and an absence of CKD-related complications. Patients showing thecomplications of decreased renal function such asanemia, phosphorous retention, and hyperkalemianeed nephrology management.

Correspondence: Jocelyn Wiggins, University of Michigan, 1150W. Medical Center Drive, 1560 MSRB II, Ann Arbor, MI 48109.E-mail: [email protected]




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END-STAGE KIDNEY DISEASE

Because Medicare mandates that all US dialysis units receivingMedicarecompensationreportclinicaldata to theUS Renal DataSystem (USRDS), information on patients reaching ESKD ismuch more robust than the data on CKD. The data for thesepatients were all taken from the USRDS 2007 annual report. 10

Data collected by USRDS show that ESKD is a disease of theolder population, with numbers starting to rise significantly after the age of 50. Mean age at the start of renal replacementtherapy is62.3yr for men and 63.4yr for women.Peakincidentcounts of treated ESKD occur in the 70- to 79-yr age group at

15,000 patients per year. Peak incident rates of treated ESKD

occur in the 70- to 79-yr-old age group at 1543 per millionpopulation (Figure 1).

This probably reflects both a real increase in the rates of patients reaching ESKD and an increase in the willingness tooffer dialysis, regardless of age or comorbidity. The data show a drop off after79 yr of age. This probably reflects the tendency of older patients, with significant burden of disease refusing

dialysis. The incident rates have been rising steadily over thelast 25 yr (Figure 2), with a narrowing gap between rates in the70- to 79-yr-old age group compared with the 80 -yr agegroup. These data reflect numbers of patients who have sur-vived at least 90 d on dialysis and do not include those who getacute dialysis in the hospital and do not progress to chronicmaintenance dialysis because of recovery or death.

Rates of morbidity and mortality are higher in the ESKDpopulation than in the general Medicare population. Hospitaladmission rates are particularly high in the oldest patients,with cardiovascular disease being by far the most commoncause for hospitalization. Patient admission rates increase lin-early with age. A 20-yr-old patient with ESKD spends an aver-

age of9 d per patient year inthe hospital compared with 15.5 dfor patients over 70 yr of age. Older patients also carry signifi-cant burden of disability. Overall, 10% carry a diagnosis of dementia, and this rises to 21% among those over 80 yr of age.This is almost certainly an underestimate because dementia isoften undiagnosed. As many as 20% of older patients withESKD have had a stroke that limits their mobility. These co-

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morbidities impact significantly on a patient’s ability to man-age a complex medical regimen.

In addition to the significant burden of comorbidity, all-cause mortality is six times higher in the ESKD populationthan in the general Medicare population. When discussing di-alysis, patients and families need to understand that, althoughrenal replacement therapy does prolong life, life expectancy isvery limited in the older population. Average 1-yr survival fora 70 to 79 yr old is 70%, and for an 80 yr old is 60%. By 2 yr,survival drops to 52.7 and 39.7%, respectively (Figure 3).

CKD and ESKD are huge financial burdens to our medical

system. In2005, Medicare costs for CKD were $42 billion and forESKD were $20 billion. The cost of ESKD was one half that of CKD, althoughonly a very smallpercentageofpatientswith CKDprogress toESKD.According toNHANESdata, about11%oftheUS population has CKD, whereas 0.2% of the US populationhasESKD.Despite this lowprevalence,ESKD wasresponsiblefor6.4% of the entire Medicare budget. The annual per person costfor dialysis alone exceeded $65,000 in 2005. If all medical care isincluded, this figure is even higher. For the 70- to 79-yr-old agegroup, theperpersonannualcost ofdialysis ismore than $69,000andin the 80 -yr group is more than $74,000.

In conclusion, CKD and ESKD are diseases of the elderly. Theincidence andprevalence of these conditions are rising, especially inthe older age groups. Progressing to ESKD carries a significant bur-den of comorbidities and clearly shortens life expectancy. TreatingpatientsforESKDisevenmoreexpensiveintheolderagegroupsthanfor younger patients. Preventing progression of CKD should be anurgentpriority forevery nephrologist, even in theoldestpatients.

TAKE HOME POINTS• eGFR declines with age but does not necessarily indicate clinically

significant CKD• Peak incidence of treated ESKD is in the 70- to 79-yr age group

• Rates of treated ESRK are increasing in all older age groups• ESKD carries a poor prognosis

DISCLOSURESNone.

REFERENCES

*Key References1. Jones CA, McQuillan GM, Kusek JW, Eberhardt MS, Herman WH,

Coresh J, Salive M, Jones CP, Agodoa LY: Serum creatinine levels inthe US population: Third National Health and Nutrition ExaminationSurvey. Am J Kidney Dis 32: 992–999, 1998*

2. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A moreaccurate method to estimate glomerular filtration rate from serumcreatinine: a new prediction equation. Modification of Diet in RenalDisease Study Group. Ann Intern Med 130: 461–470, 1999

3. Anonymous: K/DOQI clinical practice guidelines for chronic kidneydisease: evaluation, classification, and stratification. Kidney DiseaseQuality Initiative. Am J Kidney Disease 39: S1–S246, 2002

4. NobleE, Johnson DW,Gray N,Hollett P,Hawley CM,Campbell SB, MudgeDW, Isbel NM: The impact of automated eGFR reporting andeducation onnephrology service referrals. Nephrol Dial Transplant 23: 3845–3850, 2008

5. Glassock RJ, Winearls C: The Global Burden of Kidney Disease: Howvalid are the estimates? Nephron 110: c39–c47, 2008

6. Coresh J, Stevens LA, Levey AS: Chronic kidney disease is common:what do we do next? Nephrol Dial Transplant 23: 1122–1125, 2008

7. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, VanLente F, Levey AS: Prevalence of chronic kidney disease in the USduring 1988–1994 and 1999–2004. JAMA 298: 2038–2047, 2007*

8. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ: Prevalence of andfactors associated with suboptimal care beforeinitiation of dialysisin the United States. J Am Soc Nephrol 10: 1793–1800, 1999

9. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS,Sarnak MJ: Inflammation and cardiovascular events in individuals withand without chronic kidney disease. Kidney Int. 73: 1406–1412, 2008

10. US Renal Data System: USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States . Bethesda, MD, National Institutes of Health, National Instituteof Diabetes and Digestive and Kidney Diseases, 2007*

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b a

b i l i t y o

f s u r v

i v a

l

1 yr

2 yr

Figure 3. Survival probabilities for patientson dialysis: year 1 in blue and year 2 in red.Data shown for patients across the life span.All age groups show lower survival on dialysisthan age-matched controls with normal renalfunction. Data from USRDS annual report2007.



