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Annals of Clinical & Laboratory Science 31:265-273 (2001)
© 2001 Association of Clinical Scientists

A Practical Approach to Glomerular Filtration Rate Measurements: Creatinine Clearance Estimation Using Cimetidine

Muhittin A. Serdar1, Ismail Kurt1, Fatih Ozcelik1, Muammer Urhan2, Seyfettin Ilgan2, Mujdat Yenicesu3, Levent Kenar1 and Turker Kutluay1
Departments of 1 Clinical Biochemistry, 2 Nuclear Medicine, and 3 Nephrology, Gulhane School of Medicine, Ankara, Turkey.

Address correspondence to Muhittin A. Serdar, M.D., Department of Clinical Biochemistry, Gulhane School of Medicine, Etlik-06018, Ankara, Turkey; tel 90 312 304 3308; fax 90 312 323 4923; e-mail: maserdar{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Determination of creatinine clearance (Ccr) is not a reliable indicator of glomerular filtration rate (GFR), owing to tubular secretion of creatinine. It has been reported that Ccr measurements can approximate true GFR after cimetidine (Ci) administration. In this study, GFR was estimated by Cockcroft and Gault’s equation (CC-G) based on measurement of plasma creatinine, and Ccr was determined by the standard clearance equation using 4- and 24-hr urine samples (Ccr4 and Ccr24, respectively) in 17 patients and 10 healthy controls. After cimetidine administration (800 mg, 3 times daily), GFR values were recalculated at the same time periods (CCiC-G, CcrCi4 and CcrCi24, respectively). The results were all compared to those obtained by the 99mTc-DTPA protein-free double-sample method (CDTPA), which is a reference method for GFR determination. The coefficient of variation (CV%) for Ccr24/CDTPA was high before cimetidine administration; Ccr24 and CcrCi24 values were significantly different from CDTPA (CV 23.1%, Ccr24/CDTPA = 1.17, p 0.005; and CV 14.1%, CcrCi24/CDTPA = 0.92, p 0.006, respectively). Ccr4 values obtained before cimetidine ingestion showed large variation and were significantly different from CDTPA (CV 15.5%, Ccr4/CDTPA = 1.11, p 0.001). CcrCi4 values after cimetidine were similar to CDTPA (CV 6.9%, CcrCi4/CDTPA = 1.01, p 0.28). CC-G estimates were higher before cimetidine intake (CV 12.4%, CC-G/CDTPA = 1.21, p <0.001), whereas CCiC-G values were not significantly different from CDTPA values (CV 7.0%, CCiC-G/CDTPA = 1.01, p 0.67). This study shows that GFR estimations by CC-G, Ccr4, Ccr24, or CcrCi24 are insufficiently reliable. On the other hand, CCiC-G and CcrCi4 results are acceptable for true GFR estimations.

(received 18 January 2001; accepted 20 March 2001)

Keywords: glomerular filtration rate, creatinine clearance, cimetidine, Cockcroft-Gault equation, renal function


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The determination of glomerular filtration rate (GFR) is a valuable indicator of renal pathophysiology and functional renal mass [1,2]. Plasma creatinine concentration, the most common index for evaluation of renal function, is influenced by many variables, such as body muscle mass, age, physical activity, diet, and analytical method. Moreover, plasma creatinine values in patients with renal disease may be normal until renal function has decreased to approximately one-half of normal levels. Classical estimations of creatinine clearance (Ccr24) are subject to error, since creatinine is not only filtered through the glomeruli, but is also secreted by the tubules, and since accurate collection of 24-hr urine specimens is difficult, particularly in children and the elderly [3,4]. Cimetidine (Ci), an H2-receptor antagonist, inhibits the tubular secretion of creatinine. It has been reported that creatinine clearance approximates true GFR after cimetidine administration [3].

Estimation of inulin clearance, which is accepted as the "gold standard" for GFR measurements, cannot be applied in every diagnostic center, since it is invasive and is often considered impractical [5]. GFR studies that use radionuclides such as 125I-iothalamate, 51Cr-EDTA (ethylendiaminetetra-acetic acid), and 99mTc DTPA (diethylenetriaminepenta-acetic acid) are costly and complicated,but they provide good analytical precision and recovery [6,7].

