Cimetidine Improves the Accuracy of Creatinine Clearance as an Indicator for Glomerular Filtration Rate

Article information

Abstract

INTRODUCTION

A great deal of evidence indicates that endogenous creatinine clearance (C_cr) is inadequate for measuring glomerular filtration rate (GFR) in patients with renal diseases^1–8). C_cr measures GFR with a mean overestimation by 23–96%^9–14). Furthermore, the degree of overestimation varies greatly from one patient to another and even in the same individual over time^11,15).

It has been shown that tubular secretion of creatinine increases as renal function decreases, especially in patients with glomerular disorders^8–10). The overestimation seen in patients with renal diseases appears to be due to hypersecretion of creatinine by injured renal tubular cells^11,16). To circumvent these problems, while GFR can be measured with the aid of “true filtration markers” such as insulin, iothalamate, diethylenetriaminepenta-acetic acid and ethylenediaminetetra-acetic acid, these are less convenient in handling and more costly than creatinine.

Secretion of creatinine by the tubular transport system can be inhibited by several anionic and cationic substances¹⁷⁾. Among them, cimetidine has been known to reduce secretion of creatinine without impairing GFR, improving the accuracy of C_cr as a marker for GFR^12,18,19). However, previous studies simultaneously measured iothalamate clearance (C_10th), as a standard GFR, and C_cr during cimetidine treatment. Therefore, it may have not ruled out a possible effect of cimetidine on C_10th.

The present study was aimed to investigate the effect of cimetidine on the C_cr. C_cr was measured during administration of either placebo or cimetidine. C_10th was simultaneously determined to serve as standard GFR.

MATERIAL AND METHODS

2. Study Protocols

The patients were instructed to follow a 3-day schedule to take either placebo or cimetidine. They were supine-positioned throughout and had food and fluid intake every 4 h. The amount of fluid taken was 20 mL/kg, to ensure sufficient flow of urine and to prevent tubular reabsorption of creatinine. Coffee and smoking were not permitted. They were allowed to sleep from 11 : 00 pm to 08 : 00 am.

The dose of cimetidine was adjusted according to the degree of renal dysfunction in an attempt to achieve approximately equal blood cimetidine levels (Table 1). To obtain maximal inhibition on the tubular creatinine secretion, the maximally permitted oral daily dose of 2,000 mg was used in case of normal renal function.

Table 1.

Daily Doses of Cimetidine for Different Levels of Renal Function

On Day 1, they were given placebos four or five times. A 24-hour urine was collected through the Foley catheter from 08 : 00 am on Day 1 to 08 : 00 am on Day 2. No clearance measurement was done. On Day 3, 24-hour urine from 08 : 00 am to 08 : 00 am on the next day was collected.

C_10th as standard GFR was measured between 10 : 00 am and 2 : 00 pm on Days 1 and 3 using the 24 h urine.

For the measurement of C_10th, ¹²⁵I-iothalamate was continuously infused (20 μCi/h, for 3 h) following a priming dose of 50 μCi as bolus. Blood samples were obtained from the arm vein opposite to that used for the iothalamate infusion at 90, 120, 150, and 180 min of infusion. Plasma creatinine or ¹²⁵I-iothalamate concentrations at the beginning and at the end of each clearance period (30 min) were averaged. Satisfactory urinary output during these periods was maintained by replacing the urinary loss noted in the preceding clearance period with an oral load of water.

¹²⁵I-iothalamate was counted in a gamma scintillation counter (Hewlett Packard, Cobra 5000). Creatinine concentrations were measured by a modified Jaffé reaction in an autoanalyser (Impact 400E). C_10th was determined by averaging values obtained from three clearance periods. The C_cr was computed as mL/day and converted into a mL/min.

Clearances were corrected for the body surface area. C_cr/C_10th was calculated to learn to what extent C_cr overestimates GFR.

Whole blood counts, liver function tests and analysis of the urinary sediment were done to monitor possible side-effects of cimetidine.

Data are expressed as means±SD. To compare the renal function parameters during administration of placebo and cimetidine, paired t-test was applied. Linear regression was used to study the relation between C_cr/C_10th and GFR. A P-value smaller than 0.05 was considered statistically significant.

RESULTS

The subjects (12 men, 13 women) aged 41–23 years ranging between 18 and 65. Their types of renal disorders were chronic glomerulonephritis (4 cases), diabetic nephropathy (4 cases), nephrotic syndrome (3 cases), autosomal dominant polycystic kidney disease (2 cases), hypertensive nephrosclerosis (1 case), lupus nephritis(1 case), miscellaneous causes (2 cases) and unknown (4 cases).

