1326
CLIN A PR CTI E
Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate
Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/ClI) ranged from 1·14 to 2·27. With cimetidine, ClC/ClI approached unity in 8 patients (mean 1·02 [SD 0·03]), but considerably exceeded unity in 8 others (1·33 [0·14]). Plasma cimetidine/ creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p=0·01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibition previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures G FR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.
Introduction
Endogenous creatinine clearance can be measured easily, whereas accurate assessments of renal function are inconvenient, time-consuming, and expensive. However, creatinine clearance overestimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. 1,2 The contribution of tubular secretion to total clearance of creatinine is increased in patients with renal disease, especially in those with glomerular disorders,3-7 and this contribution varies over time within patients.8 Creatinine clearances twice or even three times actual GFR are not
exceptional. 3-7 Cimetidine inhibits tubular secretion of creatinine9 without altering GFR, thereby reducing the overestimation of GFR. Although use of cimetidine improves the accuracy of measuring creatinine clearance,7,10,11 guidelines for dose and duration of treatment have not been provided. Furthermore, more accurate assessment of creatinine clearance by cimetidine in short-term studies during the day7,10,11 does not necessarily imply the same improvement during the night, because tubular secretion of creatinine is highest at night-time." Also, when 24 h creatinine clearance with cimetidine is compared with short-duration GFR assessment, as in previous studies,lo,11one has to be aware of the circadian rhythm in GFR.12,13 Previously, in healthy subjects, we observed that the clearance of creatinine was similar to that of GFR during administration of cimetidine both in the day and during the ADDRESSES: Renal Unit, Department of Medicine (B. A. C. van Acker, MSc, M. G. Koopman, MD, Prof L. Arisz, MD), and Department of Clinical Chemistry (G. C. M. Koomen, MSc, D. R. de Waart, MSc), Academic Medical Centre, Amsterdam, Netherlands. Correspondence to Ms B. A. C. van Acker, Renal Unit F4-215, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
1327
night.12 Here we have investigated whether the same holds true in patients with impaired renal function. If so, 24 h creatinine clearance with cimetidine might be a simple and convenient method for accurate measurement of GFR. We measured inulin clearance simultaneously as the goldstandard for GFR.
Patients and methods Patients 22 patients with various renal dieases (14 men, aged 18-81 years) participated as inpatients or outpatients. All had impaired renal function (inulin clearance 10-68 ml/min per 1 ’73 m2). Renal biopsy in 15 patients revealed systemic lupus erythematosus (5 cases), focal local glomerulosclerosis (3), chronic glomerulonephritis (2), membranous nephropathy (2), and mesangiocapillary proliferative glomerulonephritis, microscopic polyarteritis nodosa, and IgA nephropathy (1 each). The other patients had impaired renal function due to hypertension (3), congestive heart failure or urinary tract infection (1 each), and reason unknown (2). All but 5 patients had proteinuria, with urinary albumin excretion ranging from 0’ 5 to 12 g per 24 h. No subject was oedematous. Icteric patients were excluded and no diuretics were used during the study because of possible interference with creatinine measurements.14 No drugs known to interfere with creatinine secretion were used. Immunosuppressive and/or antihypertensive drugs were continued as prescribed. All patients gave informed consent and the protocol was approved by the medical ethics committee of the University Hospital of Amsterdam.
