Evaluation of hypercalciuria in patients receiving intravenous Cefotaxime.

INTRODUCTION: Cefotaxime is one of the third generation cephalosporins, which is used against many infections. This drug has a urinary excretion and potentially may have nephrotoxic effects. Hypercalciuria can cause important complications, including the formation of kidney stones. In the recent study, we decided to evaluate hypercalciuria in children receiving cefotaxime.
MATERIALS AND METHODS: This case-control study was conducted in Amirkabir hospital (Arak, Iran), where 30 children received intravenous cefotaxime were placed in the case group and 30 children without intravenous administration of cefotaxime were included in the control group. The ratio of calcium to creatinine was measured in both groups. Data were analyzed by SPSS software version 23.
RESULTS: This study showed that the ratios of male and female children in both the groups were 19 (63.3%) and 11 (36.7%) respectively, the mean age of children in the case group was 2.36 years with a standard deviation of 0.71 and the mean age of the children in the control group was 5.18 years with a standard deviation of 3.31. The ratios of urine calcium to creatinine in the case and control groups were 0.90 with a standard deviation of 1.79 and 0.37 with a standard deviation of 0.44 (P value = 0.003).
CONCLUSION: According to the above results, it is concluded that receiving intravenous cefotaxime may increase calcium to creatinine ratio in children.

Introduction

Hypercalciuria means high levels of calcium in the urine. Hypercalciuria can be measured in a urine specimen, but it is better to be tested in a 24-hour urine sample. Increasing calcium uric acid could lead to kidney stones, nephrocalcinosis, osteopenia, and frequent urinary tract infections.[1] Hypercalciuria can show itself as urolithiasis, microscopic or obvious hematuria, abdominal or flanking pain, urinary tract infections, frequent urination, urinary incontinence, and urinary tract infection.[2] Several mechanisms have been introduced for hypercalciuria including reduction of tubular reuptake of calcium in kidneys, tubular disorders of the kidneys, increased intestinal absorption of calcium, increased initial synthesis of vitamin D, increased prostaglandin E2 renal production, and increased production of interleukin 1 and interleukin 6. These mechanisms are part of the physiologic mechanisms used to explain the idiopathic hypercalciuria.[3] These mechanisms may be associated with uroepithelial damage induced by calcium microcrystals. It seems that irritation of the uroepithelial tissue causes the destruction of the natural mucous membrane that is preventative and resistant to microbial pathogenesis.[4] This causes urinary tract infections in these patients. Hypercalciuria is one of the most common causes of isolated unexplained hematuria. Diagnostic method for hypercalciuria is not yet standardized.[5] Urine analysis for 24 hours should be performed to diagnose hypercalcemia in children with hematuria. A high level of calciuria in a random urine sample is important in the diagnosis of hypercalcemia.[6] In the same vein, third-generation cephalosporins that are widely used to treat infections in children and adults can cause false stones and kidney stones.[7]

Cefotaxime is a third-generation cephalosporin. Third-generation cephalosporins act by inhibiting bacterial cell wall enzymes and preventing the spread of bacteria. These antibiotics prevent the formation of new cell walls in bacteria.[8] The drug is widely distributed in tissues and body fluids and is metabolized relatively in the liver.[9] Cefotaxime is excreted in the urine.[10] Some of the side effects of cefotaxime include colitis, diarrhea, increased blood BUN and creatinine, increased liver transaminases, eosinophilia, fever, pain at the injection site, nausea, itching, rash, thrombocytopenia, transient neutropenia and vomiting.[11] If there are evidences of increased susceptibility to this drug, re-administration of the drug is contraindication.[11] In cases of potentially life-threatening arrhythmias in patients who received rapid bolus injection through central venous catheter, long-term treatment associated with granulocytopenia (more than 10 days) is not recommended for children with a history of allergy to penicillin or with a history of colitis.[12] Also, in patients with renal insufficiency, the dose should be adjusted. Cefotaxime can potentially have nephrotoxic effects.[12] Therefore, our aim in this study was to determine the relationship between hypercalciuria in children receiving venous Cefotaxime. Therefore, if there is a relationship between the use of cefotaxime and hypercalciuria, it can be avoided in cases who are susceptible to hypercalciuria and its complications.

