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    ANAESTHESIA AND INTENSIVE CARE MEDICINE 10:6 296 Crown Copyright 2009 Published by Elsevier Ltd. All rights reserved.

    Laboratory tests of renalfunctionAndy McWilliam

    Ross Macnab

    Abstract The human kidney provides essential regulatory and excretory functions.Body water content, plasma electrolyte composition and plasma pH are allunder the regulatory control of the kidney. In addition, the kidney providesa path of excretion for blood-borne, water-soluble, low-molecular-weightcompounds. These include the end-products of protein metabolism, suchas urea and creatinine, as well as foreign compounds with similar physico-chemical characteristics and their metabolites. Endocrine activity of the

    human kidney includes the secretion of the hormones erythropoietin andrenin and the activation of vitamin D by hydroxylation to its 1,25-dihydrox-ycholecalciferol form. The renal blood ow is immense, constituting 25%of resting cardiac output. The glomeruli form 170200 litres of ultraltrateper day and the selective reabsorption of water and solutes results inthe nal formation of approximately 1.5 litres of urine for excretion. Here,commonly used laboratory tests of renal function are discussed, includingglomerular ltration rate (GFR), creatinine clearance, serum creatinine con-centration estimation of GFR, cystatin C assay, serum urea concentration,urinalysis, free water clearance and endocrine changes in renal disease. Itmust be noted, however, that these tests require a clinical assessment ofthe patient to allow meaningful interpretation.

    Keywords creatinine; creatinine clearance; glomerular ltration rate;renal function; urea; urinalysis

    Assessment of renal function

    The assessment of renal compromise requires a number oflaboratory investigations in conjunction with a thorough clini-cal evaluation ( Box 1 ). Deviation from normal levels of manyblood and urinary constituents can reect renal insult or systemicdisorder ( Table 1 ).

    Glomerular ltration rateThis is the rate at which substances are ltered from the bloodof the glomeruli into the Bowmans capsules of the nephrons. Itis calculated by the clearance of specic substances. Endogenous

    Andy McWilliam FRCA is a Specialist Registrar in Anaesthesia in theNorth Western Deanery, UK. He qualied from Aberdeen in 1997.Conicts of interest: none declared.

    Ross Macnab FRCA is a Consultant in Anaesthesia at the ManchesterRoyal Inrmary, UK. He qualied from St Andrews University andManchester Medical School in 1993 and trained in the North WesternDeanery. He has an interest in anaesthesia for renal transplantation.Conicts of interest: none declared.

    substances should have a constant plasma concentration. Anysubstance freely ltered by the glomerulus and not subsequentlysecreted, reabsorbed or metabolized by the distal parts of therenal system has a clearance equivalent to the glomerular ltra-tion rate (GFR). 13 Renal clearance is calculated using a formulathat equates the total mass of substance cleared from plasma tothat found in urine:

    C s P s = U s V

    where C s is the volume of plasma containing the substance, P s isthe plasma concentration, U s is the urinary concentration of thesubstance and V is the urinary volume containing the lteredsubstance. Rearranging the equation and expressing the volumesas millilitres per minute gives us the equation for clearance:

    C s = ( U s V )/ P s

    The clearances of many substances have been measuredand used as an index for GFR. Exogenous markers include thecarbohydrate compound inulin, 124I-iothalamate and 51Cr-EDTA.

    After reading this article, you should: be able to list six laboratory tests that assess renal

    function know how to calculate glomerular ltration rate

    be able to state normal blood and urine biochemistryvalues.

    Learning objectives

    Equations for assessment of renal function

    1 The CockroftGault equation (UK)eCcr = (140 age) weight (kg) (constant)/serum creatinine( mol/l)where eC cr is the estimated creatine clearance; the constantis 1.23 for men and 1.04 for women. This formula provides asimple way to estimate glomerular ltration rate (GFR).2 The Modication of Diet in Renal Disease Study Groupequation

    eGFR (ml/min/1.73 m 2 ) = 186 serum creatinine ( mol/l) 1.154 age 0.203 1.21 (if black) 0.742 (if female)3 The Schwartz equationeCcr (ml/min/1.73 m 2 ) = (length in cm k )/serum creatinine(mg/dl)where k is 0.33 for premature infants, 0.45 for infants term to1 year, 0.55 for children 113 years and 0.70 in adolescentmales (constant for females remains at 0.55).4 Free water clearance (FWC)FWC = V (1 U osm / P osm )where V is the urine volume, U osm is the urine osmolality andP osm is the plasma osmolality.

