Clinical review
`
`Renal Unit, Western
`Infirmary, Glasgow
`G11 6NT
`Jamie Traynor
`specialist registrar
`Colin C Geddes
`consultant
`nephrologist
`
`Renal Unit,
`Glasgow Royal
`Infirmary
`Robert Mactier
`consultant
`nephrologist
`Jonathan G Fox
`consultant
`nephrologist
`
`Correspondence to:
`J Traynor
`jamie.traynor@
`northglasgow.scot.
`nhs.uk
`
`BMJ 2006;333:733–7
`
`How to measure renal function in clinical practice
`Jamie Traynor, Robert Mactier, Colin C Geddes, Jonathan G Fox
`
`The reliable measurement of renal excretory function
`is of great
`importance in clinical practice and in
`research. The introduction of routine reporting of esti-
`mated glomerular filtration rate and a new definition
`of chronic kidney disease has renewed interest in
`methods of measuring renal function. Coupled with
`this is the fact
`that several countries are moving
`towards population screening for renal impairment to
`try to reduce the associated increased cardiovascular
`risk. Accurate measurement
`is methodologically
`difficult
`so surrogate measures
`such as
`serum
`creatinine levels and prediction formulas (based on
`factors such as the patient’s age, sex, and serum creati-
`nine level) are more commonly used in routine
`practice. We describe routine and more specialised
`methods of assessing renal
`function and discuss
`estimated glomerular filtration rate.
`The kidney has several interlinked functions (box).
`These depend on glomerular filtration rate, the unit
`measure of kidney function. Glomerular filtration rate
`can be defined as the volume of plasma cleared of an
`ideal substance per unit of time (usually expressed as
`ml/min). The ideal substance is one that is freely
`filtered at the glomerulus and neither secreted nor
`reabsorbed by the renal tubules.
`
`Creatinine
`to an ideal endogenous
`Creatinine is the closest
`substance for measuring glomerular filtration rate.w1
`Plasma creatinine is almost exclusively a product of the
`metabolism of creatine and phosphocreatine in
`skeletal muscle, although ingestion of meat may also
`contribute slightly.w2 w3 In patients with stable renal
`function, serum creatinine levels are usually constant,
`with variability daily of about only 8%.w4 w5 Creatinine is
`freely filtered at the glomerulus and is not reabsorbed,
`but up to 15% is actively secreted by the tubules.w6 In
`advanced renal failure, excretion of creatinine through
`the gastrointestinal tract increases.w7
`
`Creatinine clearance
`Measuring the creatinine clearance using serum creati-
`nine level and a timed urine collection gives an
`estimate of glomerular filtration rate:
`creatinine clearance (ClCr) =
`(urine creatinine×volume)/serum creatinine
`As a result of tubular secretion of creatinine, creati-
`nine clearance tends to overestimate true glomerular
`filtration rate. This is a systematic error of fairly stable
`
`Summary points
`
`Estimated glomerular filtration rate forms the
`basis for the classification of chronic kidney
`disease
`
`An estimated glomerular filtration rate of 60-89
`ml/min/1.73 m2 in the absence of other evidence
`of kidney disease does not signify chronic kidney
`disease and does not indicate that further testing
`is required
`
`Patients with chronic kidney disease are at high
`risk of cardiovascular disease
`
`Estimated glomerular filtration rates, calculated
`using the “4-v MDRD” based formula, are now
`routinely reported by biochemistry laboratories
`alongside serum creatinine results (except in
`non-validated patient groups)
`
`Serum creatinine levels or estimated glomerular
`filtration rates may be used to monitor changes in
`renal function in an individual patient
`
`Formal measurement of glomerular filtration rate
`is used for accurate assessment of renal function
`in potential kidney donors and in research studies
`
`Radioisotope or iothalamate methods require
`multiple blood samples and, if renal function is
`reduced, the duration of sampling may be up to
`24 hours
`
`magnitude, however, until advanced renal failure is
`reached, allowing creatinine clearance to be a
`reasonable method of following changes of renal func-
`tion in patients. The main problem with creatinine
`clearance is the requirement for urine collection over
`24 hours; patients find this inconvenient and therefore
`collections are often inaccurate. Also a 25% daily varia-
`tion in the values obtained using this method has been
`reported.w8 Creatinine clearance is therefore no longer
`much used in clinical practice.