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REVIEW QUESTIONS: THE COMING PANDEMIC OFCKD/ESKD AND THE AGING POPULATION

1. The current prevalence of CKD in the US population isa. 1 to 5%b. 10 to 15%c. 20 to 25%d. 30 to 35%e. None of the above

2. Thepeak incidence of treated ESKD falls in which of followingage ranges?a. 50 to 59 yrb. 60 to 64 yrc. 65 to 69 yrd. 70 to 79 yre. 80 yr

3. A 70-yr-old dialysis patient will spend, on average, how many days per year in the hospital?

a. 2.5 db. 6.1 dc. 8.3 d

d. 15.5 de. 21.7 d

4. Compared with the general Medicare population, mortality inpatients with ESKD is how many fold higher?

a. 2-foldb. 6-foldc. 10-foldd. 19-fold



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Chapter 4: Kidney Senescence

Lynn Schlanger

Emory University and Veterans Affairs Medical Center at Atlanta, Atlanta, Georgia

In theUnited States, theelderly andthevery elderly population has largely exceeded that of any otherage group.1 By 1994, the population of these demo-graphic groups reached 36.5 million and has con-tinuedto increaseover thelast decade.1 Thisgrowthparallels the increasing number of elderly personsclassified with chronic kidney disease (CKD) stagesIII through V. Moreover, an estimated660,000 per-sons in theUnited Stateswill have end-stagekidney disease (ESKD) by the year 2010, with the greatestgrowthrate occurringin theelderlyandveryelderly persons.1–3 Unfortunately, understanding of thenormal biologic progression of renal disease in theelderly persons in the absence of comorbid fac-tors4 –9 or the progression of CKD is still not clearly understood.10

Cross-sectional and longitudinal studies havelookedat thenatural progressionof thekidney withaging.4,7,8,11 A linear relationshipbetweenaging anda decline in the renal function was noted,7,8 but el-derly persons who had no underlying disease hadadequaterenal reserve.12–14 TheBaltimore Longitu-dinal study (BLS) from 1958 until 1981 studied acohort of individuals for 8 or more yr who had aleast five 24-h urine collections for creatinine clear-ance.7,8 There were three groups: group 1, CKD;group 2, on anti-hypertension medications; group3, healthy patients. The overall rate of decline increatinine clearance was 0.87 ml/min per year be-ginning at age 40 and was inversely related to age.7,8

A rise in mean arterial pressure 107 mmHg waspositively correlated with a decline in renal func-tion.7 Interestingly, in the BLS, one third of the el-derly population had no decrease in renal functionas measured by creatinine clearance, and a smallsegment actually had improvement in their renalfunction.8

Inhumansand some animals,14,15 thenumberof glomeruli present in adulthood are predeterminedbetween weeks 32 and 36 of gestation,14,16 whereasthe number of glomeruli continue to increase inrats and mice after gestation.15 In humans, the su-

perficial cortex glomeruli differ in size from the

juxta-arcuateglomeruliuntil age 2. At this time, thesize of all of the glomeruli are the same, and thekidney is functioning at adult capacity.17 The num-ber of glomeruli among individuals is quite vari-able, ranging from 247,652 to 1,825,380perkidney,and decreases with age14,18 at a rate of approxi-mately 6752 glomeruli/yr after the age of 18.14

Renal mass increases from 50 g at birth to400g during the third and fourth decades of life beforedecreasing to 300 g by the ninth decade.5,13,14,18,19The latter decrease correlates with the loss of therenal cortex. Radiographically, the size of the kid-ney has been shown to decrease in size by 10%afterage 40 to 30% by age 80.20–23 Using the Xenonwashout technique, Hollenberg et al. 22 noted that adecrease in the size of the kidney correlated with adecrease in function and in the renal blood flow tothe cortex.22

HISTOLOGY

The histologic changes with aging observed in hu-mans have been obtained from information fromautopsies or nephrectomies14,19,23–26 or studies in-volving laboratory animals.27,28 With aging, therearecertainuniversalfindingsinthecortex,medulla,and, in most cases, in the interstitium and vessels(Table 1; Figure 1). These histologic changes corre-late with functional changes observed with aging,

including an inability to concentrate or dilute theurine, an increased propensity toward salt reten-tion, dehydration, and acute kidney injury.

GlomerulusWith aging, hyaline expansion within the mesan-gium results in the obliteration of the glomerular

Correspondence: Lynn Schlanger, Assistant Professor, EmoryUniversity and Veterans Affairs Medical Center at Atlanta, Atlanta,GA 30033. Phone: 404-727-2525; Fax: 404-727-3425; E-mail:[email protected]




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loops28,29 and is associated with capillary tuft collapse, intra-capsular fibrosis, and proteinuria.14 The sclerosis in the glo-meruliis primarily in thesuperficialcortex with sparsechangesin medulla.14,16,19 Cortical atrophy and loss of the renal paren-chyma result.18 One hundred forty-six cadaveric kidneys frommedical examiner offices and autopsies from hospital patientsshowed an increase in cortical glomerulosclerosis with agefrom5%atage 40 to 10% bythe eighth decade.30 The degreeof sclerosis was found to correlate with the degree of atheroscle-rosis, suggesting a hemodynamic role in the aging process.31The remaining glomeruli are enlarged to compensate for thedecrease in number of functioning cortex glomeruli.12,18,19,32,33Electron scans showed podocyte injury with features that in-cluding hypertrophy, intracellular uptake of protein/absorp-tive droplets, foot process fusion, and detachment of thepodo-cytes from the glomerular basement membranes (GBMs).29,34

Glomerular Basement MembraneThe GBM increases in width with age.27,29,35 In Sprague-Daw-ley rats, the GBM increased insizefrom1300 Å atbirth to4800Å at 24 mo.29 In humans, the basement membrane increasesuntil age 40, and after age 60, the surface area decreases withwrinkling of the basement membrane with deposition of hya-

line.29 The composition of the basement membrane alsochanges with aging.36,37 In older rats, the amino acid composi-tion shifts to a more collagen-like material marked by an in-crease in hydroxylysine, hydroxyproline, and glycine, andmore insoluble amino acids with higher content of low molec-

ular weight proteins.37 These findings differ in the humanGBM, where a decrease in hydroxylysine, 4- hydroxyproline,and glycosylation of collagen occurs with aging.26 The reasonfor these differences is not clear.