Study design The study was in two successive parts. In the first, 16 patients examined for 30 h starting at 1500 h. To create standard conditions the subjects were supine throughout and had identical intake of food and fluid every 3 h. Fluid intake was at least 300 ml per 3 h to ensure sufficient flow of urine, to prevent tubular reabsorption of creatinine.15 Sodium intake was adjusted to the sodium content of a patient’s usual diet, and ranged from 20 to 150 mmol per 24 h. Coffee and smoking were not permitted. Subjects were allowed to sleep from 2300 to 0800 h between sample and meal times. At onset of the study a priming intravenous injection of inulin 60 mg/kg (Inutest, Laevosan Gesellschaft, Linz, Austria) was administered, and followed by continuous infusion at a rate calculated to achieve plasma levels of 400 mg/1. After equilibration (1500-1800), observations started at 1800 h and continued for 27 h. Every 3 h urine was collected by spontaneous voiding and peripheral venous blood was sampled. The first 3 h clearance period was without cimetidine (Tagamet), which was then administered at 2100 h with an oral priming dose of 400 mg followed by 200 mg every 3 h. In an additional short-term study the effect of cimetidine 400 mg at 1230 h, followed by 200 mg 3 h later, was compared with that of a single dose of cimetidine 1200 mg at 1230 h. The other 6 patients were thus studied on two consecutive days. Successive 112 h clearances of inulin and creatinine were measured on both days before and during at least 6 h after cimetidine. were
Laboratory methods Urine and plasma concentrations of inulin were measured by a modification of Walser’s method with the colour reagent diphenylamine.16 Plasma and urinary creatinine concentrations were assayed by a modified Jaffé reaction in a SMAC/SMA autoanalyser (Technicon). The intra-assay coefficient of variation was 3% for inulin and creatinine. Urine and plasma concentrations of cimetidine were measured by high-performance liquid-
chromatography. 17 Calculations and statistics Clearances of inulin and endogenous creatinine
were calculated UV -’ PAt, where U is urinary concentration, V is urine volume, P is the arithmetic mean of the plasma concentrations at the
as
at baseline and during administration cimetidine in 16 patients with impaired renal function.
Fig 1-Clc/CIl
of
beginning and end of each clearance period, and At is duration of the period. Errors introduced by incomplete urine voiding were corrected.12 Creatinine relative to inulin clearance (CIc/CII) was calculated before (baseline) and during administration of cimetidine. This ratio demonstrates to what extent creatinine clearance overestimates GFR. The ratio should be close to unity when tubular creatinine secretion is completely inhibited. In each patient the clearance calculations (per 3 h periods) during cimetidine treatment (excluding the first 3 h equilibration) were averaged for further analysis. The overall coefficient of variation for CIc/CII was 6%. We therefore defined inhibition as being incomplete when CIc/CII during cimetidine exceeded 1 ’06. The rate of tubular secretion of creatinine (TSc), expressed as umol/h, was calculated by subtracting the filtered creatinine load from urinary creatinine excretion, where filtered load is GFR multiplied by plasma creatinine concentration. All data are expressed as mean (SD), unless stated otherwise. Linear regression was used to study the relation between CIc/CII and GFR. The paired t test was used for within-group comparisons. Differences between subgroups were evaluated by the two-sample t test. A one-sided test was used for the comparison of cimetidine/ creatinine ratios between two subgroups. All other tests were two-tailed, with 0-05 as the level of significance.
Results Neither dose of cimetidine had any effect on GFR measured by inulin clearance whereas creatinine clearance decreased. Mean GFR was 40-1(14.6) ml/min per 1 73 m2 at baseline compared with 40-6 (15-0) ml/min per 1-73 m2 at 1800-2 100 h with cimetidine. There was a striking variation in CIc/CII at baseline, ranging from 1- 14 to 2.27 (fig 1). The amount of overestimation of true GFR by creatinine clearance was not associated with extent of renal functional impairment. Although all patients showed smaller Clc/CII during cimetidine administration, complete inhibition of tubular creatinine secretion occurred in 8 patients only. Even with cimetidine, creatinine clearance considerably overestimated GFR in the other 8. The mean true 24 h GFR (inulin clearance) was 39-5 (15-7) ml/min per 1-73 m2 in the group with incomplete inhibition and 38 2 (12 6) ml/min per 1-73 m2 in patients with complete inhibition. The maximum effect of cimetidine was not achieved during the first urine collection period (2100-2400 h) which was therefore excluded in further analyses. Within each subject, cimetidine equally affected creatinine clearance at allclearance periods (fig 2). When complete inhibition was practically achieved, CIc/CII
1328
Average
GFR
by Clc and Cl(ml/min
Fig 4-Difference in GFR by
Clc
and
Ch
versus
per 1
73m)
average GFR.
Upper=without cimetidine and lower=with adequate dose of cimetidine, n=14.