`
`References w1-w21 are on bmj.com
`
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`Clinical review
`
`Terminal elimination phase
`Equilibrium phase
`k1
`k2
`
`Time (t)
`
`Plasma concentration of injected substance
`
`Sources and selection criteria
`
`We searched Medline from 1966 onwards using the
`search terms: “measurement of renal function”,
`“modification of diet in renal disease”, “Cockcroft and
`Gault”, “radio-isotopes”, “glomerular filtration rate”,
`“inulin clearance”, and “cystatin C”
`We also referred to several textbooks, including the
`Oxford Textbook of Clinical Nephrology third edition
`(Oxford University Press) and Comprehensive Clinical
`Nephrology second edition (Mosby)
`
`Urea
`Serum urea is a less reliable marker of glomerular fil-
`tration rate than creatinine because levels are more
`vulnerable to change for reasons unconnected to
`glomerular filtration rate. A high protein diet, tissue
`breakdown, major gastrointestinal haemorrhage, and
`corticosteroid therapy can lead to an increase in
`plasma urea whereas a low protein diet and liver
`disease can lead to a reduction. Also, 40-50% of
`filtered urea may be reabsorbed by the tubules,
`although the proportion is reduced in advanced renal
`failure.w9
`
`Mean of urea and creatinine clearance
`In advanced renal failure the mean of urea and creati-
`nine clearance may give a more accurate estimate of
`glomerular filtration rate than either clearance alone,
`as the effects of urea reabsorption and creatinine
`secretion tend to cancel each other out.w10 It is the
`recommended method for estimating residual renal
`functionw11 in patients receiving dialysis.
`
`Inulin clearance
`No endogenous ideal substance exists for measuring
`glomerular filtration rate, so the standard method
`requires infusion of an exogenous agent, such as
`inulin. Inulin, a polymer of fructose (5200 daltons), is
`found in Jerusalem artichokes, dahlias, and chicory
`and was first used for measuring glomerular filtration
`rate in 1951.w12 Its use is limited because purified inulin
`
`Functions of kidney related to glomerular
`filtration rate
`• Excretion of:
`Nitrogenous waste
`Sodium
`Free water
`Potassium
`Phosphate
`Water soluble medicines (for example, digoxin,
`gentamicin)
`• Control of blood pressure
`• Acid-base balance
`• Secretion of erythropoietin
`• Hydroxylation of vitamin D1 (activation)
`• Gluconeogenesis in the fasting state
`• Catabolism of peptide hormones (including insulin)
`
`Fig 1 Biphasic disappearance of injected substance from plasma.
`During the first phase, equilibration of the injected substance takes
`place between the intravascular and extravascular compartments (k2).
`Once equilibration has been reached, the decline in plasma levels
`(normally measured with a venous sample) should reflect removal of
`the substance from the arterial system through the kidneys. This is
`termed the terminal elimination phase (k1)
`
`is expensive and difficult to measure and measuring
`glomerular filtration rate in this way is time consuming
`for both patients and clinicians. A bolus and infusion of
`inulin are given to achieve a steady plasma level,
`followed by collection of regular blood and urine sam-
`ples over several hours for inulin estimation. This
`method (nowadays often using polyfructosan (Inutest;
`Fresenius, Austria) is only used in research studies
`when very accurate estimation of renal function is
`necessary.
`
`Radioisotopic methods
`From the late 1960s the use of radionuclides has
`offered an alternative method of estimating glomeru-
`lar filtration rate that avoids some of the practical
`disadvantages of
`inulin clearance. Estimates using
`radionuclides correlate closely with inulin clearance.1–4
`Radionuclides are usually given as a single dose and
`the glomerular filtration rate calculated by their rate of
`disappearance from the plasma, obviating the need for
`urine tests. When a substance is given under these con-
`ditions, two phases of disappearance occur (fig 1):
`Computer
`software is used to calculate the
`glomerular filtration rate based on data either from
`both phases (double pool) or from the terminal
`elimination phase (single pool). Single pool methods
`have the advantage that fewer plasma samples are
`required.