TubulointerstitiumWith aging, tubular dilation, intratubular cast formation,thickeningandsplitting of thebasementmembrane, andfibro-sis of the interstitium occurs.18,35,38 In 24-mo-old rats, scans of the interstitium showed cellular infiltrates consisting predom-inantly of macrophages and lymphocytes and an increase inintracellular adhesion molecule (ICAM)-1, osteopontin, andcollagen IV. Areas were marked by an increase of apoptosis.None of these findings were detected in the 3-mo-old pups.38After the administration of enalapril to 15-d-old CF1 mice, adecrease in the peritubular and interstitial sclerosis occurredby 18 mo of age compared with the control mice or micetreated with nifedipine.A decrease inexpressionofSM-actin, acytoskeleton protein commonly found in fibrosis and repair,was also noted in the enalapril-treated group.38

VesselsAn early angiographic study showed changes in the arteriole-

glomerulus unit with aging.24 In the arterioles, hyaline deposi-tion within the vessels walls leads to obliteration of the lumenand is associated with sclerotic glomeruli primarily in the cor-tex.22,24,31 Twostructural typesassociated with theafferent andefferentarterioles havebeendescribed.24 In thefirst case,oblit-

Table 1. Histologic change in the aging kidneySite Changes

Glomerulus Thickening basement membrane, increase mesangial matrix, focal global sclerosis, hypertrophyPodocytes Fusion intermittent, detachment, vacuolesInterstituim Tubular atrophy, tubular cast, monocytes infiltrates, interstitial fibrosis Vessels Atrophy of afferent and efferent, hyalinosis of vessels, aglomeruls vessels

Lumen obliterationHyaline deposits in arterioles

Glomerulosclerosis in cortex

RFB

RBF

“ Aglomerular” arteriolesHypertrophy of glomeruli in

FF

Peritubular capillary atrophy Tubulointerstitial fibrosis

RBF

Decrease diluting and concentrating capacity

Figure 1. Histologic changes in the agingkidney. There is a decrease in the renal bloodflow from hyaline deposition and obliteration

of the arterioles resulting in glomerular changes such as wrinkling of the loops andnoted hyaline deposition in the mesangium.The loss of these glomeruli is primarily in thecortex resulting in hypertrophy of the remain-ing glomeruli. In the medulla, the arteriolesform “ aglomerular “ arterioles that results inthe shunting of blood to the medulla and anincrease in filtration fraction in the medullaglomeruli. The tubulointerstituim in teh areaof glomerulosclerosis develop fibrosis, tubu-lar atrophy with tubular casts, and inflamma-tory cell infiltrates, and increase of peritubular capillary atrophy.

2 Geriatric Nephrology Curriculum American Society of Nephrology


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eration of efferent and afferent arterioles is associated withglomerular sclerosis, whereas in the second case, a continuouschannel between theafferent and efferent arterioles results in asclerotic glomeruli, is called an “aglomerulus “ arteriole, andshunts the blood to the medullary area.19,23,24 The small arter-ies show some elastic duplication, fibrous intimal thickening,destructive changes in themedia,narrowing of the lumen, andlamination.24,29 The blood vessel changes play a major role inrenal damage, compromising renal blood flow with subse-quent loss of renal mass.9,30

TubulesWithaging,thelengthoftheproximalconvolutingtubule,thesizeof theproximaltubularepithelial cell, and thesizeof itsrespectivenucleusdecreaseinparallelwiththedecreaseinsizeoftheglomer-ulus.12,15,23,33 Electronmicrographsof rat tubules showednon-uniform thickening of the tubular basement membrane withvacuoles in the proximal tubules, with intermittent loss of the

microvilli,28

whereas the distal tubules are dilated with diver-ticular formation.28 Similar changes in theelderly mayaccountfor an increased incidence of urinary tract infections.8

FUNCTIONAL CHANGES

With aging, renal blood flow decreases in both human andanimal populations13,19,22,27 (Table 2). Fliser et al. 13 observed amarkeddecreaseof about 10%perdecadein theeffective renalperfusion in healthy elderly volunteers compared with younger adults, with renal perfusion decreasing from 647 ml/

min per 1.73 m2

in younger volunteers to 339 ml/min per 1.73m2 in elderly volunteers. The lower renal plasma blood flow and the decrease in GFR contribute to the increase in the fil-tration fraction found in the elderly persons. The decrease inrenal blood flow may result from an imbalance and alterationsin the responsiveness to vasoactive substances, i.e., acetylcho-line,22,39 or decrease in production of certain peptides withaging.13,22,40 Hollengeret al. 22 performed Xenon washout stud-iesto evaluatepotential transplantdonorsin ages ranging from17 to 76 yr old and found a significant decrease in renal perfu-sion with aging that was associated with a reduction in corticalflow rate and kidney mass. He noted that the vasodilator re-

sponseto acetylcholine wasbluntedin theelderlybutfoundnodifference in the vasoconstrictor response to angiotensin.22 Inolder rats, the vasodilator response to nitric oxide and the en-dothelial-derived hyperpolarizing factor pathways are attenu-ated.39 This suggests the elderly may be more susceptible to

acute kidney injury in a low perfusion state because of attenu-ated responses to vasodilators and an increase in response tovasoconstrictors.5,22,39

The “functional reserve “of the kidney is defined as theacute rise in GFR that occurs after an infusion of amino ac-ids.13,41 A lack of a rise in GFR with infusion of amino acid inelderly persons with underlying renaldisease mayindicate thatthe kidney is working at maximal capacity and unable to re-cruit additional nephrons in response to the increase in thefiltered load. However, the ability of the kidney to compensateunder stress may be limited in elderly persons. Fliser et al. 13found the functional reserve in healthy older volunteers to bearound 15%, and this functional reserve was maintained untilage 80 in both men and women. This rise in the functionalreserve was notaccompaniedwitha rise ineffectiverenal bloodflow (ERBF) or a significant decrease in renal vascular resis-tance. This suggests that the increase in the renal reserve is notrelated to vasodilatation in elderly persons as was commonly

found in younger adults.

