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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 5  |  Page : 902-907
Fractional excretion of magnesium, a marker of aminoglycoside induced nephrotoxicity in neonates


1 Department of Pediatrics, MARKS Medical College and Hospital, Dhaka, Bangladesh
2 Department of Neuromedicine, National Institute of Neuroscience, Dhaka, Bangladesh
3 Department of Blood Transfusion, National Institute of Neuroscience, Dhaka, Bangladesh
4 Department of Pediatric Nephrology, Bangladesh Institute of Child Health, Dhaka, Bangladesh

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Date of Web Publication22-Sep-2016
 

   Abstract 

Aminoglycoside is a widely used antibiotic in neonatal age group at hospital setting in Bangladesh. It has underlying side effect and toxicity which is mostly unseen and ignored. The aim of the study was to evaluate the nephrotoxic effect of aminoglycoside in neonates. This study was conducted in fifty hospital admitted neonates of Dhaka Shishu Hospital from January 2012 to December 2013. Serum creatinine, blood urea nitrogen, and fractional excretion of magnesium (FEMg) were measured before starting and after seven days of aminoglycoside treatment. Statistical analyses of the results were obtained by window-based computer software devised with Statistical Packages for Social Sciences (SPSS version 16). Statistical tests for significance of difference were done using Student's paired t-test. Serum creatinine and blood urea nitrogen were not significantly changed after drug administration (P = 0.092, P = 0.247, respectively). None of the neonates in our study group had abnormal serum creatinine and blood urea nitrogen after aminoglycoside therapy. FEMg was significantly increased (P <0.001) after aminoglycoside treatment. In this study, conventional renal function test such as blood urea and serum creatinine did not reflect the nephrotoxicity of aminoglycoside. However, a biomarker of tubular damage, FEMg detected nephrotoxicity of aminoglycoside therapy.

How to cite this article:
Sonia SF, Hassan MS, Ara F, Hanif M. Fractional excretion of magnesium, a marker of aminoglycoside induced nephrotoxicity in neonates. Saudi J Kidney Dis Transpl 2016;27:902-7

How to cite this URL:
Sonia SF, Hassan MS, Ara F, Hanif M. Fractional excretion of magnesium, a marker of aminoglycoside induced nephrotoxicity in neonates. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 22];27:902-7. Available from: http://www.sjkdt.org/text.asp?2016/27/5/902/190781

   Introduction Top


Aminoglycosides play an integral role in antimicrobial chemotherapy. They are bactericidal and act mainly against Gram-negative organisms and pseudomonas and act by inhibition of bacterial protein synthesis. The common side effects of aminoglycosides are nephrotoxicity and ototoxicity. In a meta-analysis of multiple and single daily dosing of aminoglycoside, the overall rate of nephrotoxic effects was 5.5% for a single daily dose and 7.7% for multiple daily doses. [1] Aminoglycoside causes lysosomal dysfunction of proximal tubules due to phospholipid accumulation within the proximal tubular cell. Distal nephron segments may also be affected. [2] Serum creatinine and blood urea nitrogen characteristically increase 5-7 days after initiation of aminoglycoside therapy. [3] This toxicity is usually reversible. [4] Various electrolyte abnormalities, such as hypomagnesemia, hypokalemia, and hypocalcemia may occur due to tubular dysfunction. [5]

Tubular function test by mean of fractional excretion of magnesium (FEMg) has recently been reported to correlate directly with the magnitude of tubular damage. It has been shown that FEMg can reflect a tubular function for both the ability of tubules for reabsorption of the filtered magnesium and for retaining the intracellular magnesium. [6] Any disturbance to the structure and function of the tubular epithelium would affect tubular magnesium wastage and its reabsorption capacity, thereby increasing the value of FEMg above the normal range. Thus, elevated FEMg reflects tubular dysfunction. [7] The higher the value of FEMg, the greater the magnitude of tubular damage. [8] Aminoglycoside causes a statistically significant postinfusion increase in FEMg. [9]