Fig 2-Creatinine and inulin clearance before and during administration of cimetidine in 2 patients.
approached unity at each clearance interval. Similarly, incomplete inhibition of creatinine secretion was characterised by substantial overestimation of GFR throughout. The TSc that is inhibited by cimetidine was related to initial TS y x is the line on which all points would lie if inhibition was complete (fig 3). Inhibition of TSc by cimetidine was complete for low initial TSc values and incomplete for higher values, which suggests that the dose of cimetidine might have been insufficient in those with higher initial TSc. Support for this hypothesis comes from the lower plasma cimetidine/creatinine ratio observed at incomplete inhibition: 0-040 (0018) versus 0 064 (0-030). The difference (A) was 0-024 with 95% CI 0-003-0-046 =
(p 0-03). This lower ratio was due to higher renal clearance of cimetidine at incomplete inhibition: 333 (136) versus 165 (89) ml/min, A = 168 ml/min, 95% CI 45-291 (p 0-01). As a result, plasma cimetidine concentration was lower: 1 43 (0-66) versus 2-50 (1-02) mg/1, A= 1-07 mg/1, 95% CI 0-15-2-00 (p = 0-03). With a single dose of cimetidine 1200 mg, plasma cimetidine/creatinine ratio rose (0-031 [0’012] to 0-094 [0-039]). This increased dose resulted in more complete inhibition (fig 4) by movement towards y=x. Cimetidine concentrations peaked 3 h after ingestion of the drug. On average, inhibition was most complete between 3 and 6 h =
=
after cimetidine had been administered. Thereafter the effect of cimetidine on tubular creatinine secretion levelled off. In the study of the adequacy of the dose of cimetidine (ie, 1-8 g per 24 h in 8 patients and 1-2 g per 6 h in 6), the two methods of GFR measurement (inulin and creatinine clearance) disagreed without administration of drug. Good agreement was achieved after a sufficient dose (fig 4). No patient had side-effects to cimetidine.
Discussion Cimetidine 200 mg every 3 h reduced the overestimation of GFR by creatinine clearance in all patients. Although within each patient creatinine clearance was equally affected by cimetidine at all clearance periods, GFR was still overestimated in some who had a high tubular secretory rate of creatinine and in whom tubular creatinine secretion was
completely inhibited until plasma cimetidine concentration (ie, the dose of cimetidine) had been increased. Creatinine clearance in 22 patients with renal disease overestimated true GFR by 60% on average, which is similar to other studies.3,s,7,1O Most investigators attribute the disparity to tubular creatinine hypersecretion. The amount of overestimation has been associated with the extent of renal functional impairment.6,7,18 A significant, although not very strong, inverse relation occurs between CIc/CII and GFR (r=-0-61, n=123; r= -.049, not
mmai
i 5 tJJmoltn)
Fig 3-TSc inhibited by cimetidine administration of cimetidine.
versus
that without
=16 patients with impaired renal function.. = additional patients with incomplete inhibition previously, in whom ingestion of 1200 mg cimetidine resulted in increased plasma cimetidine concentration and consequently in more complete inhibition (D).
1329
this relation was not confirmed with of observations. our smaller number Reduction of tubular creatinine secretion by cimetidine is assumed to be the result of competitive inhibition of a common transport system in the proximal renal tubule. Creatinine and cimetidine are secreted by the organic cation secretory system.19 Cimetidine is supposed to have a much higher affinity for the carrier at the luminal membrane of the proximal tubule than does creatinine, which explains the inhibition of tubular secretion of creatinine.2D We indeed saw an acute fall in creatinine clearance after oral ingestion of cimetidine while GFR was unchanged. Besides the first 3 h equilibration, cimetidine equally influenced creatinine secretion during the day and night. Thus there is no need to preload patients with cimetidine several days before measurements of renal function.lO,l1 With respect to reabsorption of cimetidine and delay in urine collection, only the first 3 h period is inadequate. By contrast with our findings" in healthy volunteers, which showed complete inhibition with the same dose of cimetidine, tubular creatinine secretion was not fully inhibited in some patients with renal disease-ie, those with high tubular secretory rate of creatinine (plasma creatinine was similar in our two groups of patients). Patients with incomplete inhibition also had a larger renal clearance of cimetidine compared with patients with complete inhibition, which, similar to the situation with creatinine, was the result of higher cimetidine clearance by tubular secretion,21 and the two groups of patients had similar GFR. Because of the higher renal clearance, plasma cimetidine was lower in patients with incomplete inhibition, as was the plasma cimetidine/creatinine