The accuracy of creatinine clearance with and without

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1 Postgrd Med J (1991) 67, ) The Fellowship of Postgrdute Medicine, 1991 The ccurcy of cretinine clernce with nd without urine collection s mesure of glomerulr filtrtion rte D.G. Wller,' J.S. Fleming,2 B. Rmsy' nd J Gry2 'Clinicl Phrmcology Group nd 2Deprtment ofnucler Medicine, Southmpton Generl Hospitl, Southmpton S9 4XY, K. Summry: Conventionl cretinine clernces involving urine collections over 2, 4 nd 24 hours nd cretinine clernce predicted from plsm cretinine concentrtions without urine collection were compred to glomerulr filtrtion rte (GFR) estimted by 9'Tc DTPA clernce in 171 ptients with wide rnge of GFR. A cretinine clernce methods involving urine collection hd stndrd errors of the estimte of GFR greter thn predictions from formule. Predictions of cretinine clernce by formule hd coefficients of vrition of the estimte of pproximtely 23% when compred to isotopicly determined GFR. Cretinine clernces determined by these equtions in ptients with stble renl function re n esier nd t lest s ccurte guide to GFR s methods involving urine colection. Introduction Serum cretinine concentrtions re poor guide to glomerulr filtrtion rte (GFR) since they re highly dependent on muscle mss nd re insensitive to chnges in renl function until GFR is substntilly reduced.' When direct mesure of GFR is required, s for djusting drug dosge, the idel method would be to mesure the renl clernce of n isotopiclly lbelled chelte. Fcilities for this re not lwys vilble nd consequently, 24 hour endogenous cretinine clernce is still employed. Obtining ccurte timed urine collections is one mjor potentil source of error when determining cretinine clernces, nd to reduce this, considerbly shorter collection times hve been proposed.2 However, correltions between cretinine clernces clculted from 24 hour nd shorter timed collections hve not been close. To overcome the need for urine collections, severl formule nd nomogrms hve been devised to predict cretinine clernce from the plsm cretinine concentrtion, tking the ge, sex nd body weight of the subject into ccount. These predictions re possible since urine cretinine excretion is firly constnt cross wide rnge of renl function when djusted for the ptients' physicl chrcteristics. There hve been few comprisons of both mesured nd predicted cretinine clernces with n ccurte mesure of GFR. We hve used the plsm clernce of 9'Tc Correspondence: D.G. Wller, D.M., M.R.C.P. Accepted: 7 August 199 DTPA s reference stndrd nd compred the bility of vrious mesured or predicted cretinine clernces to estimte the GFR. Ptients nd methods One hundred nd seventy-one ptients with stble renl function, who were undergoing rdioisotopic estimtion of GFR s prt of their clinicl mngement, were studied. Plsm clernce of 99mTc DTPA (Pentette II, Amershm Interntionl) ws clculted from blood smples tken 2 nd 4 hours fter injection.3 rine ws collected by spontneous voiding between nd 4 hours post injection (37 ptients) or between nd 2 hour (92 ptients). A further 35 ptients brought n unsupervised 24 hour urine collection from home hving received full written instructions. These collections finished on the morning of the GFR mesurement. Mesured cretinine clernces were obtined using the 24, 4 nd 2 hour urine collections nd plsm cretinine tken 2 hours post isotope injection on the study dy. Predicted cretinine clernces were derived from the plsm cretinine using the formule of Hull et l.4 nd Cockcroft nd Gult' (Figure 1), nd the nomogrm of Bjornsson et l.6 Plsm nd urine cretinine were mesured using Vickers utomted multi-chnnel nlyser. Predicted cretinine clernces my be overestimted in ptients with mrked obesity.4 There- Postgrd Med J: first published s /pgmj on 1 Jnury Downloded from on 21 August 218 by guest. Protected by

