Iohexol clearance for GFR-determination in renal failure single or multiple plasma sampling?

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1 Nephrl Dial Transplant (996) : Technical Reprt Nephrlgy Dialysis Transplantatin Ihexl clearance fr GFR-determinatin in renal failure single r multiple plasma sampling? G. Sterner, B. Frennby, B. Hultberg 2 and T. Almen Divisin f Nephrlgy, Department f Vascular and Renal Diseases, 'Department f Diagnstic Radilgy, University Hspital, Malm and 2 Department f Clinical Chemistry, University Hspital, Lund, Sweden Abstract The present study examined the agreement between single and multiple sample plasma clearance f ihexl, a nn-inic cntrast agent, in renal failure. Sixty-five patients with varying degree f renal insufficiency received 0 ml ihexl (300 mg I/ml) i.v. and plasma samples were cllected fur times during the fllwing 3-24 h. Plasma-idine cncentratins were determined by X-rayflurescence.Predicted creatinine clearance was used t chse ne f the samples fr determinatin f single sample clearance. A single plasma specimen cllected at 4 h fr GFR abve 50 ml/min, at 7 h fr GFR between 20 and 50 ml/min, and at 24 h fr GFR belw 20 ml/min gave values in gd agreement with thse based n a fur sample slpe clearance. N sign f nephrtxicity was nted after administratin f the cntrast agent. It is cncluded that single sample plasma clearance after single injectin f ihexl gives a gd estimate f GFR in renal failure and is advantageus in clinical practice. Key wrds: glmerular nitratin rate; ihexl; single sample clearance; NAG Intrductin Glmerular nitratin rate (GFR) can accurately be determined frm plasma clearance f ihexl after a single blus injectin. Gd agreement was bserved between the plasma clearance f ihexl and ther GFR-markers such as radilabelled EDTA, DTPA, and inulin in adults [-5] and in children [6]. Clearance based n a single plasma sample has recently als been recmmended fr GFR-determinatin either separately [5,7-0] r in cnnectin with a radilgical examinatin []. There are tw prerequisites fr the methd: (i) there is knwledge abut the distributin vlume f the GFR-marker and (ii) the plasma sample is cllected at the time-pint when the size f the distributin vlume has a minimal influence n the Crrespndence and ffprint requests t: Gunnar Sterner MD, Divisin f Nephrlgy, Department f Vascular and Renal Diseases, Malm University Hspital, S Malm, Sweden. mathematical calculatin f the GFR. As renal functin declines this ideal time-pint must gradually be pstpned. Severe reductin f renal functin demands prlngatin f the sampling time fr at least 24 h fr bth single sample clearance and slpe clearance technique [2]. A prblem arises when chsing the timepint fr single sample clearance as renal functin culd be difficult t estimate, e.g. by serum creatinine. We hypthesized that if we guessed the apprximate level f GFR with aid f a predicted creatinine clearance [3] we might then be able t chse the apprpriate sampling time necessary fr an accurate determinatin f GFR with single sample clearance. The aim f the present study was t study patients with reduced renal functin and t cmpare ihexl clearance values based n single and multiple plasma samples. T evaluate if the prper sampling time fr single sample clearance can be estimated in advance a predicted creatinine clearance [3] was used. Furthermre the txic influence f ihexl n glmerular and tubular functins was studied. Subjects and methds Sixty-five patients (28 females) with varying degree f renal failure were included in the study. Mean age was 53 years (range 9-79 years). Frty-ne patients had received a renal transplant mre than 3 mnths earlier and had stable renal functin. The remaining 24 patients had varying degree f chrnic and stable renal failure. The diagnses f the 65 patients are shwn in Table. Mean serum-creatinine f the grup was 207 uml/ (range uml/). The patients were examined in a nn-fasting state. In the Table. Diagnsis f the 65 patients studied Chrnic glmerulnephritis/vasculitis Diabetic nephrpathy Plycystic kidney disease Pyelnephritis Nephrsclersis Alprt's syndrme r ther hereditary diseases Amylidsis Dwnladed frm by guest n 4 Nvember 208 ) 996 Eurpean Dialysis and Transplant Assciatin-Eurpean Renal Assciatin