`Radioisotopic methods have the disadvantage of
`precautions being required in handling and disposal of
`radioactive materials. They are also expensive and not
`suitable for use during pregnancy. Another important
`consideration is that the terminal elimination phase is
`significantly prolonged in advanced renal failure. In
`patients with moderate renal failure (glomerular filtra-
`tion rate 30-59 ml/min) samples are taken for up to
`five hours after injection whereas in patients with
`advanced renal failure samples are required for up to
`24 hours after injection.5
`
`Radiocontrast agents
`Radiocontrast agents were initially available in the
`1960s but difficulties
`in chemical analysis and
`
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`unacceptable amounts of free iodine in the prepara-
`tions limited their use in favour of radioisotopic
`agents.w13 These problems have largely been resolved
`and radiocontrast agents now offer the advantages of
`radioisotopes without the concerns of radioactive sub-
`stances. Agents currently in use are iothalamate (Con-
`ray; Mallinckrodt, St Louis, MO), siatrizoate meglumine
`(Hypaque; Amersham Health, NJ), and iohexol (Omni-
`paque; Amersham Health, NJ). Iohexol may be the
`agent of choice as it is relatively quick to use and its
`results are comparable to inulin clearance.6 7
`
`Cystatin C
`The past decade has witnessed an upsurge of interest
`in cystatin C as an endogenous glomerular filtration
`rate marker. Cystatin C is part of
`the cystatin
`“superfamily” of cysteine protease inhibitors. It is freely
`filtered at the glomerulus. Its use is, however, limited by
`higher variability of serum levels than creatinine (75%
`v 7%) between patients.8 Also, serum levels are
`increased in malignancy,w14 w15 HIV infection,w16 and
`glucocorticoid therapy.w17 At present cystatin C has no
`established role, but it may emerge as a useful way of
`identifying patients with early renal failure as part of
`screening programmes.w18
`
`Prediction formulas
`To circumvent the practical difficulties of formal meas-
`urement of clearance, several prediction formulas have
`been published. The most commonly used are the
`Cockcroft and Gault equation and formulas based on
`the modification of diet in renal disease study (fig 2).
`Given the limitations of serum creatinine in identifying
`renal failure, the increased use of prediction formulas,
`in particular the modification of diet in renal disease
`formulas, has been advocated.9
`
`Cockcroft and Gault equation
`The Cockcroft and Gault equation, which estimates
`creatinine clearance on the basis of serum creatinine
`level, age, sex, and weight, was one of the earliest
`prediction formulas10 and is still widely used. It was
`based on creatinine excretion in men with normal
`renal function with a correction for women, based on
`three other studiesw19-w21:
`it
`tends to overestimate
`renal function at lower levels, particularly when obes-
`ity or fluid overload is present, as the resultant
`increase in weight does not reflect an increase in
`muscle mass. However, as with creatinine clearance,
`this is largely a systematic error and the equation
`remains useful for following changes in renal function
`in a patient.
`
`Modification of diet in renal disease
`formula
`More recently Levey et al introduced a formula derived
`from data on patients with advanced renal failure in
`the modification of diet in renal disease study.11–14 This
`is referred to as the “6-variable MDRD” or “6-v MDRD”
`formula.15 This formula gives an estimate of glomeru-
`lar filtration rate in millilitres per minute adjusted for
`body surface area of 1.73 m2 and is based on a patient’s
`
`Clinical review
`
`Cockroft and Gault equation
`(140-age) x weight x 1.2
`Estimated creatinine clearance (ClCr) =
`x (0.85 if female)
`SCr
`where age is expressed in years, SCr in µmol/l, and weight in kg10
`
`6-variable MDRD15
`170 x (SCr/88.4)-0.999 x age-0.176 x (SU/0.357)-0.170 x (SAlb x 10)+0.318 x (0.762 if female) x (1.180 if black)
`where SCr = serum creatinine in µmol/l, SU = serum urea in mmol/l, SAlb = serum albumin in g/l,
`and age is expressed in years
`
`4-variable MDRD16
`186.3 x (SCr/88.4)-1.154 x age-0.203 x (0.742 if female) x (1.21 if black)
`where SCr = serum creatinine in µmol/l, and age is expressed in years
`
`Modified 4-variable MDRD (traceable by isotope dilution mass spectrometry)19
`F x 175 x (SCr/88.4)-1.154 x age-0.203 x (0.742 if female) x (1.21 if black)
`where F = correction factor, SCr = serum creatinine in µmol/l, and age is expressed in years
`
`Fig 2 Commonly used formulas for estimating renal function. MDRD=modification of diet in
`renal disease
`
`age, sex, race, and levels of serum urea, serum
`creatinine, and serum albumin. By avoiding inclusion
`of weight, the formula is less prone to errors from fluid
`overload and obesity.