ratio. This ratio is important in competitive inhibition and, depending on relative affmities for the transport process, a certain plasma ratio of unbound competitive compounds is necessary to induce complete inhibition,22 which was illustrated in the second part of our study. In patients with incomplete inhibition previously, complete inhibition was achieved by a higher cimetidine dose resulting in a higher cimetidine/creatinine plasma ratio. The patient in fig 2 with the higher tubular secretory rate of creatinine had a higher plasma creatinine (320 pmol/1) than the others ( < 220 jmol/1), which might explain the slightly less complete inhibition even at cimetidine 1200 mg. Cimetidine 1 8 g every 24 h was inadequate in some patients for 24 h measurements of creatinine clearance. A higher dose is needed here to inhibit completely tubular creatinine secretion. With 24 h creatinine clearance, however, the implication is that the maximum daily dose that is advised has to be exceeded. Clearances of shorter duration are therefore recommended. A single dose of 1200 mg cimetidine adequately inhibited tubular creatinine secretion 3-6 h post-ingestion, at least in patients with plasma creatinine up to 220 umol/1. Whether or not a patient will need a high cimetidine dose depends on a patient’s plasma creatinine, body weight, and cimetidine clearance, which all influence cimetidine/creatinine plasma ratio. Such patients cannot yet be identified, because cimetidine clearance will not be known. A CIclCI ratio of 1-16 (SD 021) after intravenous infusion of cimetidine 400 mg has been observed in glomerulopathic patients.7 In patients with lupus nephritis, creatinine relative to diethylenetriamine pentaacetic acid clearance was 1-14 (95% CI 1-06-1-22) after oral cimetidine four times 400 mg in 24 h.1D In these studies tubular creatinine secretion was seemingly not completely inhibited in all patients. Hilbrands et all’ reported a CI/CI ratio of
n=171).6However,
0 96 (008) after oral cimetidine 1000-2000 mg in 24 h in three to four smaller doses, which suggests complete inhibition. However, their pre-cimetidine ratios (123 [0’20]) were also low, which indicates no large overestimation of the GFR they had measured before
cimetidine. The procedure we advise is (1) an ample water intake during the measurements, (2) collection of urine from the third until the sixth hour after oral cimetidine 1200 mg, and (3) blood samples at the beginning and end of urine collection. We thank Dr J. G. P. Tijssen, department of clinical epidemiology and biostatistics, for statistical advice, Dr J. A. Weber and technicians from the department of clinical chemistry for measuring creatinine, Mr K. J. Hiralall for measuring cimetidine and inulin, Mrs C. F Jonkers for dietary advice, and the nursing staff of ward F5NS for technical assistance.
REFERENCES 1. Shannon J. The renal excretion of creatinine in man. J Clin Invest 1935; 14: 403-10. 2. Miller BF, Winkler AW. The renal excretion of endogenous creatinine in man. Comparison with exogenous creatinine and inulin. J Clin Invest 1938; 17: 31-40.
3. Berlyne GM, Varley H, Nilwarangkur S, Hoerni M. Endogenous creatinine clearance and glomerular filtration rate. Lancet 1964; ii: 874-76. 4. Hood B, Attman PO, Ahlmén J, Jagenburg R. Renal hemodynamics and limitations of creatinine clearance in determining filtration rate in glomerular disease. Scand J Urol Nephrol 1971; 5: 154-61. 5. Carrie BJ, Golbetz HV, Michaels AS, Myers BD. Creatinine: an
inadequate filtration marker in glomerular diseases. Am J Med 1980; 69: 177-82. 6. Bauer JH, Brooks CS, Burch RN. Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 1982; 2: 337-46. 7. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985; 28: 830-38. 8. Petri M, Bockenstedt L, Colman J, et al. Serial assessment of glomerular filtration rate in lupus nephropathy. Kidney Int 1988; 34: 832-39. 9. Burgess E, Blair A, Krichman K, Cutler RE. Inhibition of renal creatinine secretion by cimetidine in humans. Renal Physiol 1982; 5: 27-30. 10. Roubenoff R, Drew H, Moyer M, et al. Oral cimetidine improves the accuracy and precision of creatinine clearance in lupus nephritis. Ann Intern Med 1990; 113: 501-06. 11. Hilbrands LB, Artz MA, Wetzels JFM, Koene RAP. Cimetidine improves the reliability of creatinine as a marker of glomerular filtration. Kidney Int 1991; 40: 1171-76. 12. van Acker BAC, Koomen GCM, Koopman MG, Krediet RT, Arisz L. Discrepancy between circadian rhythms of inulin and creatinine clearance. J Lab Clin Med 1992; 120: 400-10. 13. Koopman MG, Koomen GCM, Krediet RT, de Moor EAM, Hoek FJ, Arisz L. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci 1989; 77: 105-11. 14. Weber JA, van Zanten AP. Interferences in current methods for measurements of creatinine. Clin Chem 1991; 37: 695-700. 15. Levinsky NG, Berliner RW. Changes in composition of the urine in ureter and bladder at low urine flow. Am J Physiol 1959; 196: 549-53. 