2 522 G. Sterner et al. mrning they were given 0 ml ihexl (Omnipaque 300 mg I/ml) i.v. in ne frearm thrugh a venus cannula. All bld samples were cllected frm the cntralateral arm. Predicted creatinine clearance using s-creatinine, age, sex and weight was calculated accrding t the Cckcrft-Gault frmula [3]. The prtcl was apprved by the lcal ethics cmmittee and every patient gave infrmed cnsent. Multiple sample plasma clearance (Cl slpe) Fur plasma samples were drawn 3, 4, 7, and 24 h after the i.v. injectin f ihexl. Plasma-idine cncentratins were determined with X-ray flurescence analysis (Renalyzer, Prvalid AB, Lund, Sweden). Using a cmputerized prgram clearance was calculated accrding t the slpe-intercept methd with estimatin f the area under the curve [4]. The area was crrected fr the early distributin phase accrding t Brchner-Mrtensen [4]. The determinatin f the slpe clearance was based n all fur plasma samples except in sme patients with nearly nrmal GFR, in whm the last sample was excluded. In these patients the last bld sample after 24 h cntained idine belw the detectin limit. Single sample plasma clearance (Cl ss ) The methd described by Jacbssn [7] was used with crrectins fr lack f cmplete unifrm distributin and nn-immediate mixing. The distributin vlume was calculated as a functin f the bdy weight [5]. The time fr plasma sampling after injectin f marker was chsen as fllws: with a predicted clearance abve 50 ml/min the plasma sample was taken after 4 h, with a predicted clearance f ml/min after 7 h and belw 20 ml/min after 24 h. CI SS = t/v Where Q tt is the ttal injected amunt f idine (mg), * = the time interval between injectin and sampling (min), C, = the idine cncentratin in the plasma sample taken at the time (t) and K=the distributin vlume (ml) f the patient. The clearance values were adjusted t.73 m 2 bdy surface. Renal txicity parameters Any adverse reactin that the patients reprted after the cntrast medium injectin was registered. The transplanted patients were examined n the mrning befre and n the tw days fllwing the injectin f ihexl. S-creatinine was measured using a rutine Jaffe methd. Albumin/creatinine rati was determined. The fractinal excretin f albumin (brmcresl purple methd) was calculated as the rati between the albumin clearance and the creatinine clearance (nrmal value belw 0.0 x 0" 3 ). Urine albumin was analysed using electrimmunassay with human albumin as standard. N-acetyl-beta-glucsaminidase (NAG) was determined in urine accrding t Hultberg and Wieslander [6]. Statistical analysis Linear regressin analysis was used t examine the assciatin between single and multiple plasma clearance. Agreement between the methds was evaluated accrding t Bland and Altman [7]. Renal txicity parameters were expressed as mean and range and differences between grups assessed by ANOVA, and paired and unpaired Mest. Results Crrelatin between ihexl clearance derived frm a single plasma sample and frm the traditinal multiple sample slpe was gd (r 2 = 0.96). The individual measurements fr the whle material and fr GFR belw 40 ml/min are given in Figures and 2. The difference between the fur sample and the single sample plasma clearance against the mean f the tw methds is shwn in Figure 3a tgether with the 95% limits f agreement. Figure 3b shws the lgtransfrmed data. The antilgs f the limits f agreement was 0,66 and,24 demnstrating that 95% f the single sample clearance fell within 0,66 and,24 times the fur sample clearance values. By chsing a t early plasma sample (n the basis f the predicted creatinine clearance) an verestimatin f GFR was nted fr the single sample methd in sme cases. When the sampling time fr Clss was chsen retrspectively frm the slpe clearance, Clss Slpe clear, ml/min/.73 m2 Fig.. Ihexl plasma clearance determined with the fur-sample methd and the single sample methd using the predicted sampling time-pint-whle material Slpe clear, ml/min/.73 m2. Fig. 2. Ihexl plasma clearance determined with the fur-sample methd and the single sample methd. Only values belw 40 ml/min/.73 m 2 are included. Dwnladed frm by guest n 4 Nvember 208