Tubular functionElderly persons arenotable to diluteorconcentrate theirurineas well as younger healthy adults. This may stem from a com-bination of interstitial damage, end organ resistance, or a de-crease in production of various hormones.42–44 As a conse-quence, elderly persons are more prone to water disorders andvolume depletion than the general population. The dysnatre-mias are the most common electrolyte disorders recordedamong elderly persons admitted to the hospital and are asso-ciated with high morbidity and mortality.45 In older female

WAG/Rij rats, aquaporin (AQP)-2 and -3 are downregulatedcompared with in 3-mo-old rats. This correlated with labora-tory findingsbetween the twoagegroups. Therewasa decreasein the urine output in older rats compared with younger rats(3.9 0.3 versus 12.8 0.8 ml in 24 h). Older rats also had alower urine osmolality compared with younger rats (1042 ver-sus 2511 54 mosmol/kg).44 Moreover, there was no changein the expression of AQP-1 in the proximal convoluting tu-bules and descending loop of Henle’s or in AQP-4 in the baso-lateral membrane in the collecting tubules.44 These finding areconsistent with a decreased ability to concentrate urine in theelderly with normal levels of circulating vasopressin. This

could result in decreased insertion of apical AQP-2 into theapical membrane and an inability to concentrate urine.Thelevelsofserumrenin,reninactivity,andaldosterone42,43,46

are low in elderly persons, and their response in a hypovolemicstate is also blunted.12,44,47 Similarly, Sprague-Dawley adult ratswere found to have a downregulation of intrarenal mRNA reninand a blunted release of the serum renin in response to hypo-tension compared with the younger rats.46

Despite a mild decline in renal function, elderly persons arecapable of secretinganacid load when placedona 70-g proteindiet and maintain normal serum bicarbonate levels and anappropriate urine pH.48 Although the serum aldosterone levelis decreased in theelderly, healthy elderly volunteers and those

Table 2. Functional changes in the aging kidneyDecrease renal blood flow by 10%/yr after age 40GFR decrease by 0.87 ml/min per year Increase in RVRDecrease diluting capacityDecrease concentrating capacityNormal renal reserve



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with CKD are able to excrete potassium to maintain normalserum potassium.49

MECHANISM FOR AGING

The biologic mechanisms for aging are still unknown. Variouspossible mechanisms for aging have been touted and includedrecruitment of senescence genes, changes in hormones relatedto gender,27,28,50 replicative senescence,51 damage caused by anunrestricteddiet,52 andchanges inoxidative stress53 (Figure2).The cell cycle regulator gene regulator, p16INK4a , a cyclin-de-pendent kinase inhibitor, and a possible senescence gene can-didate are found in the kidney of rats, mice, and humans.54 Inthe aging human kidney, there is an increase in p16 INK4amRNA expression in the cortex.54 In vitro experiments in theaginghumankidney suggestedothergenecandidates. Increaseexpression of p16INK4a and p53 was found in the sclerotic glo-

meruli areas, whereas p16INK4a

, p53

, cyclooxygenase-1 (COX-1), transforming growth factor (TGF)-, and heat shock pro-tein A5 (HSPA5) were found in the interstitium.54

Knockout mice or transgenic animals have been created toevaluate thecorrelationbetween certain proteinsandaging. Intransgenic male rats, the antisense growth hormone (GH)showed a suppression of the expression of GH/insulin-likegrowth factor-1 (IGF-1) activity.55 The suppression of this ac-tivity prevented histologic changes normally seen in the agingrat kidney. Associated with the decrease activity of GH/IGF-1was a decrease in macrophage infiltrates, the extracellular ma-trix, and collagen production. The decrease activity of GH/

IGF-1 seems to be renoprotective,55

and upregulation may contribute to sclerosis found in certain disease states such asdiabetes mellitus.Another candidategene forsenescence is theSMP-30 gene, which seems to be important in anti-apoptotic

function.56 Knockout mice for the SMP-30 gene showed anincrease in mortality and increase deposition of lipofuscin inthe renal tubular epithelial cells, marked degeneration in themitochondria,podocytefusion, andan increasein apoptosis.56

Klotho is considered the anti-aging gene and has shownexpression in the kidney. The klotho mouse model (KI/KI) foraging was genetically made by transgene disruption of theklothogene locus.57 The klotho (kl/kl ) mouse exhibits manyof the phenotypic features of aging including the following: shortlifespan, growth retardation, infertility, osteoporosis, athero-sclerosis, obstructive pulmonary disease, renal sclerosis, andatrophyoftheskin.57 Histologicchangesinthekl/kl rat showedfibrosis in the renal arteries, the interstitium, and the glomer-uli, aswell ascalcification within thecortexin theoldermice.57

The imbalance between the accumulation and degradationof extracellular matrix (ECM) may play a role in fibrosis. AhomozygoteTIMP-1 transgenic micewasconstructed to study the effect of TIMP-1 on ICAM-1 and fibrosis in the aging kid-

ney.58

TIMP-1 is a tissue inhibitor of metalloproteinase(MMP), which is known to increase the degradation of ECMand ICAM-1. In the aging rat, there was an upregulation of TIMP-1 correlating with upregulation of ICAM-1 and TGF.Fibrosis seems to be promoted by the regulation of profibroticproteins and inhibition of the breakdown of ECM.58

Besides genetic programming, there seems to be a sex di-morphism in the development of glomerulosclerosis in ani-mals, with the female gender being protected until meno-pause.27,28,59 This relationship may not hold for humans. 17-estradiol seems to have many protective functions includinginhibition of apoptosis in mesangial cells, an increase in the

expression of metalloproteinase, and a decrease in collagenproduction, which would point to a beneficial effect on ag-ing.28,59 Aging female Dahl salt-sensitive rats were placed on17 -estradiol replacement therapy after undergoing ovariec-