It is accepted that the concentration of serum creatinine is an insensitive and delayed measure of decreased kidney function following AKI. Serum creatinine rises significantly above the baseline levels only when 25-50% of renal function has been lost. [10] Furthermore, creatinine is a marker of glomerular filtration and not an indicator of proximal tubule function. [10] Hence, FEMg may be a sensitive marker for detecting low-level tubular injury that would lead to early detection of renal disease. [11] This study is designed to find out aminoglycosideinduced nephrotoxicity by conventional biomarkers (blood urea and serum creatinine) and tubular biomarker (FEMg).


   Patients and Methods Top


Fifty neonates (thirty males and twenty females) who were admitted to Dhaka Shishu Hospital from January 2012 to December 2013 were enrolled in the study. Indications for aminoglycoside treatment at the time of patient admission included neonatal sepsis (n = 22), pneumonia (n = 24), and meningitis (n = 4). Relevant information such as antenatal and perinatal history, comorbid condition, demographic characteristics of newborn, age and weight of getting first dose of aminoglycoside were collected. Preterm babies, neonate with perinatal asphyxia, presence of dehydration, patients undergoing surgical procedure, initially abnormal blood urea nitrogen, serum creatinine and FeMg, and abnormal liver function tests were excluded from the study. Patients receiving other potentially nephrotoxic drugs were also excluded from the study. Among the neonates, 34 patients were treated by amikacin and 16 patients were treated by gentamycin. Two milliliter of venous blood and 5 mL of urine through urobag were collected before and after seven days of aminoglycoside treatment. Serum creatinine, blood urea nitrogen, and fractional excretion of Mg + were measured before starting and after aminoglycoside therapy. The quantitative determination of magnesium in human serum and urine was performed on the Dimension (RxL Max) clinical chemistry system. FeMg was calculated by formula:

Fractional excretion of magnesium (FEMg) which is (UMg/SMg)/(Ucr/Scr) ×100.

Where UMg = Urinary magnesium, SMg = Serum magnesium, Ucr = urinary creatinine, Scr = Serum creatinine.

All data were recorded systematically in preformed data collection form, and quantitative data were expressed as a mean and standard deviation. Statistical analyses of the results were obtained by window-based computer software devised with Statistical Packages for Social Sciences (SPSS version 16, Chicago, IL, USA). Statistical tests for significance of difference were done using Student's paired ttest. A P <0.05 was considered as significant.


   Results Top


The general characteristics of patients treated with aminoglycosides are shown in [Table 1]. In this study, renal function was assessed in 50 admitted neonates (60% male and 40% female) of Dhaka Shishu Hospital treated by aminoglycoside for suspected infection including neonatal sepsis (44%), pneumonia (48%), and meningitis (8%). All the neonates were term and within normal birth weight. The mean age of the neonate was 17.08.
Table 1: General characteristics of patients treated with aminoglycosides.

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Biochemical parameters of patients treated withaminoglycosides are shown in [Table 2]. The level of serum creatinine and blood urea nitrogen did not significantly change after aminoglycoside administration (P = 0.092, P = 0.247 respectively). None of the neonates had abnormal serum creatinine and blood urea nitrogen after aminoglycoside therapy. How-ever, the normal postnatal decline of serum creatinine was not observed. FEMg were significantly increased (P <0.001) after aminoglycoside treatment.
Table 2: Biochemical parameters of patients treated with aminoglycosides.

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[Table 3] shows the comparison of biochemical parameters of patients treated with gentamicin and amikacin. Blood urea nitrogen and serum creatinine did not significantly change after treatment with amikacin (P = 0.24, P = 0.179, respectively), as well as gentamicin (P = 0.77, P = 0.33, respectively), but FEMg was significantly increased (P <0.001) after treatment with both gentamicin and amikacin. Biochemical parameters of patients in relation with diagnosis are shown in [Table 4]. After aminoglycoside treatment, blood urea nitrogen and serum creatinine did not significantly change in cases of neonatal sepsis (P = 0.36, P = 0.52, respectively), pneumonia (P = 0.39, P = 0.07, respectively), and meningitis (P = 0.96, P = 0.63, respectively). However, FEMg was significantly increased after aminoglycoside treatment in all the diagnosis group (P <0.001, P <0.001 and P = 0.03, respectively).
Table 3: Comparison of biochemical parameters of patients treated with gentamicin and amikacin.