2 CREATININE CLEARANCE TESTS Cockcroft nd Gult5 Mles Ccr= 1.23 x (14-ge in yers) x (wt in kg) plsm cretinine pmol/i Femles Ccr = 1.4 x (14-ge in yers) x (wt in kg) plsm cretinine itmol/l 2. Hull et l.4 Mles Ccr = 1.26 x (145-ge in yers) x (wt in kg) 3 plsm cretinine jimol/l Femles Ccr = 1.4 x (145-ge in yers) x (wt in kg) plsm cretinine ftmol/l Figure 1 Equtions evluted for the prediction of cretinine clernce (Ccr). fore, when body weight ws > 3% bove idel, the ltter vlue ws used in the equtions nd nomogrm. Correltions between the estimtes from ech cretinine clernce technique nd reference isotopic GFR were obtined by lest squres nlysis, nd the stndrd error of the estimte of GFR nd the corresponding coefficient of vrition clculted in ech cse. The significnce of differences between coefficients ofvrition ws determined by the F test. To ssess whether there ws ny systemtic difference in the vlues of the cretinine clernces compred to the reference isotopic GFR, pired Student's t-tests were performed. In ddition to the bove clcultions, the vlues on subjects with isotopic GFR below 5 ml/min nd those bove 5 ml/min were nlysed seprtely. In ech cse the men differences between the cretinine clernce vlues nd GFR were ssessed using pired Student's t-test. Results A summry of the correltions between the vrious methods for deriving cretinine clernce nd the reference GFR obtined from plsm clernce of 9'Tc DTPA is shown in Tble I. The reltionships between predicted or mesured cretinine clernce nd reference GFR ll tended to demonstrte n incresing bsolute error in the estimte ofgfr with higher GFR vlues (Figure 2). It ws therefore considered more pproprite to use mesure of the reltive dispersion (the coefficient of vrition) rther thn the bsolute dispersion when compring the ccurcy of estimtion of the different techniques. The Cockcroft nd Gult nd Bjornsson predictions of cretinine clernce showed no systemtic difference from GFR wheres the Hull eqution gve smll but significnt overestimte (P<.1). The coefficients of vrition of estimting GFR were similr for both equtions nd the nomogrm. The reltionship between GFR nd the Cockcroft nd Gult prediction of cretinine clernce is shown in Figure 2. The mesured cretinine clernce techniques ll produced systemticlly higher vlues compred to reference GFR. The coefficient of vrition of estimting GFR from the 2 hour clernces ws significntly higher thn both the 4 nd 24 hour clernces (P <.1). The coefficients of vrition of estimting GFR using the formule or nomogrm were significntly E 14 *.. Line of i 12.*/ X Identity CD / C EBO 18 c 6 CD 4. /..2 2 o * DTPA Clernce (ml/min) Figure 2 Regression reltionship between glomerulr filtrtion rte mesured by plsm clernce of 99mTc DTPA nd predicted cretinine clernce by the method of Cockcroft nd Gult. Postgrd Med J: first published s /pgmj on 1 Jnury Downloded from on 21 August 218 by guest. Protected by

3 44 D.G. WALLER et l. ' C).~ L ( ra C1. ' ' JD W. Cd. O E O; Cd ) l CG l) 4) 3t ) s: s_ 5-E 2, 4 -o' % - ON CO en4 sri or OONm W) oei C- N C1 en, N C1 - C - n coi en on otr_ N't O Ql% r O o 7 r st r-.io%.o 5v-v-trfl l ri e~o m 11 C. <8 -_ oo WI C, r- W) ) _ o) oo W'S o _. oo r- t- r- W W-, ) C- ' l) 6 V 4- ) ' Postgrd Med J: first published s /pgmj on 1 Jnury Downloded from r_ ) In. b ~~ ~ ~ ~ Oe % y81 cd. E cr6 c ci ' - CA.q 6 i:-i&, " l C) t- e 4 V on 21 August 218 by guest. Protected by