`In 2000 a simplification of the modification of diet
`in renal disease formula using only patient’s age, sex,
`race, and serum creatinine level was derived from the
`original data.16 This is referred to as the “4-variable
`MDRD” or “4-v MDRD” formula. With the exception
`of race, the other variables required are normally pro-
`vided routinely when a sample is submitted to the
`laboratory. It is therefore much easier for laboratories
`to report estimated glomerular filtration rate using this
`formula.
`One important issue concerning the use of predic-
`tion formulas is that different laboratories use different
`methods for creatinine estimation. Some assays are
`more sensitive than others to non-creatinine chro-
`mogens, which falsely increase creatinine values. This
`error is magnified in prediction formulas, particularly
`in patients with higher levels of renal function.17 18 To
`replicate as closely as possible the results obtained in
`the modification of diet in renal disease study, all
`serum creatinine values should ideally be determined
`using the methods of the Cleveland Clinic laboratory
`in the original modification of diet in renal disease
`study.17 18 This raises problems for different providers
`of analytical systems and would not be straightforward
`to achieve. However, some of the difference in assay
`methods can be corrected for and there are plans to
`adopt correction factors throughout the United King-
`dom. The United Kingdom National External Quality
`Assessment Service has played a key part
`in this
`change. When using a correction factor, the formula
`used is a slightly modified form of the 4-v MDRD
`formula.19
`The modification of diet in renal disease formulas
`have been validated in an ever increasing number of
`patient groups, including elderly patients and recipi-
`ents of renal transplants,20–22 although concern has
`been expressed over reliability in different ethnic
`groups such as Chinese and Indian patients.23 24 Also,
`as these formulas were based on data from patients
`with advanced renal failure, their validity has been
`questioned in patients with normal or near normal
`
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`Clinical review
`
`Clinical relevance of the five stages of chronic kidney disease
`
`Stage of chronic
`kidney disease
`1
`
`2
`
`Estimated
`glomerular filtration
`rate (ml/min)
`≥90
`
`60-89
`
`Clinical significance
`With another abnormality*,
`otherwise regard as normal
`With another abnormality*,
`otherwise regard as normal
`3
`Moderate impairment
`30-59
`4
`Severe impairment
`15-29
`5
`Advanced renal failure
`<15
`*Patients with estimated glomerular filtration rate ≥60 ml/min/1.73 m2 should
`be regarded as normal unless they have evidence of kidney disease (persistent
`proteinuria or haematuria, or both, microalbuminuria in patients with diabetes,
`structural kidney disease such as polycystic kidney disease in adults or reflux
`nephropathy).
`
`Tips for non-specialists
`
`Use estimated glomerular filtration rate as a guide to
`renal function in conjunction with advice on renal
`disease from the Renal Association’s website
`(www.renal.org/eGFR/)
`If the estimated glomerular filtration rate is < 60
`ml/min then:
`• Review previous results or repeat the
`measurement to assess if renal function is stable or
`declining
`• Measure blood pressure and test urine for protein
`and blood
`• Review drugs for potentially nephrotoxic agents,
`such as angiotensin converting enzyme inhibitors or
`angiotensin receptor blockers, diuretics,
`non-steroidal anti-inflammatory drugs, and
`antibiotics
`• Check for urinary symptoms, signs of fluid
`retention or hypovolaemia, and palpable bladder
`• Enter into a chronic disease management
`programme and decide whether referral to a renal
`clinic is appropriate, using local guidelines or those
`from the Renal Association
`
`gists. In the case of Australia and New Zealand, specific
`attention is recommended to high risk subgroups such
`as those of aboriginal descent. The potential impact of
`identifying patients with reduced renal function has
`been recognised by the United Kingdom’s health serv-
`ice and is reflected in the General Medical Services
`contract for general practitioners, which now provides
`remuneration for the identification and monitoring of
`chronic kidney disease.
`
`Conclusion
`Prediction formulas using serum creatinine levels are
`by far the most widely used methods of measuring
`renal excretory function in routine clinical practice.
