|Year : 2011 | Volume
| Issue : 3 | Page : 476-481
|Fractional excretion of magnesium (FEMg), a marker for tubular dysfunction in children with clinically recovered ischemic acute tubular necrosis
Alaleh Gheissari1, Alireza Andalib2, Narges Labibzadeh1, Mohammadreza Modarresi3, Afshin Azhir1, Alireza Merrikhi1
1 Department of Pediatric Nephrology, Isfahan University of Medical Sciences, St. Al Zahra Hospital, Isfahan, Iran
2 Department of Immunology, Isfahan University of Medical Sciences, St. Al Zahra Hospital, Isfahan, Iran
3 Department of Pediatrics, Isfahan University of Medical Sciences, St. Al Zahra Hospital, Isfahan, Iran
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|Date of Web Publication||7-May-2011|
| Abstract|| |
Among the different etiologies of acute renal failure (ARF), acute tubular necrosis (ATN) is one of the most common causes. There is no consensus on the duration of follow-up needed among these patients and also on choosing a reliable screening test to recognize early signs of chronic kidney injury that may ensue. The aim of this study was to evaluate the clinical and biochemical findings in children with a history of clinically recovered ischemic ATN, to detect the patients who may be at risk of ensuing chronic kidney disease. A cross-sectional study was carried out on 20 children between six months and 10 years of age, admitted at St. Al Zahra Hospital and Amin Children's Hospital, Isfahan, Iran, with a past history of ischemic ATN. Eighteen patients were evaluated between 12 and 24 months, and two patients were evaluated at 30 months. The second sample of urine while still fasting was used for assessing urinary sodium, creatinine and magnesium. The mean ages for study and control groups were 3.4 ± 1.3 years and 4.5 ± 1.1 years, respectively. Glomerular filtration rate, urinary magnesium, fractional excretion of magnesium (FEMg), urinary sodium and fractional excretion of sodium (FENa) were significantly higher in the study group compared to those in the control group. No significant differences were demonstrated in systolic and diastolic blood pressures between the two groups. Since FEMg can reflect tubular function for both the ability of tubules for reabsorption of the filtered magnesium and for retaining the intracellular magnesium, FEMg can be used as a marker to detect early stages of chronic renal injury. However, further studies with larger number of cases are needed to evaluate the sensitivity of this test.
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2011 [cited 2021 Dec 3];22:476-81. Available from: https://www.sjkdt.org/text.asp?2011/22/3/476/80483
| Introduction|| |
Acute renal failure (ARF) is defined as the sudden loss of renal function over several hours to several days. The prevalence of community acquired ARF is approximately 209 patients per million population.  Up to 50% of patients with ARF are known to have varying degree of ensuing renal impairment.
ARF is not uncommon in children admitted at emergency departments. Among the different etiologies of ARF, acute tubular necrosis (ATN) is one of the most common causes and ische-mic ATN is one of the most frequent causes of ARF in an ICU setting. In a retrospective cohort study on 593 patients with ARF, 88% were categorized as ATN and a majority had ischemic ATN.  The incidence of ATN ranges from 150 to 600 per million populations. ,,,, Renal failure phase of ATN lasts between seven and 21 days  and in most cases renal function tends to recover.  There is no consensus on the duration of follow-up needed among these patients and also on choosing a reliable screening test that may recognize early stages of chronic kidney injury. Among the different accessible tests, normal value of fractional excretion of magnesium (FEMg) is a marker of an intact tubulointerstitial structure in patients with glomerular disease and also this value increases in early stages of chronic kidney disease (CKD 1 and 2). It has been shown that FEMg can reflect tubular function for both the ability of tubules for reabsorption of the filtered magnesium and for retaining the intracellular magnesium, which is the second most abundant intracellular cation after potassium.  Considering the fact that during ischemic ATN, the target of lesion is at tubulointerstitium, we conducted the study to evaluate two of the available biochemical tests to evaluate the functional status of tubulo-interstitium, namely, FEMg and fractional excretion of sodium (FENa), in children with a past history of ischemic ATN.
| Methods|| |
A cross-sectional study was carried out on 20 children aged between six months and 10 years, admitted to St. AlZahra Hospital and Amin Children's Hospital, Isfahan, Iran. All had a record of ischemic ATN from 12 to 30 months before getting enrolled in the study. None of them needed dialysis during hospitalization. Also, 20 age-matched normal children were recruited as control group.
The following were included in the study:
- History of dehydration or intravascular volume depletion before ARF.
- Urine output less than 0.5 mL/kg/hour for more than 6 hours up to 12 hours (mild category by RIFLE classification).
- Daily increase of serum creatinine more than 0.5-1 g/dL  or decrease in glomerular filtration rate (GFR) more than 50% compared to the baseline and/or increasing serum creatinine more than two times compared to the baseline (mild category by RIFLE classification).
- The presence of renal epithelial cell or renal epithelial cell cast and/or granular cast in urinary sediment. 
- Fractional excretion of sodium (FENa) more than 2% in the presence of volume deficit and oilguria. 
- Renal artery resistive index of more than 0.75 in color Doppler ultrasound evaluation, if it was performed for the patient. 
- Lack of any previous record of kidney disease or intake of nephrotoxic drugs
- Patients belonging to the mild category according to RIFLE classification. 
We excluded from the study patients with other causes of ARF, those who were using diuretics within five days before sampling and those who were using cathartics containing magnesium before sampling.
As per the above criteria, from March 2004 to February 2006, there were a total of 47 patients under 10 years of age with the diagnosis of mild ischemic ATN admitted in these two hospitals. However, informed consent for inclusion into the study could be obtained only from 20 out of them. Eighteen patients were evaluated between 12 and 24 months after the episode of ARF and two patients were evaluated after a period of 30 months.