4 lower thn those of the 2 nd 4 hour mesured cretinine clernces (P<.1) nd showed trend to lower error thn for the 24 hour mesured clernce. The differences between mesured cretinine clernces nd reference GFR for subjects with GFR greter or less thn 5 ml/min re shown in Tble II. In ech cse the men cretinine clernce vlues were higher thn the reference GFR. In ddition the reltive overestimte ws higher when the GFR ws less thn 5 ml/min thn when it ws greter thn 5 ml/min, lthough only for the 2 hour clernce vlues ws this sttisticlly significnt. The results for the Cockcroft nd Gult predicted cretinine clernce showed closer greement cross the whole GFR rnge thn mesured cretinine clernces. Discussion Plsm clernce of 9"Tc DTPA hs been shown to ccurtely reflect GFR mesured by inulin clernce, provided preprtion with low protein binding is used.' The technique used for mesurement of the reference GFR in this study gives stndrd error of the estimte of less thn 3 ml/min when compred to multiple plsm smpling.3 This should therefore provide n cceptbly ccurte stndrd with which to compre the cretinine clernces. The mny potentil sources of error in the mesurement of cretinine clernce, which include the lbortory methods for mesuring cretinine nd the ccurcy of urine collection, hve been reviewed by Bjornsson.' The current study demonstrted the inccurcy of ll the cretinine clernce estimtes when compred with isotope clernce GFR nd grees with previous ssessments.8 Mesured cretinine clernce tends to overestimte low GFR.9" In the current study, the mesured cretinine clernces gve considerble overestimtion of the men GFR, most mrked t low GFR. CREATININE CLEARANCE TESTS 45 By contrst, the Cockcroft nd Gult predicted cretinine clernces showed smller men overestimte t low GFR nd n underestimte t high GFR. Chrleson et l." demonstrted correltion of.83 between predicted cretinine clernce by the method of Cockcroft nd Gult nd 5'chromium EDTA clernce. The regression eqution ws not given but the sctter digrm suggested tht the eqution gve similr overestimtion of GFR t low cretinine clernces with n underestimte t high clernces. The relibility of the predicted cretinine clernces in determining GFR in the current study is similr to those found by previous workers, who clculted relibility to be between ± 21-35%.2 13 Brochner-Mortensen'4 suggested tht 24 hour cretinine clernce is more relible thn predicted clernces, but bsed this conclusion on dt from the men of three urine collections discrding ptients with vrible results from the nlyses. The comprisons from our study suggest tht mesured cretinine clernce in clinicl prctice, even with short supervised urine collection periods, is likely to be no better thn nd probbly less ccurte thn predicted clernces. The limittions of the prediction methods hve been reviewed recently by Smith.'5 In ptients with mrked obesity predicted cretinine clernce will overestimte true GFR4 nd in this sitution, idel body weight cn be used in the equtions to improve ccurcy. Prediction methods should lso be voided in ptients with heptic dysfunction,5 6 nd if renl function is rpidly chnging. Appliction of this pproch without considertion of such fctors my hve contributed to the conclusions of other investigtors tht the coefficient of vrition of predicted cretinine clernce ws too gret for it to be of clinicl vlue Cretinine clernce is more esily interpreted index of renl function thn serum cretinine lone. Our results suggest tht predicted cretinine clernce provides simpler nd probbly more ccurte lterntive to mesured clernces for determining GFR. Nevertheless, it should be Tble II Percentge ( ± stndrd error) overestimte between cretinine clernces reltive to isotopic GFR for subjects with GFR less thn 5 ml/min compred to those with GFR greter thn 5 ml/min GFR less GFR greter thn thn Significnce 5 ml/min 5 ml/min of difference 2 h Cretinine clernce 61 ± ± 4 P<.5 4 h Cretinine clernce 16 ± 1 11 ± 5 N.S. 24 h Cretinine clernce 28 ± ± 4 N.S. Cockcroft nd Gult 6 ± 3-2 ± 2 P <.5 Postgrd Med J: first published s /pgmj on 1 Jnury Downloded from on 21 August 218 by guest. Protected by