Material and Methods

This study was a case-control study with simple random sampling. All patients referred to Amirkabir Hospital (Arak, Iran) who were received cefotaxime for any clinical indication were in the case group and patients who admitted to hospital for any causes except kidney problems and were not received cefotaxime placed in the control group. A total of 30 cases were considered for each study group. Patients who received at least 48 hours of cefotaxime enrolled in the case group. For all patients, urine calcium to creatinine ratio was measured in the laboratory. The ratio higher than normal range was considered hypercalciuria. Finally, the data were analyzed using SPSS software (version 23). Descriptive statistics were used for central indexes and distributions. Chi-square, odds ratio and independent T-test were also used.

Results

The aim of this study was to compare the hypercalciuria in patients receiving intravenous cefotaxime in 60 cases in both case and control groups. In all, 38 patients were males (19 children in the case group and 19 children in the control group) and 22 children were females (11 children in the case group and 11 in the control group). The mean age of children in the case group was 2.36 years with a standard deviation of 0.71 and the mean age of the children in the control group was 5.18 years with a standard deviation of 3.31. The mean age of the 60 children was 2.94 years with standard deviation of 3.64.

It was observed that the average birth weight of all 60 children was 3.12 kg with a standard deviation of 0.50 kg. Also, in relation to the height of the birth time of the children examined in this study, it was observed that the mean height of the birth time of the total of these 60 children was 49.51 cm with a standard deviation of 1.71 cm. It was observed that the mean head circumference of children at birth was 33.55 cm with a standard deviation of 2.28 cm.

In the study of the parents’ job status, the children in both case and control groups found that out of a total of 59 children whose parents information was available, maternal job of 55 children was housewife and paternal jobs of 28 cases was self-employment [Tables 1 and 2].

Table 1

Maternal occupational status of the children

Group	Job			P
	Housewife, n (%)	Self-employment, n (%)	Employee, n (%)
Case	26 (89.7%)	1 (3.4%)	2 (6.9%)
Control	29 (96.7%)	1 (3.4%)	0	0.34
Total	55 (93.2%)	2 (3.4%)	2 (3.4%)

Table 2

Paternal occupational status of the children

Group	Job			P
	Self-employment, n (%)	Employee, n (%)	Worker (%)
Case	12 (41.4%)	10 (34.5%)	7 (24.1%)
Control	16 (53.3%)	7 (23.3%)	7 (23.3%)	0.58
Total	28 (47.5%)	17 (28.8%)	14 (23.7%)

In the study on the status of parent's education for children in both case and control groups, it was observed that out of a total of 59 children whose information was available, maternal education in 30 patients and paternal education in 23 patients were subordinate [Tables 3 and 4].

Table 3

Maternal education status of the children

Group	Education degree				MSc and PhD	P
	Illiterate, n (%)	Subordinate, n (%)	Diploma, n (%)	Associate Degree and bachelor, n (%)
Case	1 (3.4%)	13 (44.8%)	7 (24.1%)	7 (24.1%)	1 (3.4%)
Control	1 (3.4%)	17 (56.7%)	10 (33.3%)	2 (6.7%)	0	0.36
Total	2 (3.4%)	30 (50.8%)	17 (28.8%)	9 (15.3%)	1 (3.4%)

Table 4

Paternal education status of the children

Group	Education degree					P
	Illiterate, n (%)	Subordinate, n (%)	Diploma, n (%)	Associate Degree and bachelor, n (%)	MSc and PhD
Case	1 (3.4%)	12 (41.4%)	6 (20.7%)	6 (20.7%)	4 (13.8%)
Control	3 (10.4%)	11 (36.7%)	12 (40%)	3 (10%)	1 (3.4%)	0.21
Total	4 (6.8%)	23 (39%)	18 (30.5%)	9 (15.3%)	5 (8.5%)

In the present study, the aim of this study was to compare the income status of children in both case and control groups. Of the total of 59 children whose family information was available, 31 children had a family monthly income less than 10 million Rials [Table 5].