AgingKidney

+sclerosis

GH/IGF-1TIMP-1HSP47

AndrogenspINK4ap53ROSPAI-1

COX-1TGF β

FasHSP47

+apoptosis

Klotho geneMMPEstradiol

Ace inhibitorET- inhibitor

-sclerosis

Restricted caloriesSMP-30 geneKlotho gene

-apoptosis

Figure 2. Aging kidney. A schematic outline of the various modulators that may be responsible for damage or reno-protection of theaging kidney. The restricted caloric intake has a reno-protective effect through modulating various proteins by suppressing GH/IGF-1activity, Fas, and HSP47. The upregulation of MMP, downregulation of TIMP-1 and ICAM-1, and decrease in oxidative stress results ina decrease in matrix dysregulation and inflammation. The SMP-30 and klotho genes are anti-apoptotic. The klotho gene seems to bereno-protective by decreasing sclerosis. The inhibition of ET-1 and angiotensin II are known to decrease sclerosis. Areas of fibrosis arefound to have an increase in PA1–1, COX-1, TGF- , PINK4a , and p 53 . The hormones estradiol and androgen have opposite effects onaging. 35,40,50–59



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REVIEW QUESTIONS: KIDNEY SENESCENCE

1. A 68-yr-old Caucasian male has been quite concerned afterreading inhislocalnewspaper about theincreased incidenceof chronic kidney diseases in the elderly population. He wasnever told by his primary care physician he had any kidney

problems. He made an appointment to see a nephrologist todiscuss his possible kidney disease. He presents at the clinic,and his BP is 125/70 mmHG, and there are no pertinent find-ings on his physical exam. He does not take any prescribedmedications and only vitamins. Laboratory values show a se-rum creatinine of 1.2 mg/dl. Which the following is true?a. The rate of decline in his renal function is normal for his

age groupb. He will be on renal replacement therapy by the time he

reaches 90 yr oldc. Elevated BP has no effect on his progressiond. The aging process affects all organs and all elderly people

have progression of their renal function2. Thehistologic changes in thekidneywith agearethefollowing

except

a. Glomerulosclerosis in the medulla more than the cortex b. The arterioles in the cortex become sclerosed leading to

“aglomeruli”c. There isshuntingofblood to themedullary regionsecond-

ary arteriolar structural changesd. There is thickening of the glomerular membrane and

change in composition with aging3. Community-dwelling elderly persons are able to maintain

electrolyte balance secondary to adequate residual renal re-servea. Trueb. False

4. The biologic causes of aging are unknown; however, there arecertain medical interventions that mayslow down renal loss inelderly person with normalrenal function.Thecorrect answeris which of the following?a. Controlled hypertension

b. High caloric intakec. Low protein dietd. Testesterone



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Chapter 5: Rate of Decline in eGFR and ClinicalEvaluation of the Elderly With a Low eGFRRosemarie L. Shim* and Ann M. O’Hare †

*Department of Medicine, Ohio State University, Columbus, Ohio; and † Department of Medicine, University of Washington, and VA Puget Sound Healthcare System, Seattle, Washington

AGE AND RATE OF DECLINE OF RENALFUNCTION

In cross-sectional studies, levels of renal functionare on average lower in older compared with younger participants. 1–3 However, the extent towhich this phenomenon results from an age-asso-ciateddecline in renal function versusa higherprev-alence of comorbidities linked to chronic kidney disease (CKD) in the elderly is uncertain. Relatively fewstudieshave explicitly examined ratesof declinein renal function across age groups. Most of whatwe know about longitudinal changes in renal func-tion comes from the Baltimore Longitudinal Study of Aging (BLSA).4 – 6 A subset of participants in thisstudy underwent serial creatinine clearance mea-surements over time. Observations on these pa-tients have provided some important insights intothe effect ofage on change in level of renal function.First, even in individuals without known comorbidconditions and without intrinsic renal disease orproteinuria, level of creatinine clearance declinedon average by 0.75 ml/min per year. 4 Second, renalfunction was stable and even improved in somesubjects.4 Hemmelgarn et al.7 reported a similarphenomenon among community-dwelling elderly in Canada followed over a 2-yr period (Figure 1).Thus, these reports suggest that, on average, renal

function declines with increasing age even in theabsence of comorbidity. At the same time, declinein renal function does not seem to be an inevitableconsequence of aging.

Among participants in the BLSA without CKD,the rate at which creatinine clearance declined overtimewasgreater amongolder participants. 6 Consis-tent with these results and with prior cross-sec-tionalstudies showing lower levelsof renal functionamong older people, older age seems to be a risk factor for the development of CKD, defined as anestimated GFR (eGFR) 60 ml/min per 1.73 m 2 .8

However, the relationship between age and rate of

changein eGFR seems tobesomewhatcomplex andperhaps dependent on baseline level of eGFR.Among a national cohort of veterans with an eGFR

60ml/minper1.73m2

, eGFR declined morerapidly for older than for younger patients at higher levels of eGFR (i.e., 45 ml/min per 1.73 m 2 ). However, theopposite was true at lower levels of eGFR ( i.e., 45ml/min per 1.73 m 2 ), where eGFR declined moreslowlyinolder than inyounger patients. 9 Collectively,these data seem to suggest that, although older pa-tients aremore likely to developCKD, thosewhosur-vive long enough to reach more advanced stages of CKD are actually less likely than their younger coun-terparts to experience progressive loss of eGFR.

AGE AND RISK OF PROGRESSION TO END-STAGE RENAL DISEASE

Studies of rate of change in measured or estimatedrenal function can be difficult to interpret for a va-riety of reasons: (1) progression may not occur in apredictable and linear fashion; (2) the clinical sig-nificance of changes renal function, particularly within the normal range, is uncertain; and (3) it canbe difficult to account for differences in survivaland follow-up among participants. Thus, results of studies reportingchangein levelof renal functionasan outcome are probably quite sensitive to the an-alytic approach selected. Progression to end-stagekidney disease (ESKD) often represents a moremeaningful clinical outcome than change in level of renal function. This outcome is easily defined andidentified, and the clinical significance of ESKD (de-

Correspondence: Ann M. O’Hare, MA, MD, Division of Nephrol-ogy, VA/Puget Sound Medical Center, Nephrology and RenalDialysis Unit, Building 100, Room 5B113, 1660 S. Columbian Way,Seattle, WA 98108. Phone: 206-277-3192; Fax: 206-764-2022;E-mail: [email protected]




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morbidconditions aremore likelyto impactoverall healthandquality of life, interventions to slow progression of CKDshould perhaps not be prioritized to the same extent as theseother comorbid conditions. On the other hand, if the patienthasfewcomorbid conditions andCKDis their primary clinicalproblem, a stronger focus on efforts to diagnose and manageprogressive CKD may be very appropriate, particularly if theirCKDis clearly progressive or they have risk factors forprogres-sion such as proteinuria.