This study compares GRF values estimated by Cockcroft and Gault’s equation (CC-G) based on analysis of plasma creatinine, and by the standard creatinine clearance equation, based on urine collections for 4 hr (Ccr4) and 24 hr (Ccr24). The effects of cimetidine on determinations of CC-G, Ccr4 and Ccr24 were investigated. Finally, the reliablity of these methods was established by comparisons with 99mTc-DTPA clearance results obtained by the protein-free double-sample method (CDTPA), which is equivalent to the inulin clearance assay [6,7].


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study population.  Seventeen patients (12 male, 5 female, age 20–48 yr) with histopathologically-proven renal disease and 10 healthy controls (5 male, 5 female, age 22–40 yr) were enrolled in the study. The renal histopathogy findings included membranoproliferative glomerulonephritis (6 patients), focal glomerulosclerosis (4 patients), polycystic kidney (2 patients), and membranous glomerulonephritis (2 patients). Patients with diabetes mellitus, pregnancy, cimetidine allergy, body mass index (BMI) >30 kg/m2, or those who were receiving drugs such as trimethoprim and salicylates (which inhibit tubular secretion of creatinine) and cephalosporin, guanidine, pyruvate, and ascorbic acid (which interfere with creatinine analysis) were excluded from the study [8–10]. The protocol was approved by the Medical Ethics Committee of the Gulhane School of Medicine. The study was fully explained to the subjects and their informed consent was obtained.

Study Design.  Base-line blood samples (with EDTA anticoagulant) and urine collections (4-hr and 24-hr) were obtained from all subjects. Creatinine was assayed in plasma and urine. Ccr4 and Ccr24 were calculated by the standard clearance equation (#1); CC-G was calculated by the Cockroft-Gault equation (#2) [11].


(#1)

Ccr
creatinine clearance (ml/min/1.73 m2)

Ucr
urine creatinine (µmol/L)

Pcr
plasma creatinine (µmol/L)

V
urine volume (ml/min)

A
body surface area (m2)


(#2)

CC-G
Cockcroft-Gault estimate of glomerular filtration rate (ml/min/1.73 m2)

BW
body weight (kg)

Pcr
plasma creatinine (µmol/L)

Clearance measurements after cimetidine.  The dosage schedule and study protocol are outlined in Fig. 1Go. On the first day, the subjects were hydrated orally (at least 200 ml/hr) for 4 hr to ensure sufficient urine flow and to suppress the reabsorption of cimetidine. The volumes of the urine specimens were measured, and, after centrifugation, an aliquot of each urine specimen was stored at -40°C until assay. Blood samples were collected into tubes with EDTA anticoagulant, and, after centrifugation, the plasma samples were stored at -40°C until assay. Body surface areas were estimated from body height and weight measurements using the equation of DuBois and DuBois [12]. Plasma and urine creatinine concentrations were measured in duplicate by a kinetic Jaffé method using a Technicon Dax-48 analyzer (Bayer Diagnostica, Germany).



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  		Fig. 1. Two-day protocol for administration of cimetidine and measurement of creatinine and 99mTc-DTPA clearances.

 
On the morning of the second day, 99mTc-DTPA was administered to the subjects and blood samples were drawn for GFR measurements by the 99mTc-DTPA protein-free double-sample method (see below). All subjects were instructed to rest during the test period. In 10 controls, assays by the 99mTc-DTPA method were performed before and after the administration of cimetidine in order to evaluate the effect of cimetidine on GFR and CDTPA.