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Table 4: Biochemical parameters of patients in relation with diagnosis.

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   Discussion Top


One of the major reasons of acute kidney injury is drug-induced nephrotoxicity. Incidence has been reported to be as high as 36% among patients diagnosed with AKI. [12] Aminoglycoside-induced nephrotoxicity is a relatively common complication in hospitalized patients. [13] Conventional blood and urine parameters of kidney injury are insensitive, nonspecific, and do not indicate the region affected by the toxic insult. [14] Serum creatinine does not provide a sensitive marker because aminoglycoside causes an initial proximal tubular dysfunction, which is not promptly reflected by serum creatinine levels. Thus, there is a clear need for biomarkers of nephrotoxicity that could indicate when damage begins, assess the level of damage, and help to localize the lesion.

In this study, the level of serum creatinine and blood urea nitrogen did not significantly change after drug administration (P = 0.092, P = 0.247, respectively). None of the neonates had abnormal serum creatinine and blood urea nitrogen after aminoglycoside therapy. However, the normal postnatal decline of serum creatinine was not observed. FEMg was significantly increased (P <0.001) after aminoglycoside treatment. These data agree with several studies in humans. [15],[16],[17]

von Vigier et al measured the effect of amikacin on renal magnesium homeostasis. Treattment with amikacin significantly increased FEMg. Their study demonstrated that amikacin therapy causes increased magnesium loss through kidney even in the absence significant rise of blood urea and serum creatinine. [18] This finding is similar to our present study. One previous study evaluated FEMg as a marker for tubular dysfunction in children with clinically recovered ischemic acute tubular necrosis. They recommended FEMg as a marker of tubular injury. [19] Deekajorndech demonstrated that the FEMg correlates directly with the degree of tubulointerstitial disease. [20] In our study, we found a significant increase in FEMg (P <0.001) after aminoglycoside treatment. This indicates that there was tubular damage in these children.

Giapros et al evaluated renal function and effect of aminoglycoside (amikacin, netilmicin, and gentamicin) therapy during the first 10 days of life. Gentamicin but not amikacin affected the normal plasma creatinine (PCr) decline. FEMg was significantly affected in infants treated with gentamicin. [21] These findings are contrary to our findings as we found FEMg was significantly affected by both gentamicin and amikacin treatment and both gentamicin and amikacin affected the normal PCr decline. Falakolaflaki et al performed a quasi-experimental study on 23 neonates with suspected sepsis who were treated with gentamicin. Serum creatinine levels decreased in all patients. [22] In our study, serum creatinine levels were insignificantly increased which is contrary to their study.

Zappitelli et al at Texas Children's Hospital conducted a retrospective cohort study of children treated with an aminoglycoside. The AKI rate was 33% and 20% by pRIFLE and AKIN definitions, respectively. [23] This finding is contrary to our finding as we did not find any case of AKI either by pRIFLE or by AKIN definitions. Vasilis Tzovaras studied 19 previously healthy patients who were hospitalized in clinic due to bacterial infections. FEMg was significantly increased (P = 0.05 and P = 0.02, respectively). However, none of the study participants developed renal failure. [3] This finding is similar to our study as none of our participant developed renal failure, but FEMg was significantly increased (P <0.001).

Despite the highest possible effort, our study could not overcome some limitations. The study was done in Dhaka Shishu Hospital only. A multicentered study would be more significant. Blood antibiotic level was not done as it was not readily available. Other newer biomarkers for renal injury were not done due to economical constrain. So far no follow-up has yet been done to see the longterm effect of aminoglycoside treatment, but there is a plan to evaluate the renal function of these neonates in the future.