    Box 1

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    Practical difculties in the administration and measurement ofthese substances preclude their usefulness in clinical settings, sothey remain predominantly research tools. Therefore, the com-mon practice is to use endogenous compounds as markers forGFR.

    Creatinine clearanceCreatinine is the most commonly used endogenous marker forrenal function. It is a product of muscle metabolism that is freely

    ltered at the glomerulus and secreted in small amounts in theproximal tubule. This results in a small overestimation of GFR,the impact of which is attenuated by the plasma creatinine assay,which generally also leads to an overestimation of the actualconcentration of creatinine by also measuring non-creatininechromogens(such as acetone and ascorbic acid). The measure-ment of the clearance of creatinine normally involves a 24-hourcollection of urine and a measurement of serum creatinine con-centration, assumed to represent the steady-state concentrationfor the measurement period. A clearance value is then given andexpressed in terms of millilitres per minute, thus giving an inter-pretable value for estimation of the GFR. Shorter time periods forcollection, for example 2 hours, have been used in catheterizedpatients on an intensive care unit. 4 The limitations of this methodinclude collection errors and inconvenience for the patient. Thepredictions of GFR made from serum creatinine levels are moreconvenient and are a mainstay of modern GFR assessment.

    Creatinine-based equations for glomerular ltration rateCreatinine concentration alone can be used to estimate GFR by anumber of mathematical models. The most commonly used arethe CockroftGault (CG) and modication of diet in renal disease(MDRD) formulae. The CG model estimates creatinine clearance(eCcr), and hence GFR, based on serum creatinine, age, sex andbody mass. The original formula used weight in kilograms andcreatinine in milligrams per decilitre, as is standard in the USA:

    eCcr = ((140 age) weight (kg) (0.85 if female ))/72 serum creatinine (mg/dl)

    Because serum creatinine in the UK is measured in micromoleper litre, the formula is modied and a constant is used for bothmen and women to complete the estimation:

    eCcr = ((140 age) weight (kg) (constant))/serumcreatinine ( mol/l)

    The constant is 1.23 for men and 1.04 for women. This for-mula provides a simple way to estimate GFR.

    The MDRD Study Group developed an alternative to this for-mula that was indexed to body surface area. In its original form,it used six measurements to estimate GFR (eGFR), includingblood urea nitrogen and albumin levels. A basic four-variableform of the calculation containing serum creatinine, age, raceand gender is:

    eGFR (ml/min/1.73 m 2) = 186 (serum creatinine ( mol/l)/

    88.4) 1.154 age 0.203 1.21 (if black) 0.742 (if female)

    These equations are not validated in children, in whom analternative, the Schwartz equation, should be used. ( Box 1 )Height in centimetres is multiplied by an age-dependent constant;this total is then divided by the serum creatinine concentration togive an estimation of GFR indexed to body surface area.

    Creatinine-based equations have many limitations, reect-ing the variability of creatinine production with many factors.The diuretics spironolactone and triamterene, as well as otherdrugs such as trimethoprim, cimetidine and probenecid, inter-fere with tubular secretion of creatinine, and thus can increaseserum creatinine concentrations while not reecting alterations

    in GFR. Extremes of muscle mass or breakdown, pregnancy, verylow body mass index or rapidly changing renal function impairaccuracy and extrapolation of GFR. It must be noted also that arise in plasma creatinine concentration is regarded as a late signof renal dysfunction, with estimates of a reduction in GFR ofmore than 50% occurring before there is any alteration in serumcreatinine.

    Serum ureaAs a breakdown product of hepatic protein metabolism ureahas important physiological functions in the maintenance of therenal concentrating function and provides the route of excretionof nitrogenous waste. Elevated urea levels may indicate renalimpairment, but this is a non-specic nding and can be relatedto other things such as the absorption of blood following gastro-intestinal haemorrhage. Urea-based models are to be regarded asless sensitive and specic than creatinine-based models.