16. Brown P, Nolph KD. Chemical measurements of inulin concentrations in peritoneal dialysis solution. Clin Chim Acta 1977; 76: 103-12. 17. Ziemniak JA, Chiarmonte DA, Schentag JJ. Liquid chromatographic determination of cimetidine, its unknown metabolites and creatinine in serum and urine. Clin Chem 1981; 27: 272-75. 18. Giovannetti S, Barsotti G. In defense of creatinine clearance. Nephron 1991; 59: 11-14. 19. van Ginneken CAM, Russel FGM. Saturable pharmacokinetics in the renal excretion of dogs. Clin Pharmacokinet 1989; 16: 38-54. 20. Gisclon LG, Giacomini KM. Inhibition of cimetidine transport by creatinine in luminal membrane vesicles prepared from rabbit kidney. Drug Metab Disp 1988; 16: 331-32. 21. Somogyi A, Gugler R. Clinical pharmacokinetics of cimetidine. Clin Pharmacokinet 1983; 8: 463-95. 22. Brater C, Sokol PP, Hall SD, McKinney TD. Renal elimination of drugs: methods and determinants. In: Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology. 2nd edition. New York: Raven Press, 1992: 3597-628.
CLIN A PR CTI E
Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate
Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/ClI) ranged from 1·14 to 2·27. With cimetidine, ClC/ClI approached unity in 8 patients (mean 1·02 [SD 0·03]), but considerably exceeded unity in 8 others (1·33 [0·14]). Plasma cimetidine/ creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p=0·01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibition previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures G FR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.
Introduction
Endogenous creatinine clearance can be measured easily, whereas accurate assessments of renal function are inconvenient, time-consuming, and expensive. However, creatinine clearance overestimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. 1,2 The contribution of tubular secretion to total clearance of creatinine is increased in patients with renal disease, especially in those with glomerular disorders,3-7 and this contribution varies over time within patients.8 Creatinine clearances twice or even three times actual GFR are not
exceptional. 3-7 Cimetidine inhibits tubular secretion of creatinine9 without altering GFR, thereby reducing the overestimation of GFR. Although use of cimetidine improves the accuracy of measuring creatinine clearance,7,10,11 guidelines for dose and duration of treatment have not been provided. Furthermore, more accurate assessment of creatinine clearance by cimetidine in short-term studies during the day7,10,11 does not necessarily imply the same improvement during the night, because tubular secretion of creatinine is highest at night-time." Also, when 24 h creatinine clearance with cimetidine is compared with short-duration GFR assessment, as in previous studies,lo,11one has to be aware of the circadian rhythm in GFR.12,13 Previously, in healthy subjects, we observed that the clearance of creatinine was similar to that of GFR during administration of cimetidine both in the day and during the ADDRESSES: Renal Unit, Department of Medicine (B. A. C. van Acker, MSc, M. G. Koopman, MD, Prof L. Arisz, MD), and Department of Clinical Chemistry (G. C. M. Koomen, MSc, D. R. de Waart, MSc), Academic Medical Centre, Amsterdam, Netherlands. Correspondence to Ms B. A. C. van Acker, Renal Unit F4-215, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
1327
night.12 Here we have investigated whether the same holds true in patients with impaired renal function. If so, 24 h creatinine clearance with cimetidine might be a simple and convenient method for accurate measurement of GFR. We measured inulin clearance simultaneously as the goldstandard for GFR.
Patients and methods Patients 22 patients with various renal dieases (14 men, aged 18-81 years) participated as inpatients or outpatients. All had impaired renal function (inulin clearance 10-68 ml/min per 1 ’73 m2). Renal biopsy in 15 patients revealed systemic lupus erythematosus (5 cases), focal local glomerulosclerosis (3), chronic glomerulonephritis (2), membranous nephropathy (2), and mesangiocapillary proliferative glomerulonephritis, microscopic polyarteritis nodosa, and IgA nephropathy (1 each). The other patients had impaired renal function due to hypertension (3), congestive heart failure or urinary tract infection (1 each), and reason unknown (2). All but 5 patients had proteinuria, with urinary albumin excretion ranging from 0’ 5 to 12 g per 24 h. No subject was oedematous. Icteric patients were excluded and no diuretics were used during the study because of possible interference with creatinine measurements.14 No drugs known to interfere with creatinine secretion were used. Immunosuppressive and/or antihypertensive drugs were continued as prescribed. All patients gave informed consent and the protocol was approved by the medical ethics committee of the University Hospital of Amsterdam.