CONCLUSION

Among patients with similar levels of eGFR, clinical outcomesvary substantially by age. In general, older patients are morelikely than their younger counterparts to have a low eGFR butare less likely to experience progression to ESKD. At the sametime, older patients represent the largest and fastest growingcontingent of the ESKD population. Therefore, the main chal-lenge in managing older patients with CKD is to identify thesmall proportion but large number who are most likely toprogress to ESKD and who may benefit the most from aggres-sive efforts to diagnose and treat their underlying renal disease.

TAKE HOME POINTS• A growing number and proportion of all patients initiating chronic

dialysis are 75 yr and older• Most older patients who meet criteria for CKD are much more likely to

die before they reach ESKD; this is true even for older patients withsevere reductions in eGFR

• It is often difficult to know which subset of older patients with CKD willprogress to ESKD

• Most older patients who meet the criteria for CKD have other healthconditions

• The importance of interventions to slow progression of CKD should beweighed against other, perhaps competing, health priorities

DISCLOSURESNone.

REFERENCES

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2. O’Hare AM, Bertenthal D, Covinsky KE, Landefeld CS, Sen S, Mehta K,Steinman MA, Borzecki A, Walter LC: Mortality risk stratification inchronic kidney disease: one size for all ages? J Am Soc Nephrol 17:846–853, 2006*

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P, Scharling H, Appleyard M, Jensen JS: Very low levels of microalbu-minuria are associated with increased risk of coronary heart diseaseand death independently of renal function, hypertension, and diabe-tes. Circulation 110: 32–35, 2004

18. Jager A, Kostense PJ, Ruhé HG, Heine RJ, Nijpels G, Dekker JM,Bouter LM, Stehouwer CD: Microalbuminuria and peripheral arterialdisease are independent predictors of cardiovascular and all-causemortality, especially among hypertensive subjects: five-year follow-upof the Hoorn Study. Arterioscler Thromb Vasc Biol 19: 617–624, 1999

19. Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D, De Jong PE; Prevend Study Group:Microalbuminuria is common, also in a nondiabetic, nonhypertensivepopulation, and an independent indicator of cardiovascular risk fac-tors and cardiovascular morbidity. J Intern Med 249: 519–526, 2001

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21. Arnlöv J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, Benjamin EJ,D’Agostino RB, Vasan RS: Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic

individuals: the Framingham Heart Study. Circulation 112: 969–975,200522. Ljungman S, Wikstrand J, Hartford M, Berglund G: Urinary albumin

excretion—a predictor of risk of cardiovascular disease. A prospective10-year follow-up of middle-aged nondiabetic normal and hyperten-sive men. Am J Hypertens 9: 770–778, 1996

23. Dinneen SF, Gerstein HC: The association of microalbuminuria andmortality in non-insulin-dependent diabetes mellitus. A systematicoverview of the literature. Arch Intern Med 157: 1413–1418, 1997

24. Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE: Microalbu-minuria as predictor of increased mortality in elderly people. BMJ 300:297–300, 1990

25. Agewall S, Wikstrand J, Ljungman S, Fagerberg B: Usefulness of

microalbuminuria in predicting cardiovascular mortality in treated hy-pertensive men with and without diabetes mellitus. Risk Factor Inter-vention Study Group. Am J Cardiol 80: 164–169, 1997

26. Hallan S, Astor B, Romundstad S, Aasarod K, Kvenild K, Coresh J:Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: the HUNT II study. ArchIntern Med 167: 2490–2496, 2007

27. Foster MC, Hwang SJ, Larson MG, Parikh NI, Meigs JB, Vasan RS,Wang TJ, Levy D, Fox CS: Cross-classification of microalbuminuria andreduced glomerular filtration rate: associations between cardiovascu-lar disease risk factors and clinical outcomes. Arch Intern Med 167:1386–1392, 2007

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REVIEW QUESTIONS: RATE OF DECLINE IN EGFR AND CLINICAL EVALUATION OF THE ELDERLY WITH A LOW EGFR

1. An 86-yr-old woman in good health with no comorbidities isfound to have an eGFR of 54 ml/min per 1.73 m 2 on routinetesting. Three months later, her eGFR is 55 ml/min per 1.73m 2 . Urine testing shows an albumin to creatinine ratio of 12mg/g, and her urinalysis is bland. Her primary care physicianasks you whether a renal consultation is needed. Which of thefollowing do you think is the most appropriate response to hisor her question?a. At this point, probably little to gain from renal consulta-

tion; however, would make sure all her medications areappropriately dosed and reasonable to follow serum creat-inine to make sure her eGFR does not fall markedly

b. Would recommend seeing the patient for thorough review ofpossible causesfor herchronic kidneydisease andappro-priate management

c. Would recommend checking for complications of chronickidney disease and seeing the patient at least annually innephrology for management of any complications of chronic kidney disease she might develop

d. Would recommend referral to nephrology with consider-ation for renal biopsy to identify the underlying cause of this patient’s chronic kidney disease

2. A 72-yr-old woman has aneGFRof 25 ml/minper 1.73 m 2 thathas been stable for 5 yr. Her albumin to creatinine ratio is 21mg/g and her urinalysis is bland. Her hematocrit is 35, hercalcium is 9 mEq/L, phosphorus is 4 mEq/L, and parathyroid

hormone is 120 mEq/L. Her serum potassium is 5.0 mEq/L.Every day she takes Lisinopril 40 mg, amlodopine 10 mg, lasix 40 mg, and a multivitamin. In the past, she used nonsteroidalagents heavily but discontinued these about 5 yr ago when shefound outabout herkidney disease. Which of thefollowing do you regard the most appropriate next step?a. Make sure that all her medications are appropriately dosed

and advise her to consult her pharmacist any time a new medication is started to make sure it is notnephrotoxic andis appropriately dosed

b. Discuss dialysis treatmentmodality with a view for sendingher for vascular access placement if she starts hemodialysis

c. Seeher back monthly forsurveillancefor thecomplicationsof chronic kidney disease