    Serum cystatin CThis alkaline non-glycosylated protein is produced at a con-stant rate by almost all nucleated cells. It is freely ltered at theglomerulus and is almost completely reabsorbed and catabolizedin the proximal tubule. Estimation of the GFR using cystatin C(e.g. the Filler equation) 1 has been found to compare favourablywith creatinine-based methods. Although initially it was thoughtthat serum levels of cystatin C were independent of age, sex,

    Normal values a

    Blood biochemistry Urine biochemistry

    Sodium 132144 mmol/l Sodium 100200 mmol/24 hPotassium 3.55.5 mmol/l Potassium 3090 mmol/24 h

    Urea 3.57.4 mmol/l Urate 312

    mmol/24

    hCreatinine 4480 mol/l Protein < 0.15 g/24 h

    Chloride 95110 mmol/l Creatinine 917 mmol/24 hVenous bicarbonate2430 mmol/l

    Creatinine clearance120 ml/min

    Urate (male) 0.170.48 mmol/lUrate (female) 0.140.39 mmol/lPlasma osmolality 275295mosmol/kgAnion gap (Na + + K+ ) (HCO3 + Cl ) 1216 mmol/l

    Reference ranges quoted from the Biochemistry Laboratories at the Man-chester Royal Inrmary, 2009.a Always consult local laboratory for values.

    Table 1

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    body morphology and composition, we now know they varywith lean body mass. 1

    Free water clearanceAlthough rarely calculated, this allows quantication of urinaryexcretion of water and electrolytes by theoretically separatingurine into two components: one consisting of isosmotic urine

    containing all solutes and the other containing only free water.Clearance of this free water is responsible for altering plasmaosmolality and, in particular, the plasma sodium concentration.Clearance of free water can indicate the ability of the kidneysto conserve water by the production of concentrated urine (freewater clearance of less than zero): the production of isosmoticurine is indicated by a clearance of 1 and the production ofhypotonic urine and thus free water loss is indicated by freewater clearance of greater than 1. In the diagnosis of acute renalfailure, this measurement yields no advantage over creatinineclearance, and it is subject to limitations by factors that affecturine osmolality. It may, however, still offer practical benetsin the assessment of hypernatraemia in resolving acute renal

    failure.

    Other serum biochemistry in glomerular ltration ratereductionSerum electrolyte levels are non-specic markers of renal dys-function and offer little in the way of quantitative analysis. Acutereduction in GFR is often accompanied by an elevation of serumpotassium, urate and phosphate (as well as urea and creatinine)and a reduction in serum bicarbonate and calcium levels.Additionally, metabolic acidosis with an elevated anion gap ischaracteristic.

    Tests for tubular dysfunctionProximal tubular failure causes acidosis accompanied by a fallin serum potassium, phosphate, urate and bicarbonate levels,reecting a failure of reabsorption. Usually, urea and creatininelevels are normal. Acidication of the urine by oral ammoniumchloride is occasionally carried out to indicate the presence ofrenal tubular acidosis. This measures the ability of the kidney toproduce acidic urine (pH < 5.3) in response to the ammoniumchloride. This compound is metabolized hepatically to urea withthe consumption of bicarbonate. Exclusions to this test includealkaline urine in the presence of metabolic acidosis (diagnostic ofrenal tubular acidosis) and hepatic impairment, and difcultiesin interpretation occur when urinary infection, low potassium orelevated calcium are present.

    The ability of the distal tubules to reabsorb water may beassessed by the water deprivation test. This test is conductedwhen diabetes insipidus is suspected and involves repeated mea-surements of urine osmolality and body weight while allowingonly dry food for 8 hours. The measurement of urine osmolalityprovides information on the ability of the kidneys to concentrateurine in response to water balance. The urine osmolality andvolume and body weight are measured at hourly intervals untilsteady state or a urine osmolality of 750 mosmol/l is reached. Ifthe urine osmolality fails to rise by 30 mosmol/l, a desmopressintest can be conducted. Recovery of concentrating ability, whichis indicated by an increase in the urine osmolality of greater

    than 50% after administration of desmopressin, suggests cranialdiabetes insipidus rather than a nephrogenic cause of impairedtubule function.