Determination of true GFR.  DTPA was reconstituted in 2–4 ml (total volume) of sterilized saline with 1850–3700 MBq (50–100 mCi) 99mTc pertechnetate. Radiochemical quality control included estimation of the free and unchelated hydrolyzed-reduced 99mTc. After reconstitution, 2 aliquots containing equal activity (110 MBq) and volume of 99mTc-DTPA were prepared; one was used as the standard and the other as the patient dose. The patients were hydrated with 10–15 ml/kg of oral fluids prior to scintigraphic analysis. Patient dosages of 99mTc-DTPA were measured with a dose calibrator (Veenstra Instruments, VDC-202, Austria). Blood samples were withdrawn from the contralateral arm into EDTA-anticoagulated tubes at 60 and 180 min after the injection. The blood samples were centrifuged at 2000 rpm for 10 min. The plasma samples were centrifuged in ultrafiltration tubes (Amicon, USA) for 45 min at 7500 rpm to prepare 99% protein-free ultrafiltrates. Aliquots of plasma, ultrafiltrate, and diluted standard were counted in a gamma counter (Wallac 1260 Multigamma II, LKB, Finland). GFR was computed by the following equation [6,13,14]:


D
injected dose (cpm)

T1
time of first plasma sample (60 min)

T2
time of second plasma sample (180 min)

P1
first sample activity (cpm)

P2
second sample activity (cpm)

Statistical Analysis.  Statistical analyses were performed by using SPSS and EXCEL software. The data were expressed as means ± SD. Comparisons of results obtained with and without cimetidine ingestion were based on paired-sample t-test. Correlation coefficients between GFR estimates and CDTPA results were computed by linear regression analysis. The ratios of the various clearances to CDTPA were calculated before and after the administration of cimetidine. These ratios showed how accurately the clearance values approached the true GFR value. This method is preferred to correlation coefficients as it analyzes the agreement between two methods (as CV%), not the relationship between them [15]. In a perfect correlation, the ratio points lie along the line of equality. A p value <=0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Following cimetidine administration, plasma creatinine levels increased both in the patients (mean 24%, range 12.5– 46) and the controls (mean 18 %, range 11.3–22) (Table 1Go, Fig. 2aGo). The absolute and percentage increases of plasma creatinine after cimetidine administration showed significant correlation with the basal serum creatinine levels (Fig. 2b,cGo, respectively).


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  		Table 1. Observations and renal clearances in controls and patients before and after cimetidine administration.
 


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  		Fig. 2. Plasma creatinine concentrations (Scr) before and after the administration of cimetidine. Panel a: the absolute concentrations of Scr (µM/L); panel b: the absolute increase of Scr (µM/L) in relation to each subject’s baseline Scr level; panel c: the percentage increase of Scr in relation to each subject’s baseline Scr level.

 
To study the effect of cimetidine on CDTPA, assays were performed by the 99mTc-DTPA protein-free double-sample method before and after cimetidine administration in 10 controls; no significant difference was found (r 0.997, slope 0.974, intercept 1.52).

Ratios of the various clearances to CDTPA and the corresponding CV values were significantly decreased after cimetidine administration (Table 1Go). The mean Ccr24 value was higher than CDTPA and the mean CcrCi24 was lower than CDTPA. Both Ccr24 and CcrCi24 values were significantly different from CDTPA (Table 1Go, Fig. 3Go).



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  		Fig. 3. Regression analyses for estimation of creatinine clearance, based on 24-hr urine collections, versus 99mTc-DTPA clearance (CDTPA). In panels a and b, the regression lines are solid and the lines of equality are dotted. Panel a: before cimetidine (Cr24 versus CDTPA); panel b: after cimetidine (Crci24 versus CDTPA). In panels c and d are plotted, respectively, the differences of (Ccr24 –CDTPA) and (Ccrci24 – CDTPA), as a function of each subject’s CDTPA value.

 
The results for Ccr4 were lower than Ccr24, but were significantly different from CDTPA. The CcrCi4 results showed close agreement with the CDTPA values; after cimetidine intake, the CcrCi4 and CDTPA values were not significantly different (Table 1Go, Fig. 4Go).



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  		Fig. 4. Regression analyses for estimation of creatinine clearance by the Cockcroft and Gault equation, based on measurements of plasma creatinine, versus 99mTc-DTPA clearance (CDTPA). In panels a and b, the regression lines are solid and the lines of equality are dotted. Panel a: before cimetidine (CrC-G versus CDTPA); panel b: after cimetidine (CrciC-G versus CDTPA). In panels c and d are plotted, respectively, the differences of (CC-G – CDTPA) and (CC-G – CDTPA), as a function of each subject’s CDTPA value.