d. Avoid potassium-containing foods

3. An 85-yr-old man has an eGFR of 25 ml/min per 1.73 m 2 , analbumin to creatinine ratio of 9000 mg/g, hematuria with dys-

morphic red blood cells, normal complements, negativeANCA, anti-GBM, hepatitis serologies, UPEP and SPEP, andan ANA of 1:80. In the last year, his eGFR has gone from 65 to25 ml/min per 1.73 m 2 . In the past and as recently as 1 yr ago,his urinalyses showed no proteinuria on dipstick. He is feelingvery fatigued and listless compared with usual and has notbeen able to do his usual daily 3-mile walk. Which do youthink is the most appropriate next step?a. Refer the patient for a renal biopsy to identify the underly-

ing cause of his renal diseaseb. Start the patient on an ACE inhibitorc. Discuss dialysis modality and send the patient for vascular

access placement if they choose hemodialysisd. Discuss end of life issues and hospice placement given the

patient’s poor prognosis

4. A new patient comes to see you. She is a 78-yr-old nondiabeticwoman with an eGFR of 30 ml/min per 1.73 m 2 that has de-creased from 40 ml/min per 1.73 m 2 inthelast year. She has analbumin to creatinine ratio of 1000 mg/g. She is on amlodop-ine for hypertension. Her BP today is 170/80 mmHg. Shecomes into your office quite upset because she got lost on herway to clinic and actually forgot where she was. This is the firsttime this has ever happened to her. Her vital signs are other-

wise stable and her blood sugar is 110 mg/dl. What should bethe first priority for her care?a. Review her urinalysis to determine whether she needs a

biopsy b. Obtain a serologic work up to identify the cause of her

proteinuriac. Talk with herprimary care provider andreview hermedical

record to determine whether she has any underlying cog-nitive issues to determine whether she needs an acute neu-rologic evaluation

d. Start her on an ACE inhibitor



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Chapter 6: Limitations of Various Formulae and Other Ways of Assessing GFR in the Elderly: Is There a Rolefor Cystatin C?

Devraj Munikrishnappa

Department of Internal Medicine, The Nephrology Division, St. Louis University School of Medicine, St. Louis,Missouri

GFR is the best index available to assess kidney function in disease and in health in an individual. Itis 120 to 130 ml/min per 1.73 m 2 in young, healthy adults, and it decreases by about 0.8 ml/min per1.73 m2 per year after 40 yr of age. However, it isimportant to note that, in the Baltimore Longitudi-nal Study on Aging, about one third of the patientsthat were followed did not have a decrease in GFR with aging.

The GFR cannot be measured directly in an in-dividual. Therefore, it is assessed using either exog-enous markers or endogenous markers in theirsteady states as shown in Table 1.

MEASURING GFR USING EXOGENOUSMARKERS

The direct methods in the general population andin elderly persons are riddled with a number of problems (Table 1). Therefore, except in rare situ-ations such as in a prospective kidney donor withborderline GFR for eligibility, these methods arenot used in clinical practice.

METHODS OF GFR ESTIMATION USINGENDOGENOUS MARKERS

Serum Creatinine (S cr )GFR estimation based on serum creatinine alone isnot an ideal method, especially in elderly personsbecause it is influenced by a number of variablessuch as age, gender, muscle mass, diet, and medica-tions that block creatinine’s tubular secretion. Forexample, despite reductions in GFR to 60 ml/minper 1.73 m 2 , there may not be a significant increasein creatinine in the elderly persons with decreased

muscle mass. On the other hand, if the muscle mass

and diet are stable, serum creatinine could be usedfor monitoring GFR more closely. In general, achange in serum creatinine 15% is likely to indi-cate a significant fall in GFRin an individual patientrather than being caused by simplebiologic andan-alytical variations. Table 1 shows other limitationsof Scr .

Creatinine ClearanceCreatinine clearanceas measured from a 24-h urinecollectioncan beused tomeasure GFR,but it isvitalto remember the high likelihood of inaccurate col-lection, especially in some elderly people with cog-nitive impairment or the bed bound. It is impor-tant, therefore, to check for adequacy of urinary collection before interpretation of clearance. Thecollection is said to be adequate if the creatinineexcretion is 20 to 25 mg/kg per day in a younghealthy man and if it is 15 to 20 mg/kg per day in a young healthy woman. In elderly people, adequacy is similarly checked because it is assumed that themuscle mass (and hence creatinine generation) andrenal function decline simultaneously with age.Caution must, therefore, be used if this assumptioncannot be made in individual instances. If thismethod is used in the setting of acute renal failure

or rapidly changing serum creatinine, it is necessary to measure an average from simultaneous serial se-rum creatinine values during urine collection. Cre-atinine clearance systematically overestimates GFR because of tubular secretion of creatinine. The24-hurine collection for the estimation of GFR has beenshown by many studies to not be any more reliable,

Correspondence: Devraj Munikrishnappa, Department of Inter-nal Medicine, The Nephrology Division, St. Louis UniversitySchool of Medicine, 1402 South Grand, St. Louis, MO 63104.E-mail: [email protected]




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Table 1. Methods of determining GFR and their limitationsMethod of Determining GFR Limitations

Using exogenous markers: GFR can bemeasured as the urinary or plasmaclearance of an ideal filtrationmarker or of alternative exogenousmarkers

Ideal filtration marker: inulin clearance Gold standard: for GFR assessment but isdifficult to use in routine practice

Alternate exogenous markers to inulin: Expensive, less widely available and complextests

Iohexol51 Cr EDTA125 I-iothalamate, 99m Tc-DTPA

Using endogenous markers:endogenous markers, such as serumcreatinine or serum cystatin C canbe used to estimate GFR from their serum levels if they are in a steadystate. 1 The estimation equationsusing these endogenous markers

adjust to other variables in anattempt to improve accuracy of estimation of GFR from thesemarkers.