Table 5

Family monthly income of the children

Group	Monthly income				P
	<10 million Rials	1-2 million Rials	2-3 million Rials	>3 million Rials
Case	17 (58.6%)	10 (34.5%)	1 (3.4%)	1 (3.4%)
Control	14 (46.7%)	15 (50%)	1 (3.4%)	0	0.51
Total	31 (52.5%)	25 (42.4%)	2 (3.4%)	1 (1.7%)

In the studies with the aim of comparing the hypercalciuria and the ratio of urine calcium to creatinine in study groups, the difference was significantly different (P-value = 0.003) [Table 6].

Table 6

Hypercalciuria of the children

Group	Job			P
	Frequency	Mean	Std deviation
Case	30	0.9	1.79	0.003
Control	30	0.37	0.44
Total	60	0.64	1.32

Discussion

Hypercalciuria is one of the most commonly diagnosed and recognizable metabolic problems that causes calcium kidney stones.[1314] Hypercalciuria is a 24-hour accumulation of calcium in the urine. Its rate of excretion is known to be more than 4 mg/kg per day in a child weighing less than 60 kg. This amount and excretion of calcium in urine in infants less than 3 months of age are defined as calcium excretion of 5 mg/kg body weight per day. In other words, in infants less than 3 months of age, urinary calcium excretion up to 5 mg/kg of body weight per day is considered as a normal upper limit.[1415] Studies in developing countries have shown a different outbreak of hypercalciuria. Some studies reported a prevalence of hypercalciuria between 2.9% and 3.8% among healthy children.[1314] According to some studies, the prevalence of hypercalciuria in Iranian children at school age was reported to be between 3% and 5.4%.[1315161718] Hypercalciuria is one of the main risk factors for kidney stones in both children and adults. It also causes widespread symptoms in children, including microscopic and macroscopic hematuria, bone pain, and urinary tract infections. It has also been observed that hypercalciuria has a negative calcium balance, which results in a negative balance of osteopenia.[19] Recent studies have shown that ceftriaxone, as one of the third generation cephalosporins, is widely used to treat infections in children and adults that can cause false kidney stones.[7] Also, in several studies, the incidence of ceftriaxone-induced renal stones was reported to be between 1.4% and 7.8%.[202122] Studies of the cause of these rocks have reported interactions between ceftriaxone and free calcium.[23] High concentrations of ceftriaxone and calcium in urine can be considered as a serious risk factor for the development of kidney stones.[242526] There are similarities between cefotaxime and ceftriaxone, as third-generation cephalosporins; therefore, the aim of the recent study was to investigate hypercalciuria in children receiving intravenous cefotaxime.

The results of our study showed that the mean calcium/creatinine ratio in the intravenous recipient group was 0.90 with a standard deviation of 1.79, and this ratio in the control group was 0.37 with a standard deviation of 0.44. This difference observed between the study groups was statistically significant (P-value = 0.003). Regarding these results, it seems that intravenous cefotaxime increases the ratio of calcium to creatinine in children, which can cause hypercalciuric complications in these children.

A study by Kimata et al. found that the ratio of calcium to creatinine in children receiving ceftriaxone was 0.19 with a standard deviation of 0.16, while this ratio was 0.09 with standard deviation of 0.09 in children who did not receive this drug. The criterion was 0.09, which was statistically significant in their study (P value < 0.001).[27] The results of the recent study on children receiving cefotaxime are similar to the results of a study conducted by Kimata et al. Children receiving ceftriaxone confirms the effect of intravenous cefotaxime on increased hypercalciuria.

Conclusion

Based on the results of the recent study, it is concluded that administration of intravenous cefotaxime in children results in an increase in the urine calcium to creatinine ratio which can be found in children who are prone to kidney stone disease, or children with underlying kidney problems.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.