    Urinalysis

    The physicochemical properties of urine as well as the presence

    and concentration of substances can be used as non-specicmarkers of renal disease but are also assessors of renal func-tion. Urine dipstick testing allows bedside cost-effective analysisand screening for many common conditions. Indices examinedon dipstick testing include pH, specic gravity, protein, glucose,ketones, nitrite, blood, bilirubin, urobilinogen and leucocytes.The urine specic gravity reects the concentration of the urine,providing an indication of tubular function. This is subject tomany limitations, with an altered specic gravity found in manyother circumstances including glycosuria, proteinuria, drugs andextremes of age.

    Microscopic analysis of urine can identify the presence of redblood cells (RBCs), white blood cells (WBCs), epithelial cells,

    hyaline casts, RBC casts, WBC casts and bacteria. Althoughnon-specic, many of these ndings can indicate signicantrenal pathology. The presence of dysmorphic RBCs and, inparticular, RBC casts suggests glomerulonephritis or signi-cant tubule damage with RBC leakage. WBC casts may indicateintrarenal disease such as pyelo- or glomerulonephritis becausethese casts are formed in the kidney not in the distal urinarytract. Hyaline casts are non-specic and can be found in healthypatients. Bacteria are commonly seen in urine under micro-scopy, often reecting contamination. The diagnosis of infec-tion requires culture; however, a colony count of >100,000/mlfrom a true clean catch, catheter or suprapubic sample carriesgreater signicance.

    Microalbuminuria, as dened by an albumin excretion of>20 g/min or 30300 mg/day, suggests hypertensive diseasein patients with diabetes. The presence of macroalbuminuria(>200 g/min or >300 mg/day) suggests diabetic nephropathy,which can be conrmed by the co-existence of a declining GFRand elevated blood pressure.

    Urine tests for differentiation between pre-renal and intrarenalfailure

    The use of urinary components to distinguish between pre-renalcompromise and acute tubular necrosis relies on the normalresponse of the kidney to conserve sodium and water in thepresence of reduced renal perfusion. Clinical assessment is vitalin making the diagnosis, with emphasis on assessment of uidstatus, medication or toxin ingestion, heart or liver disease ora history suggestive of excessive muscle breakdown. However,information from urinary and blood tests can provide supportingevidence. Pre-renal failure is characterized by concentrated urinewith low sodium excretion (20 mEq/l. A raised ratio of urine to serum urea andcreatinine and a urinary osmolality >500 mosmol/l suggest thatrenal concentrating function is intact, which supports a diagnosisof pre-renal failure. In practice, no single test can differentiate

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    between pre-renal and intrarenal impairment. Inadequate man-agement of pre-renal failure can result in the development ofintrarenal damage.

    Endocrine tests in renal disease

    Many hormone levels may be altered from their normal values

    by the presence of renal disease. Alterations in breakdown (e.g.reduced metabolism of insulin, calcitonin or parathyroid hor-mone (PTH)), alterations in secretion (e.g. increased secretionof insulin) or alterations in production (e.g. erythropoietin and1,25-vitamin D 3) can all occur. The presence of anaemia withco-existing chronic kidney disease suggests impaired erythro-poietin production. Assays of this hormone are rarely conductedbecause the diagnosis relies on the clinical picture, exclusion ofother causes and the response to therapy. Assays of hormonessuch as PTH can be conducted as part of the overall assess-ment of a patient with chronic renal failure, but again these arenon-specic tests. Elevated parathyroid hormone levels can indi-cate secondary or tertiary hyperparathyroidism.

    REFERENCES1 Craig R, Hunter J. Recent developments in the perioperative

    management of patients with chronic kidney disease. Br J Anaesth 2008; 101: 296310.

    2 Stevens L, Coresh J, Greene T, Levey A. Assessing kidney function:measured and estimated glomerular ltration rate. N Engl J Med 2006; 354: 247383.

    3 Power I, Kam P. Principles of physiology for the anaesthetist.London: Arnold, 2001.

    4 Sladen R, Endo E, Harrison T. Two-hour versus 22-hour creatinineclearance in critically ill patients. Anaesthesiology 1987; 67:101316.

    FURTHER READINGBarrett J, Harris K, Topham P. Oxford desk reference nephrology.

    Oxford: Oxford University Press, 2009.eGFR Calculator. Also available at: http://www.renal.org/eGFRcalc/GFR.pl

    (accessed 4 Jan 2009).

    http://www.renal.org/eGFRcalc/GFR.plhttp://www.renal.org/eGFRcalc/GFR.pl