Serum creatinine (S cr ) Factors influencing Scr :

(1) Creatinine production: e.g., muscle mass,ingested cooked meat, protein restriction

(2) creatinine filtration: with age, excretiondecreases resulting in underestimation of GFR

(3) creatinine secretion:(i) because of tubular secretion, tends to

overestimate GFR by about 10%,increasing significantly as GFR declines

(ii) cimetidine, trimethoprim inhibit secretion(4) Creatinine assay:(i) Calibration bias: large variations between

laboratories in calibration of the creatinineassays may lead to differences ininterpretation of values

(ii) Factors influencing assay methods-Jaffèreaction based assays-glucose, ketones,bilirubin, cephalosporins and enzymaticmethod- flucytosine

(5) Extrarenal elimination may be increasedwith decreasing GFR (degradation of creatinine by intestinal bacteria)

Serum cystatin C See belowMeasured urinary clearance using

creatinineProne to errors, unpleasant, inconvenient

and adequacy of urinary collection needsto ascertained prior to interpretation. Thelimitations of Scr also applies to thismethod.

Serum creatinine-based estimationequations:

See below

1. CG formula2. MDRD formulaEstimation of GFR from combined serum

creatinine and cystatin C–basedequation

Recently published—experience limited



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and frequently lessreliable, than serumcreatinine-based equa-tions. However, in individuals with variation in dietary intake(e.g., vegetarian diet, creatine supplements) or muscle mass(e.g., amputation, malnutrition, muscle wasting), as is seen inmany elderly persons, this may be a preferred method becausemany of these factors are not specifically taken into account inprediction equations. Table 1 shows other limitations.

Creatinine clearance (C Cr ) can be calculated if values forurine creatinine concentration (U Cr ), urine flow rate (V), andplasma creatinine concentration (P Cr ) are known:

C cr (UCr V)/PCr

For thecreatinine clearances to be comparable among individ-ualsof different sizes, it isoften corrected to that of an average-sized person, which is 1.73 m 2 and expressed as ml/min per1.73 m2 . If the sizes are extreme, Ccr should be corrected fortheir actual body surface area as follows:

Corrected C cr C cr 1.73)/Actual body surface area

GFR Estimation by Serum Cystatin CCystatin C is an endogenous substance like creatinine but isconstitutively produced by all nucleated cells, freely filtered,reabsorbed, and catabolized by the kidney. Most studies haveshown that serum cystatin C levels correlate better with GFR than does serum creatinine alone, especially at higher levels of GFR. Its physiologic role is that it is a cysteine proteinase in-hibitor with important roles in extracellular proteolysis, im-mune modulation, and antibacterial and antiviral activities.

Some in vitro studies have indicated that cystatin C may beaffected by some stimuli such as steroids and transforminggrowth factor . Additionally, cystatin C was thought to beeither less influenced or not influenced at all by certain demo-graphic factors such as age, race, gender, or muscle mass com-pared with serum creatinine in reflecting GFR until recently.There are now emerging data showing that it is, in fact, influ-enced by some of these factors. For instance, a recent study,although not necessarily focusing entirely on elderly people,with subjects with a mean age of 52 yr, concluded that cystatinC was 9% lower in women and 6% higher in blacks for a givenGFR 2,3 . Similarly, another recent study that reported popula-

tion distributions of cystatin C in the United States using serasamples from the Third National Health and Nutritional Ex-amination Survey noted that abnormal cystatin C was moreprevalent with increasing age from 1% in the 20- to 40-yr-oldgroup to 50% in persons over age 80 yr of age within eachdemographic subgroup. 3,4 However, the definition of abnor-mal cystatin C levels was chosen as the 99th percentile distri-bution among 20 to 40 yr olds, without hypertension or dia-betics. Although it is plausible that cystatin C rises with age forthe reason that there is, in general, a decline in kidney functionasnoted after the age of40yr, it isequallyplausible thatit couldbe elevated in the elderly, at least partly, for reasons that arerelated to the primary function of cystatin C, for example, im-

munity-related reasons, and not for reasons related to the kid-ney.

Tables 2 and 3 show factors likely to influence cystatin Clevels and limitations, respectively. 5

GFR ESTIMATION FROM SERUM CREATININE-BASED EQUATIONS

The two most commonly used equations to estimate GFR areserum creatinine based: Cockcroft-Gault (CG) and the Modi-fication of Diet in Renal Disease (MDRD) equations. Essen-tially, compared with serum creatinine, these equations in-crease the accuracy of estimated GFR (eGFR) to the measuredGFR by accounting for variables such as age and weight in theformer equation and age, gender, and race in the latter one.

CG EquationThis is one of the most widely used equations, even amongelderly people, although it was originally derived from mostly younger subjects, with only a 4% female representation. 6 Themain intention of the equation was to predict creatinine clear-ance instead of GFR, and hence, it was validated against mea-sured creatinine clearance. Creatinine clearance, as we know,overestimates GFR; therefore, the CG equation that estimatescreatinine clearance should also overestimate GFR. However,studies indicate that it actually underestimates GFR in the el-derly, especially at higher GFRs. According to one study, forinstance, both the MDRD and CG equations underestimatedGFR in hospitalized older individuals, but CG did so morethan MDRD. 7 Nevertheless, most of theestimatedvaluesusingthis equation (a median of 75%) were within 30% of measuredGFR, which was acceptable for good clinical decision makingand superior to serum creatinine alone. Table 4 shows addi-tional limitations.

The CG equation is as follows:

For men: CrCl ml/min 140 – Age in yr

Weight kg /SCr mg/dl 72

where CrCl is creatinine clearanceandSCr is serum creatinine.

For women, the above equation should be multiplied by 0.85.In cases of persons of extreme weights, some have used lean

body mass,whereas othershave used correction of theeCrCl toaverage body surface area.

Table 2. Factors considered to influence cystatin c levelsSerum Cystatin C

Level Factors

Elevated Hypothyroidism, steroid use,Rheumatoid arthritis

Reduced Hyperthyroidism



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MDRD EquationThe original equation was derived from a study of 1628 mid-dle-aged,nondiabetic, chronic renal insufficiency patients that

used a directly measured GFR by urinary clearance of 125

I-Iothalamate. 8 It has several advantages over the CG equationincluding providing an estimate of GFR rather than creatinineclearance, and in addition, a greater percent of these estimatesare within the clinically useful range for decision making: 90%of the MDRD based estimates were within 30% of the mea-sured GFR compared with about 75% of CG-based estimates.However, the MDRD equation also has several limitations in-cluding that it is less accurateat levelsabove60 ml/minper 1.73m 2 . Consequently, it may lead to misdiagnosis and misclassi-fication of CKD in individuals with mild renal insufficiency. 1,9

Table 4 shows additional limitations.There have been some validation studies of the MDRD

equation in

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