Study design The study was in two successive parts. In the first, 16 patients examined for 30 h starting at 1500 h. To create standard conditions the subjects were supine throughout and had identical intake of food and fluid every 3 h. Fluid intake was at least 300 ml per 3 h to ensure sufficient flow of urine, to prevent tubular reabsorption of creatinine.15 Sodium intake was adjusted to the sodium content of a patient’s usual diet, and ranged from 20 to 150 mmol per 24 h. Coffee and smoking were not permitted. Subjects were allowed to sleep from 2300 to 0800 h between sample and meal times. At onset of the study a priming intravenous injection of inulin 60 mg/kg (Inutest, Laevosan Gesellschaft, Linz, Austria) was administered, and followed by continuous infusion at a rate calculated to achieve plasma levels of 400 mg/1. After equilibration (1500-1800), observations started at 1800 h and continued for 27 h. Every 3 h urine was collected by spontaneous voiding and peripheral venous blood was sampled. The first 3 h clearance period was without cimetidine (Tagamet), which was then administered at 2100 h with an oral priming dose of 400 mg followed by 200 mg every 3 h. In an additional short-term study the effect of cimetidine 400 mg at 1230 h, followed by 200 mg 3 h later, was compared with that of a single dose of cimetidine 1200 mg at 1230 h. The other 6 patients were thus studied on two consecutive days. Successive 112 h clearances of inulin and creatinine were measured on both days before and during at least 6 h after cimetidine. were
Laboratory methods Urine and plasma concentrations of inulin were measured by a modification of Walser’s method with the colour reagent diphenylamine.16 Plasma and urinary creatinine concentrations were assayed by a modified Jaffé reaction in a SMAC/SMA autoanalyser (Technicon). The intra-assay coefficient of variation was 3% for inulin and creatinine. Urine and plasma concentrations of cimetidine were measured by high-performance liquid-
chromatography. 17 Calculations and statistics Clearances of inulin and endogenous creatinine
were calculated UV -’ PAt, where U is urinary concentration, V is urine volume, P is the arithmetic mean of the plasma concentrations at the
as
at baseline and during administration cimetidine in 16 patients with impaired renal function.
Fig 1-Clc/CIl
of
beginning and end of each clearance period, and At is duration of the period. Errors introduced by incomplete urine voiding were corrected.12 Creatinine relative to inulin clearance (CIc/CII) was calculated before (baseline) and during administration of cimetidine. This ratio demonstrates to what extent creatinine clearance overestimates GFR. The ratio should be close to unity when tubular creatinine secretion is completely inhibited. In each patient the clearance calculations (per 3 h periods) during cimetidine treatment (excluding the first 3 h equilibration) were averaged for further analysis. The overall coefficient of variation for CIc/CII was 6%. We therefore defined inhibition as being incomplete when CIc/CII during cimetidine exceeded 1 ’06. The rate of tubular secretion of creatinine (TSc), expressed as umol/h, was calculated by subtracting the filtered creatinine load from urinary creatinine excretion, where filtered load is GFR multiplied by plasma creatinine concentration. All data are expressed as mean (SD), unless stated otherwise. Linear regression was used to study the relation between CIc/CII and GFR. The paired t test was used for within-group comparisons. Differences between subgroups were evaluated by the two-sample t test. A one-sided test was used for the comparison of cimetidine/ creatinine ratios between two subgroups. All other tests were two-tailed, with 0-05 as the level of significance.