5 46 D.G. WALLER et l. remembered tht ll methods for determining cretinine clernce re inccurte nd tht isotopic estimtions of GFR re desirble when greter precision is required. References 1. Bjornsson, T.D. se of serum cretinine concentrtions to determine renl function. Clin Phrmcokinet 1979, 4: Richrdson, J.A. & Philbin, P.E. The one hour cretinine clernce rte in helthy men. JAMA 1971, 216: Wller, D.G., Kest, C.M., Fleming, J.S. & Ackery, D.M. Mesurement of glomerulr filtrtion rte with Tc99m- DTPA: Comprison of plsm clernce techniques. J Nuci Med 1987, 28: Hull, J.H., Lwrence, J.H., Kock, G.G., Wrgin, W.A., Shelly, L.C. & Mttocks, A.M. Influence of rnge of renl function nd liver disese on predictbility of cretinine clernce. Clin Phrmc Ther 1981, 29: Cockcroft, D.W. & Gult, M.H. Prediction of cretinine clernce from serum cretinine. Nephron 1976, 16: Bjornsson, T.D., Cocchetto, D.M., McGown, F.X., Verghese, C.P. & Sedor, F. Nomogrm for estimting cretinine clernce. Clin Phrmcokinet 1983, 8: Rehling, M., Moller, M.L., Thmdrup, B., Lund, J. & Trp-Jensen, J. Simultneous mesurement of renl clernce nd plsm clernce of 99mTc DTPA, 51Cr EDTA nd inulin in mn. Clin Sci 1984, 66: Brochner-Mortensen, J. & Rodbro, P. Selection of routine method for determintion of glomerulr filtrtion rte in dults. Scnd J Clin Lb Invest 1976, 36: Miller, B.F., Lef, A.L., Mmby, A.R. & Miller, Z. Vlidity of the endogenous cretinine clernce s mesure of glomerulr filtrtion rte in the disesed humn kidney. J Clin Invest 1952, 31: Hgstm, K.E., Nordenfelt, I., Svensson, L. & Svensson, S.E. Comprison of different methods for determintion of glomerulr filtrtion rte in renl disese. Scnd J Clin Lb Med 1974, 34: Acknowledgements We thnk Sue O'Toole for nursing ssistnce, the Chemicl Pthology stff for cretinine clernce nlyses nd Dinne Wilson for typing the mnuscript. 11. Chrleson, H.A., Biley, R.R. & Stewrt, A. Quick prediction of cretinine clernce without the necessity of urine collection. NZ Med J 198, 92: Brochner-Mortensen, J., Jensen, S., & Rodbro, P. Assessment of renl function from plsm cretinine in dult ptients. Scnd J rol Nephrol 1977, 11: Heierli, Ch., Th6len, H. & Brtels, H. Schtzung des glomerulumfiltrtes durch ds serum kretinin. Dtsch Med Wochenschr 1972, 97: Brochner-Mortensen, J. Routine methods nd their relibility for ssessment of glomerulr filtrtion rte in dults. Dn Med Bull 1978, 25: Smith, S.A. Estimtion of glomerulr filtrtion rte from the serum cretinine. Postgrd Med J 1988, 64: Cocchetto, D.M., Tschnz, C. & Bjornsson, T.D. Decresed rte ofcretinine production in ptients with heptic disese: implictions for estimtion ofcretinine clernce. Ther Drug Mon 1983, 5: Rolin, H.A., Hll, P.M. & Wei, R. Inccurcy of estimted cretinine clernce for prediction ofiothlmte glomerulr filtrtion rte. Am J Kidney Dis 1984, 4: Trollfors, B., Alestig, K. & Jgenburg, R. Prediction of glomerulr filtrtion rte from serum cretinine, ge, sex nd body weight. Act Med Scnd 1987, 221: Trollfors, B., Alestig, K. & Jgenburg, R. Prediction of glomerulr filtrtion rte from chnges in serum cretinine. Scnd J Clin Lb Invest 1988, 48: Groth, S., Asted, M. & Vestergrd, B. Screening of kidney function by plsm cretinine nd single-smple Cr EDTA clernce determintion - comprison. Scnd J Clin Lb Invest 1989, 49: Postgrd Med J: first published s /pgmj on 1 Jnury Downloded from on 21 August 218 by guest. Protected by