`One of these, the modified 4-v MDRD estimated
`glomerular filtration rate formula19 is now being used
`for direct reporting of estimated glomerular filtration
`rates by laboratories and has become the standard
`method used to identify and monitor patients with
`reduced renal function in the United Kingdom and
`elsewhere.
`It
`is anticipated that recognition and
`appropriate management of patients with chronic
`kidney disease will reduce cardiovascular events and
`slow further deterioration in renal function in these
`patients.
`
`Contributors: JT wrote the main draft of the manuscript and
`oversaw submission. He is guarantor. RM, CCG, and JGF
`assisted with writing and amending the manuscript.
`Competing interests: None declared.
`
`1 Chantler C, Garnett ES, Parsons V, Veall N. Glomerular filtration rate
`measurement in man by the single injection methods using 51Cr-EDTA.
`Clin Sci 1969;37:169-80.
`2 Rehling M, Moller ML, Thamdrup B, Lund JO, Trap-Jensen J. Simultane-
`ous measurement of
`renal clearance and plasma clearance of
`99mTc-labelled
`diethylenetriaminepenta-acetate,
`51Cr-labelled
`ethylenediaminetetra-acetate and inulin in man. Clin Sci
`(Lond)
`1984;66:613-9.
`3 Israelit AH, Long DL, White MG, Hull AR. Measurement of glomerular
`filtration rate utilizing a single subcutaneous
`injection of 125I-
`iothalamate. Kidney Int 1973;4:346-9.
`4 Dondi M, Fanti S. Determination of individual renal function through
`noninvasive methodologies. Curr Opin Nephrol Hypertens 1995;4:520-4.
`
`is therefore recom-
`glomerular filtration rates. It
`mended that they are not used routinely at levels
`greater than 60 ml/min/1.73 m2. It should be stressed
`that these formulas are not valid in certain clinical set-
`tings such as acute renal failure, pregnancy, severe mal-
`nutrition, diseases of skeletal muscle, paraplegia, and
`quadriplegia, in children, or when renal function is
`changing rapidly.
`Plans are in progress to report estimated glomeru-
`lar filtration rates whenever measurement of serum
`creatinine is requested throughout the United King-
`dom. Some centres have already started providing esti-
`mated glomerular filtration rates routinely and most
`centres should be doing so by the end of 2006. This is
`likely to identify large numbers of patients with
`reduced glomerular filtration rates who may have been
`overlooked when their renal function was assessed by
`serum creatinine levels alone: data from the United
`States suggest that around 5% of adults have chronic
`kidney disease stages 3 (glomerular filtration rate
`30-59 ml/min), 4 (15-29 ml/min), or 5 ( < 15 ml/min).
`These people have a markedly increased risk of cardio-
`vascular morbidity and mortality and identification of
`them should enable earlier initiation of measures to
`reduce cardiovascular risk and also the rate of progres-
`sion of renal failure. A similar prevalence figure has
`been reported in the United Kingdom.25 The table lists
`the five stages of chronic kidney disease.
`The UK Renal Association among associations in
`other countries, including Canada and Australia, has
`introduced guidelines for targeted screening to detect
`reduced renal function in primary care using estimated
`glomerular filtration rate. These guidelines describe
`how to manage most patients in primary care and
`advise which patients should be referred to nephrolo-
`
`Additional educational resources
`
`Renal Association (www.renal.org/eGFR/)—this
`website has clear information on definition of chronic
`kidney disease and provides guidelines on
`management. A section is included for patients
`NHS Employers (www.nhsemployers.org/primary)—
`this website provides further details of the general
`practitioner contract and remuneration of general
`practitioners within the United Kingdom
`National Kidney Foundation (www.kidney.org/
`kidneyDisease/)—this website provides useful
`information for patients as well as another good
`resource for health professionals
`
`736
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`

`Clinical review
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`15 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accu-
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`16 Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict
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`17 Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, et al.
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`18 Van Biesen W, Vanholder R, Veys N, Verbeke F, Delanghe J, De Bacquer
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`21 Poge U, Gerhardt T, Palmedo H, Klehr HU, Sauerbruch T, Woitas RP.
`MDRD equations for estimation of GFR in renal transplant recipients.
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`22 Pierrat A, Gravier E, Saunders C, Caira MV, Ait-Djafer Z, Legras B, et al.