Results Neither dose of cimetidine had any effect on GFR measured by inulin clearance whereas creatinine clearance decreased. Mean GFR was 40-1(14.6) ml/min per 1 73 m2 at baseline compared with 40-6 (15-0) ml/min per 1-73 m2 at 1800-2 100 h with cimetidine. There was a striking variation in CIc/CII at baseline, ranging from 1- 14 to 2.27 (fig 1). The amount of overestimation of true GFR by creatinine clearance was not associated with extent of renal functional impairment. Although all patients showed smaller Clc/CII during cimetidine administration, complete inhibition of tubular creatinine secretion occurred in 8 patients only. Even with cimetidine, creatinine clearance considerably overestimated GFR in the other 8. The mean true 24 h GFR (inulin clearance) was 39-5 (15-7) ml/min per 1-73 m2 in the group with incomplete inhibition and 38 2 (12 6) ml/min per 1-73 m2 in patients with complete inhibition. The maximum effect of cimetidine was not achieved during the first urine collection period (2100-2400 h) which was therefore excluded in further analyses. Within each subject, cimetidine equally affected creatinine clearance at allclearance periods (fig 2). When complete inhibition was practically achieved, CIc/CII
1328
Average
GFR
by Clc and Cl(ml/min
Fig 4-Difference in GFR by
Clc
and
Ch
versus
per 1
73m)
average GFR.
Upper=without cimetidine and lower=with adequate dose of cimetidine, n=14.
Fig 2-Creatinine and inulin clearance before and during administration of cimetidine in 2 patients.
approached unity at each clearance interval. Similarly, incomplete inhibition of creatinine secretion was characterised by substantial overestimation of GFR throughout. The TSc that is inhibited by cimetidine was related to initial TS y x is the line on which all points would lie if inhibition was complete (fig 3). Inhibition of TSc by cimetidine was complete for low initial TSc values and incomplete for higher values, which suggests that the dose of cimetidine might have been insufficient in those with higher initial TSc. Support for this hypothesis comes from the lower plasma cimetidine/creatinine ratio observed at incomplete inhibition: 0-040 (0018) versus 0 064 (0-030). The difference (A) was 0-024 with 95% CI 0-003-0-046 =
(p 0-03). This lower ratio was due to higher renal clearance of cimetidine at incomplete inhibition: 333 (136) versus 165 (89) ml/min, A = 168 ml/min, 95% CI 45-291 (p 0-01). As a result, plasma cimetidine concentration was lower: 1 43 (0-66) versus 2-50 (1-02) mg/1, A= 1-07 mg/1, 95% CI 0-15-2-00 (p = 0-03). With a single dose of cimetidine 1200 mg, plasma cimetidine/creatinine ratio rose (0-031 [0’012] to 0-094 [0-039]). This increased dose resulted in more complete inhibition (fig 4) by movement towards y=x. Cimetidine concentrations peaked 3 h after ingestion of the drug. On average, inhibition was most complete between 3 and 6 h =
=
after cimetidine had been administered. Thereafter the effect of cimetidine on tubular creatinine secretion levelled off. In the study of the adequacy of the dose of cimetidine (ie, 1-8 g per 24 h in 8 patients and 1-2 g per 6 h in 6), the two methods of GFR measurement (inulin and creatinine clearance) disagreed without administration of drug. Good agreement was achieved after a sufficient dose (fig 4). No patient had side-effects to cimetidine.
Discussion Cimetidine 200 mg every 3 h reduced the overestimation of GFR by creatinine clearance in all patients. Although within each patient creatinine clearance was equally affected by cimetidine at all clearance periods, GFR was still overestimated in some who had a high tubular secretory rate of creatinine and in whom tubular creatinine secretion was
completely inhibited until plasma cimetidine concentration (ie, the dose of cimetidine) had been increased. Creatinine clearance in 22 patients with renal disease overestimated true GFR by 60% on average, which is similar to other studies.3,s,7,1O Most investigators attribute the disparity to tubular creatinine hypersecretion. The amount of overestimation has been associated with the extent of renal functional impairment.6,7,18 A significant, although not very strong, inverse relation occurs between CIc/CII and GFR (r=-0-61, n=123; r= -.049, not
mmai
i 5 tJJmoltn)
Fig 3-TSc inhibited by cimetidine administration of cimetidine.
versus
that without
=16 patients with impaired renal function.. = additional patients with incomplete inhibition previously, in whom ingestion of 1200 mg cimetidine resulted in increased plasma cimetidine concentration and consequently in more complete inhibition (D).