Cimetidine had no effect on GFR measured as C_10th, being 44±27 and 44±29 mL/min/1.73m², during the placebo and during cimetidine treatment, respectively (Table 2). However, cimetidine resulted in a significant decrease of C_cr, from 69±36 during the placebo to 50±31 mL/min/1.73m² during the cimetidine. The difference between C_cr and C_10th decreased from 24±16 to 5±4 mL/min/1.73m².

Table 2.

Creatinine Clearance (C_cr), Iothalamate Clearance (C_10th) and Ratio of C_cr to C_10th During Placebo and Cimetidine Administration

C_cr/C_10th also significantly decreased from 1.72±0.51 to 1.17±0.20, indicating an improvement in validity (Fig. 1). When the patients were classified into three groups, according to their renal function as measured by C_10th, C_cr/C_10th was larger in those with more severe renal dysfunction, indicating a more pronounced overestimation of GFR (Table 3). A significant inverse relation was noted between C_cr/C_10th and GFR (Fig. 2).

Fig. 1.

C_cr/C_10th during placebo and cimetidine administration. (^*p<0.001)

Table 3.

C_cr/C_10th at Various Levels of Renai Function during Placebo and Cimetidine Administration

Fig. 2.

C_cr/C_10th vs. C_10th during administration of cimetidine.

C_cr and C_10th disagreed during the placebo treatment, which was improved by the cimetidine treatment (Fig. 3). No patient reported any side effect due to cimetidine.

Fig. 3.

Differences between C_cr and C_10th vs. GFR determined by averaging C_cr and C_10th.

DISCUSSION

C_cr in 25 patients with renal diseases overestimated GFR by 72%, being similar to those reported in the previous studies^4,9). In addition, the degree of overestimation was larger in those with more severe renal dysfunction. A significant inverse correlation noted between C_cr/C_10th and GFR, as has been shown in the previous studies^1,10), suggests that the degree of overestimation is associated with the degree of renal functional impairment.

Creatinine and cimetidine are secreted by the organic cation secretary system²²⁾. The reduction of tubular creatinine secretion due to cimetidine is assumed to result from competitive inhibition on the common transport system in the proximal tubule, cimetidine having a higher affinity than creatinine for the carrier at the luminal membrane²³⁾.

Cimetidine only incompletely reduced the tubular creatinine secretion. Previous studies^19,24) reported that patients with incomplete inhibition had a larger cimetidine clearance, along with lower plasma cimetidine concentration and cimetidine/creatinine ratio, than did those with complete inhibition¹⁹⁾. This ratio is important, in that certain plasma ratio of unbound competitive compounds is necessary to induce complete inhibition²⁵⁾. Taken together, it may be recommended that a maximal permitted dose of cimetidine should be used to make the validity of C_cr better.

In the previous studies^{1,12,18,19,26,27)}, C_cr/C_10th after administration of cimetidine varied from 0.89 to 1.35. The variation may be related to different dosage schedules and routes of administration of cimetidine. In addition, the fall of C_cr/C_10th below 1.0²⁶⁾ raises the question whether tubular reabsorption of creatinine might exist. Although tubular reabsorption of creatinine has been reported in rats²⁸⁾, evidence is lacking in humans.

On the other hand, no serious adverse effects due to cimetidine were noted, which may be of special importance where cimetidine is used for a non-therapeutic purpose. In a recent meta-analysis of randomized clinical trials with cimetidine, the adverse effect was negligible even with the dosage as high as 2,000 mg/day²⁹⁾.

The cimetidine-aided creatinine clearance can be promoted as a convenient and inexpensive as well as an exact measure of GFR. It may replace classical measurement of GFR with a true filtration marker as this is more expensive and less convenient, especially for the long-term follow-up studies of renal function³⁰⁾. Moreover, monitoring the progress of renal deterioration by plotting the reciprocal values of serum creatinine against time³¹⁾ might become more reliable by the use of cimetidine. Finally, cimetidine may improve the sensitivity of serum creatinine in detecting minimal changes in renal function by restoring the inverse relationship between serum creatinine and GFR, which is actually blunted by the increase of tubular secretion and reduction of GFR¹⁾.

In summary, our results show that oral administration of cimetidine improves the accuracy of C_cr as a marker for GFR.

Article information Continued