In this study, conventional renal function test such as blood urea and serum creatinine did not reflect the nephrotoxicity of aminoglycoside. However, the biomarker of tubular damage, FEMg detected nephrotoxicity of aminoglycoside therapy. Hence, FEMg may be a useful indicator of renal injury in neonates treated with aminoglycoside compared with other routine clinical indicators.


   Acknowledgment Top


The authors owe their heartiest thanks to Dr. Nazma Akhter, RP and Consultant of Diabetic Clinic, MARKS Medical College and Hospital and Mr. Habib, Biochemist, Dhaka Shishu Hospital, for their generous help and informative suggestions. They are also grateful to the study patients and their parents for their full cooperation.

 
   References Top

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Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: A meta-analysis. BMJ 1996;312:338-45.  Back to cited text no. 1
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Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Pediatric Nephrology. 6 th ed. USA: Springer; 2009. p. 1579-615.  Back to cited text no. 2
    
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Tzovaras V, Tsimihodimos V, Kostara C, Mitrogianni Z, Elisaf M. Aminoglycosideinduced nephrotoxicity studied by proton magnetic resonance spectroscopy of urine. Nephrol Dial Transplant 2011;26:3219-24.  Back to cited text no. 3
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Futrakul P, Yenrudi S, Futrakul N, et al. Tubular function and tubulointerstitial disease. Am J Kidney Dis 1999;33:886-91.  Back to cited text no. 6
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Deekajorndech T. Fractional excretion magnesium (FE Mg) in systemic lupus erythematosus. J Med Assoc Thai 2005;88:743-5.  Back to cited text no. 7
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Wiland P, Szechcinski J. Proximal tubule damage in patients treated with gentamicin or amikacin. Pol J Pharmacol 2003;55:631-7.  Back to cited text no. 15
    
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Marchewka Z, Dlugosz A. Enzymes in urine as markers of nephrotoxicity of cytostatic agents and aminoglycoside antibiotics. Int Urol Nephrol 1998;30:339-48.  Back to cited text no. 17
    
18.
von Vigier RN, Trutman AC, Bettinelli A, Wermuth B, Bianchetti MG. Aminoglycoside and renal homeostasis of magnesium in human. Nephrol Dial Transplant 2000;15:822-6.  Back to cited text no. 18
    
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Gheissari A, Andalib A, Labibzadeh N, Modarresi M, Azhir A, Merrikhi A. Fractional excretion of magnesium (FEMg), a marker for tubular dysfunction in children with clinically recovered ischemic acute tubular necrosis. Saudi J Kidney Dis Transpl 2011;22:476-81.  Back to cited text no. 19
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20.
Deekajorndech T. A biomarker for detecting early tubulointerstitial disease and ischemia in glomerulonephropathy. Ren Fail 2007;29: 1013-7.  Back to cited text no. 20
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21.
Giapros VI, Andronikou SK, Cholevas VI, Papadopoulou ZL. Renal function and effect of aminoglycoside therapy during the first ten days of life. Pediatr Nephrol 2003;18:46-52.  Back to cited text no. 21
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22.
Falakolaflaki M, Habibi M, Hamadan J. Effects of gentamicin on urinary electrolyte excretion in admitted neonate. Sci J Hamadan Univ Med Sci 2008;14(4):13-8.  Back to cited text no. 22
    
23.
Zappitelli M, Moffett BS, Hyder A, Goldstein SL. Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study. Nephrol Dial Transplant 2011;26:144-50.  Back to cited text no. 23
[PUBMED]    

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Correspondence Address:
Sheikh Farjana Sonia
Department of Pediatrics, MARKS Medical College and Hospital, Dhaka-1206
Bangladesh
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DOI: 10.4103/1319-2442.190781

PMID: 27751996

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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    Abstract
   Introduction
   Patients and Methods
   Results
   Discussion
   Acknowledgment
    References
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