3 Ihexl clearance in renal failure Q -40 (a) ID "5.,8,6 -,4 ",2 T -.2" in ' - -, 6 - Q -.8 (b) a Mean f slpe and single sample clear. D cp (P v Mean f slpe and single sample clear. Fig. 3. Relatinship between the difference f multiple and single sample clearance and the average f the tw methds, (a) The mean difference and the 95% limits f agreement are given (ml/min/.73 m 2 ). (b) Lg-transfrmed values. and Clslpe agreed better than abve (Fig. 4). As culd be expected a very lw degree f agreement was fund when cmparing predicted creatinine clearance directly with fur sample clearance (Fig. 5). As bld sampling was extended fr 24 h the patients were under clse supervisin. There were n reprted adverse effects (as urticaria, flushing, and itching) in cnjunctin with the injected cntrast medium in any f the 65 subjects. U-NAG levels were significantly raised befre injectin f cntrast medium in the grup f transplanted patients cmpared with a reference ppulatin (0.57, versus 0.2, ; mean, range, P<0.00). Table 2 shws the effect f a lw dse ihexl administratin t patients with a renal graft. There was n statistically significant change in neither the U-NAG cncentratins nr in s-creatinine and the albumin-creatinine clearance rati. Discussin GFR is frequently calculated frm the dse given and the plasma slpe curve after single injectin f a Mean f slpe and single sample clear, (retrsp. value) Fig. 4. Difference between multiple and single sample clearance against the mean (ml/min/.73 m 2 ). The time pint fr single sample clearance was estimated retrspectively frm slpe clearance. S g *? r O cp 0 0 CD 9ft Mean f slpe and predict creat clear. Fig. 5. Agreement between fur sample plasma clearance and predicted creatinine clearance (Cckcrft-Gault). Difference against mean fr the tw methds (ml/min/.73 m 2 ). suitable marker [4]. Recently reprts have described a simplicatin using nly ne plasma sample [8,9]. Jacbssn [7] intrduced crrectin factrs fr lack f unifrm distributin f the GFR-marker and fr the nn-immediate mixing. Several ther substances have been utilised fr determinatin f single sample clearance [8,20-22]. The single sample methd has been recmmended dwn t a GFR f 30 ml/min [23]. Accrding t theretical estimatins later plasma samples are necessary fr accurate determinatin f single sample clearance when renal functin declines further. Jacbssn [7] calculated the ptimal sampling time at a GFR f 30 ml/min t be 8-9 h. We have reprted excellent agreement between single and multiple plasma sample ihexl clearances in patients with lw GFR [2]. Prlngatin f the sampling time up t 24 h is necessary in either clearance methd if reliable GFR values are sught. In clinical practice it is, hwever, smetimes difficult in advance t estimate renal functin and thus t chse the Dwnladed frm by guest n 4 Nvember 208

4 524 G. Sterner et al. Table 2. Results f the renal txicity study in patients with stable renal allgraft after the administratin f ihexl. Values are given as mean and range. Analysis f variance was perfrmed and revealed n changes between the grups Befre day after 2 days after S-creatinine (uml/) n = 40 Albumine/creat. clearance rati H = 40 U-NAG (U/mml creat.) TJ = 38 40, , , , , , , , , prper bld sampling time which is crucial in single sample clearance. The present study clearly demnstrates that a predicted creatinine clearance is useful t estimate the prper bld sampling time fr an accurate GFR determinatin. Althugh a better agreement culd be achieved between single and multiple sample clearance by chsing the sampling time retrspectively, the predicted single sample clearance seems t be useful in the clinic. Brwn and O'Reilly [5] nted an excellent crrelatin between the renal clearance f inulin and f ihexl, as well as between the renal clearance f inulin and the plasma slpe clearance f ihexl. Clearance based n a single plasma sample at three hurs shwed slightly less gd crrelatin with renal inulin clearance, at least in the lwer GFR range (r = 0.96). Thmsen et al. [24] examined patients underging radi cntrast enhanced CT. The crrelatin between single sample clearance after three t fur hurs and multiple plasma sample clearance was gd. A tendency twards falsely high values fr single sample clearance when GFR was lw and the ppsite when GFR was high was nted using this early bld sampling. The single sample clearance has shwn slightly larger variatin than clearance based n fur plasma samples when cmpared with a clearance where a 'true' estimatin f the area under the curve was calculated frm 4 bld samples [9]. Difficulties in determining the extracellular vlume in which the GFR-marker is distributed has been reprted fr