1329
this relation was not confirmed with of observations. our smaller number Reduction of tubular creatinine secretion by cimetidine is assumed to be the result of competitive inhibition of a common transport system in the proximal renal tubule. Creatinine and cimetidine are secreted by the organic cation secretory system.19 Cimetidine is supposed to have a much higher affinity for the carrier at the luminal membrane of the proximal tubule than does creatinine, which explains the inhibition of tubular secretion of creatinine.2D We indeed saw an acute fall in creatinine clearance after oral ingestion of cimetidine while GFR was unchanged. Besides the first 3 h equilibration, cimetidine equally influenced creatinine secretion during the day and night. Thus there is no need to preload patients with cimetidine several days before measurements of renal function.lO,l1 With respect to reabsorption of cimetidine and delay in urine collection, only the first 3 h period is inadequate. By contrast with our findings" in healthy volunteers, which showed complete inhibition with the same dose of cimetidine, tubular creatinine secretion was not fully inhibited in some patients with renal disease-ie, those with high tubular secretory rate of creatinine (plasma creatinine was similar in our two groups of patients). Patients with incomplete inhibition also had a larger renal clearance of cimetidine compared with patients with complete inhibition, which, similar to the situation with creatinine, was the result of higher cimetidine clearance by tubular secretion,21 and the two groups of patients had similar GFR. Because of the higher renal clearance, plasma cimetidine was lower in patients with incomplete inhibition, as was the plasma cimetidine/creatinine ratio. This ratio is important in competitive inhibition and, depending on relative affmities for the transport process, a certain plasma ratio of unbound competitive compounds is necessary to induce complete inhibition,22 which was illustrated in the second part of our study. In patients with incomplete inhibition previously, complete inhibition was achieved by a higher cimetidine dose resulting in a higher cimetidine/creatinine plasma ratio. The patient in fig 2 with the higher tubular secretory rate of creatinine had a higher plasma creatinine (320 pmol/1) than the others ( < 220 jmol/1), which might explain the slightly less complete inhibition even at cimetidine 1200 mg. Cimetidine 1 8 g every 24 h was inadequate in some patients for 24 h measurements of creatinine clearance. A higher dose is needed here to inhibit completely tubular creatinine secretion. With 24 h creatinine clearance, however, the implication is that the maximum daily dose that is advised has to be exceeded. Clearances of shorter duration are therefore recommended. A single dose of 1200 mg cimetidine adequately inhibited tubular creatinine secretion 3-6 h post-ingestion, at least in patients with plasma creatinine up to 220 umol/1. Whether or not a patient will need a high cimetidine dose depends on a patient’s plasma creatinine, body weight, and cimetidine clearance, which all influence cimetidine/creatinine plasma ratio. Such patients cannot yet be identified, because cimetidine clearance will not be known. A CIclCI ratio of 1-16 (SD 021) after intravenous infusion of cimetidine 400 mg has been observed in glomerulopathic patients.7 In patients with lupus nephritis, creatinine relative to diethylenetriamine pentaacetic acid clearance was 1-14 (95% CI 1-06-1-22) after oral cimetidine four times 400 mg in 24 h.1D In these studies tubular creatinine secretion was seemingly not completely inhibited in all patients. Hilbrands et all’ reported a CI/CI ratio of
n=171).6However,
0 96 (008) after oral cimetidine 1000-2000 mg in 24 h in three to four smaller doses, which suggests complete inhibition. However, their pre-cimetidine ratios (123 [0’20]) were also low, which indicates no large overestimation of the GFR they had measured before
cimetidine. The procedure we advise is (1) an ample water intake during the measurements, (2) collection of urine from the third until the sixth hour after oral cimetidine 1200 mg, and (3) blood samples at the beginning and end of urine collection. We thank Dr J. G. P. Tijssen, department of clinical epidemiology and biostatistics, for statistical advice, Dr J. A. Weber and technicians from the department of clinical chemistry for measuring creatinine, Mr K. J. Hiralall for measuring cimetidine and inulin, Mrs C. F Jonkers for dietary advice, and the nursing staff of ward F5NS for technical assistance.
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3. Berlyne GM, Varley H, Nilwarangkur S, Hoerni M. Endogenous creatinine clearance and glomerular filtration rate. Lancet 1964; ii: 874-76. 4. Hood B, Attman PO, Ahlmén J, Jagenburg R. Renal hemodynamics and limitations of creatinine clearance in determining filtration rate in glomerular disease. Scand J Urol Nephrol 1971; 5: 154-61. 5. Carrie BJ, Golbetz HV, Michaels AS, Myers BD. Creatinine: an
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