 
The CC-G values estimated by Cockcroft and Gault’s equation were significantly higher than the CDTPA values. However, following cimetidine intake, the CCiC-G results did not differ significantly from the CDTPA values (Table 1Go, Fig. 5Go).



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  		Fig. 5. Regression analyses for estimation of creatinine clearance, based on 4-hr urine collections, versus 99mTc-DTPA clearance (CDTPA). In panels a and b, the regression lines are solid and the lines of equality are dotted. Panel a: before cimetidine (Cr4 versus CDTPA); panel b: after cimetidine (Crci4 versus CDTPA). In panels c and d are plotted, respectively, the differences of (Ccr4 –CDTPA) and of (Ccrci4 – CDTPA), as a function of each subject’s CDTPA value.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Inulin, the "gold standard" compound for measurements of GFR, is completely filtered by the glomeruli and not metabolized by the kidney. However, inulin clearance is seldom measured routinely, even in research laboratories, because of technical difficulties [5]. New test compounds, such as cystatin C, sinistrin, and iohexol, have been extensively studied in searching for a practical technique for GFR measurements [16–21]. Evaluating GFR by immunonephelometric measurement of cystatin C has been reported to give reliable results, including children and renal transplant patients [17,20].

Cimetidine can be used to inhibit the tubular secretion of creatinine (3,22–27). Ixkes et al [3] reported that daily intake of 2400 mg of cimetidine inhibits the tubular secretion of creatinine and that the effect remains constant for 6 hr. In the present study, tubular secretion of creatinine was also inhibited completely in patients and controls after the administration of 2400 mg of cimetidine per day in divided doses. There were no side effects except transient fatigue, which was noted in one patient. Hilbrands et al [24] reported that cimetidine administration may cause rare side effects, including tinnitus, fatigue, dyspepsia, diarrhea, and sleeplessness.

Other investigators have also observed that, after cimetidine administration, the clearance values for creatinine closely approximate those obtained for inulin, 125I-iothalamate or 51Cr-EDTA [23,25]. As shown in Fig. 2Go, a prominent increase was observed in plasma creatinine levels after cimetidine ingestion. The alteration of creatinine levels after cimetidine suggests that tubular secretion of creatinine shows significant correlation with the basal levels of plasma creatinine. Similar results have been reported by others [3,25]. The mechanism for tubular secretion of creatinine has not been completely explained. It has been suggested that creatinine is secreted by both cationic and anionic transport systems, due to its amphoteric properties, though the cationic route is probably dominant [28]. Cimetidine, an H2-receptor antagonist, evidently inhibits the cationic transport of creatinine competitively, but has no effect on GFR [28–30].

In the present study, cimetidine had no significant effect on glomerular filtration of 99mTc-DTPA and the resultant CDTPA values in 10 controls. Olsen et al [31] likewise found that cimetidine did not influence the clearances of inulin or 125I-iothalamate. In the present study, Ccr4, Ccr24 and CC-G values were diminished after cimetidine administration and their respective correlations with CDTPA were closer than were observed without cimetidine.

Van Acker et al [25] and Ixkes et al [3] reported that estimates of creatinine clearance after cimetidine were not significantly different from inulin clearance values. Coresh et al [32] found that creatinine clearance values were higher than 125I-iothalamate GFR values. In the present study, neither Ccr24 nor CcrCi24 values were in agreement with CDTPA. Partial inhibition of creatinine secretion and miscollections of urine during the 24-hr period are likely reasons for the discordance among these studies (3,23–25,32).

In the present study, the GFR estimates obtained by Cockcroft and Gault’s equation were 21% higher than CDTPA values when the CC-G values were based on creatinine concentrations in plasma collected before cimetidine administration. Coresh et al [32] likewise found that such CC-G values were higher than true GFR values. However, the present study shows that, after cimetidine, CCiC-G values showed close agreement with CDTPA values. The CcrCi4 values were also closely comparable to CDTPA values.

In summary, following cimetidine administration, the clearance estimates obtained by Cockcroft and Gault’s equation and the creatinine clearance values obtained with 4-hr urine collections are more practical and reliable methods for estimating GFR and evaluating renal function, when compared to others. Further studies are needed to validate this conclusion in pediatric and geriatric populations.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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