single sample clearance [4,23]. Knwledge f the distributin vlume is mandatry when calculating single sample clearance. Severe edema, smetimes fund in patients with renal r hepatic failure, culd interfere with the calculatin f distributin vlume fr the GFR-marker. In these ccasins single sample but als multiple sample clearance culd give errneus values fr GFR [5,25]. We nted identical values fr ihexl when cmparing single and multiple sample clearance in three patients with ascites (nn-published bservatins). Renal clearance f e.g. radi cntrast media is the nly way t eliminate the prblem with capricius estimatins f the extracellular vlume. A prerequisite fr using the GFR-marker in renal failure is that it is nn-txic. The safety f the cntrast agent used in this study was therefre paid special interest. We fund n signs f cntrast nephrtxicity as n statistically significant increase culd be fund f urinary NAG after the ihexl administratin. This enzyme is knwn t be a very sensitive test and is cnsidered t detect even a slight renal injury [26,27]. This cnfirms the results frm an earlier ihexl study [2]. The cntrast dse used in the present study was well tlerated by the patients. In a larger material f apprximately 4000 ihexl clearance measurements n severe adverse reactin was nted [28]. In cnclusin clearance based upn multiple bld samples can be substituted by a single bld specimen clearance in patients with reduced renal functin. The accuracy f the methd is, hwever, dependent n prper sampling time and n universal pint f time can be used fr all GFR-levels. Single sample clearance gives fr clinical purpse useful estimatin f GFR and is clearly advantageus fr the patients. References. Krutzen E, Back SE, Nilssn-Ehle I, Nilssn-Ehle P. 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5 Ihexl clearance in renal failure Jacbssn L. The use f ihexl clearance t determine GFR in patients with severe chrnic renal failure. Clin Nephrl 995; 43: Gault MH, Lngerich LL, Haraett JD, Weslvski C. Predicting glmerular functin frm adjusted serum creatinine. Nephrn 992; 62: Brchner-Mrtensen J. A simple methd fr the determinatin f glmerular nitratin rate. Scand J Clin Lab Invest 972; 30: Graneus G, Jacbssn L. Berakning av 5 Cr-EDTA single injectin clearance jamfrelse mellan flerpunkts ch enpunktsfrmel. Svensk frening fr Medicinsk Radilgi. Frhandlingar Hultberg B, Wieslander J. Urinary excretin f betahexsaminidase in patients with vesic-ureteric reflux. Ada Med Scand 982; 2: Bland JM, Altman DG. Statistical methds fr assessing agreement between tw methds f clinical measurement. Lancet 986; i: Fisher M, Veall N. Glmerular filtratin rate, estimatin based n a single bld sample. Br Med J 975; 2: Grth S, Aastad M. Cr-EDTA clearance determined by ne plasma sample. Clin Physil 98; : Russel CD, BischffPG, Kntzen FN, Rwell KL, Yester MV, Llyd LK, Tauxe WN, Dubvsky EV. Measurement f glmerular filtratin rate: single injectin plasma clearance methd withut urine cllectin. J Nucl Med 985; 26: Tauxe WN. Determinatin f glmerular filtratin rate by singleplasma sampling technique fllwing injectin f radiidinated diatrizate. J Nucl Med 986; 27: Schumann L, Wustenberg PW, Hrtian B, Kuhnle HF. Determinatin f glmerular filtratin rate (GFR) n tw cnsecutive days using inulin in a single sample plasma clearance methd. Clin Nephrl 993; 39: Chattertn BE. Limitatin f the single sample tracer methd t determining glmerular filtratin rate. Br J Radil 978; 5: Thmsen HS, Vestergaard A, Glman K, Drph S. One r tw samples fr determinatin f ttal plasma clearance f a nninic cntrast medium in patients underging enhanced CT. Ada Radil 992; 33: Brchner-Mrtensen J. Current status n assessment and measurement f glmerular filtratin rate. Clin Physil 985; 5: Hultberg B, Isakssn A, Sterner G, Weibull H. Enzyme immunassay f urinary beta-hexsaminidase isenzymes in patients with renal transplants. Clin Chim Ada 990; 92: Sterner G, Weibull H, Hultberg B, Bergqvist D, Hulthen L, Isakssn A, Manheim P. Determinatin f urinary N-acetylbeta-glucsaminidase in patients with hypertensin and renal artery stensis. J Int Med 993; 234: Nilssn-Ehle P, Grubb A. New markers fr the determinatin f GFR: ihexl clearance and cystatin C serum cncentratin. Kidney Int 994; 46 (Suppl. 47): S7-S9 Received fr publicatin: Accepted in revised frm: Dwnladed frm by guest n 4 Nvember 208