`Predicting GFR in children and adults: a comparison of
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`Cockcroft-Gault, Schwartz, and modification of diet in renal disease for-
`mulas. [See comment.] Kidney Int 2003;64:1425-36.
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`25 Anandarajah S, Tai T, De Lusignan S, Stevens P, O’Donoghue D, Walker
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`
`(Accepted 29 August 2006)
`doi 10.1136/bmj.38975.390370.7C
`
`When I use a word
`Consultation
`
`In his account of the Persian wars, Herodotus tells how the
`Lydian king Croesus consulted the Delphic oracle, asking
`whether he should go to war with Persia. If Croesus attacks the
`Persians, said the oracle, he will destroy a mighty empire. Croesus
`confidently marched on Cappadocia, but it was his own mighty
`empire that he destroyed by doing so, not that of the enemy king,
`Cyrus. Other oracular pronouncements were equally ambiguous.
`According to Ennius, “Aio te Romanos vincere posse” (quoted by
`Shakespeare in Henry VI, Part 2) was the answer that Pyrrhus, king
`of Epirus, received when he asked about making war with Rome:
`“I assert that you can conquer the Romans/the Romans can
`conquer you.” The lesson is clear: listen carefully to those whom
`you consult—they may not be saying what you would like them to
`say. It is a lesson that seems to have been forgotten.
`The word consult comes from the Latin verbs consulere
`(supine consultum) and consultare, both of which mean to apply
`to someone for advice or information. Consultare also means to
`consult an oracle. The Oxford English Dictionary gives several
`definitions for “consult,” including “to have especial respect or
`beneficial reference to (a person’s good, interest, convenience,
`etc.) in forming plans; ... To ask advice of, seek counsel from; to
`have recourse to for instruction, guidance, or professional advice
`... to seek permission or approval from (a person) for a proposed
`action.”
`My concern that modern methods of consultation do not
`conform to this description received another dig in the ribs
`recently when an organisation enthusiastic to introduce author
`pays, “open access” publishing, and institutional repositories (with
`apparently little regard for the various deleterious effects that
`these policies may have (BMJ 2005;330:759) including damage to
`learned societies that publish their own journals) proclaimed that
`it would “discuss with the learned societies ways in which they can
`adapt to and exploit new models of publication.” To me this is
`rather like a doctor telling her patient that she will see him
`through his terminal illness, helping him to adapt to the
`
`inevitable. The patient may have consulted the doctor, but the
`doctor has not consulted the patient.
`One way of getting the answer you want is to ask the right
`question. My local council (a word, incidentally, that comes from
`concilium; not to be confused with counsel), keen to introduce
`charges for allowing me to park outside my own house, recently
`sent me a consultation questionnaire. Did I agree that there
`should be a consistent policy about such charges throughout the
`city? My gut reaction was “yes,” because surely consistency is
`desirable. Well actually it isn’t always. What is good and necessary
`in some parts of town may be harmful in others. So, should the
`same policy be applied throughout? I answered “no,” but it won’t
`do any good—I suspect that they have already decided what
`they’re going to do.
`All too often today consultation seems to mean, as Paul
`Glasziou suggested to me when we discussed it, “This is what we
`intend to do; tell us how much you agree.” I therefore propose a
`novel Likert scale for responding to modern consultations:
`Agree/Agree strongly/Agree very strongly/Agree
`enthusiastically/Couldn’t agree more.
`I also note that another meaning of the Latin word consulere,
`listed in the Oxford Latin Dictionary, is “[with male, duriter, and
`similar] to plan harm (to), act mischievously, prejudicially, etc
`(towards) . . . [and with contra] to take steps against.”
`Jeff Aronson clinical pharmacologist, Oxford
`(jeffrey.aronson@clinpharm.ox.ac.uk)
`We welcome articles up to 600 words on topics such as
`A memorable patient, A paper that changed my practice, My most
`unfortunate mistake, or any other piece conveying instruction,
`pathos, or humour. Please submit the article on http://
`submit.bmj.com Permission is needed from the patient or a
`relative if an identifiable patient is referred to. We also welcome
`contributions for “Endpieces,” consisting of quotations of up to
`80 words (but most are considerably shorter) from any source,
`ancient or modern, which have appealed to the reader.
`
`BMJ VOLUME 333 7 OCTOBER 2006 bmj.com
`
`737
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1045, p. 005
`
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