Blood pressure, urine for microalbuminuria, GFR and FENa and FEMg were determined for all patients.
Urinary sodium, and serum sodium, creatinine and magnesium were measured among an age-matched control group to have a comparative value of FEMg and FENa in normal population with a regular Iranian diet.
Blood pressure was measured on two consecutive visits by the same assigned person using a standard sphygmomanometer for both the study and control groups.
Urinary sodium, creatinine and magnesium were measured in the second sample of urine passed while maintaining fasting status. For the purpose of this study, we determined urinary microalbuminuria by enzyme-linked immunosorbent assay (ELISA) method and a microalbumin/creatinine ratio of more than 30 was considered as abnormal microalbuminuria.
As most patients did not cooperate to collect timed urine for 24 hours, the GFR was estimated by using Schwartz formula:
Estimated GFR (mL/min/1.73 m2) = kl/Pcr,
where l = length (cm); Pcr = plasma creatinine (g/dL); and k = 0.45 during the first year of life, 0.55 for children and adolescent girls, and 0.7 for adolescent boys.
FEMg was calculated from the following formula: 
SeCr × UMg × 100 / 0.7 × SeMg × UCr,
where SeCr = serum creatinine, Umg = urinary magnesium, SeMg = serum magnesium, and UCr = urinary creatinine.
| Results|| |
The mean ages for the study and control groups were 3.4 ± 1.3 years and 4.5 ± 1.1 years, respectively. Mean of urinary microalbumin/creatinine ratio in the study group was in normal range (15.98 ± 6.25). Microalbuminuria was not assessed in the control group.
A significant difference was shown in GFR between the study and control groups (81.79 ± 13.55 mL/min and 109.75 ± 9.03 mL/min, respectively (P < 0.05).
[Table 1] shows the mean values of urinary sodium and magnesium, serum sodium and magnesium, GFR, FENa and FEMg in both the study and control groups. FEMg, urinary magnesium, urinary sodium and FENa were significantly higher in the study group compared to those in the control group.
|Table 1: Mean of urinary and plasma magnesium and sodium, FEMg, FENa and GFR in both study and control groups.|
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The mean values of systolic and diastolic blood pressure in case group were 103.5 ± 4.89 mmHg and 63 ± 6.56 mmHg, respec-tively, and the results of systolic and diastolic blood pressure for control group were 98.95 ± 13.07 mmHg and 64.3 ± 12.1 mmHg, respectively. The differences were not statistically significant between the two groups.
| Discussion|| |
There are a considerable range of prognostic factors affecting patients with ARF/ATN in ICU setting, such as using mechanical ventilation, presence of respiratory complications, metabolic acidosis and alkalosis, septic and cardiogenic shock, multi-organ failure, the use of vasopressors, pre-existing renal impairment, oliguria and/or anuria, the category of RIFLE classification the patient is in, the time of nephrologist's intervention and intense use of dialysis. All these have been implicated as prognostic factors in short-term outcome of patients in an ICU. ,,,,,,,, However, Schiffl in a prospective study could not show any relationship between patient characteristics, severity of illness, mode and duration of renal replacement therapy with recovery of renal function. 
To assess the long-term outcome of ARF, Askenasi et al evaluated renal function in 29 children with a history of ARF of varying causes. After 3-5 years, most of them (59%) had at least one sign of renal injury such as microalbuminuria, evidence of hyperfiltration, decreased GFR and hypertension. 
Georgaki et al showed increased filtration fraction (inulin clearance/para aminohippurate (PAH) clearance) during a 7-12 year follow-up of 10 children with a history of ARF with different etiologies, but normal tubular reabsorption of phosphate, glucose, amino acids and also normal proximal and distal sodium reabsorption. 
Liano et al declared that 81% of patients with a previous history of ischemic ATN had normal or adequate renal function after long-term follow-up. 
Decreased GFR and non-nephrotic range proteinuria were demonstrated in 14 patients with ATN after 2-36 months of follow-up by Abdul-kader et al. 
Futrakul et al investigated patients with nephrotic syndrome for the most sensitive markers of tubular dysfunction. They could demonstrate FEMg as a sensitive index to detect early abnormality of tubular structure and function. 
The improvement of renal perfusion and function after recovering from renal injury due to chronic oxidative stresses comes with increasing creatinine clearance, GFR and a decline in FEMg. 
Inadequate blood flow (low intravascular volume) can result in ischemic ARF. However, restoration of renal blood flow does not immediately reverse the maintenance phase of ATN. Thus, epithelial cell damage occurs and persists independent of total renal blood flow. Different segments of nephron have different propensities to ischemia. The straight proximal tubule and the thick ascending loop of Henle (TAL) are the two segments that are most sensitive to ischemia.  Magnesium reabsorption in the TAL and distal tubule is load dependent.  The major part of magnesium reabsorption occurs in TAL. Therefore, it can be expected that tubular magnesium handling disturbances appear before the abnormalities for other cations and anions during ischemia. However, pathological events such as extracellular volume expansion and ureter occlusion do not affect the FEMg. ,
In this study, we aimed to determine any abnormality of FEMg, FENa, GFR and micro-albuminuria to detect signs of possible tubular dysfunction in children who did not have a severe course of ischemic ATN. Probably due to the choice of children with mild ATN (according to RIFLE classification), who did not need dialysis, and the lower possibility of severe tubulointerstitial fibrosis and the method of measuring microalbuminuria [ELISA but not high performance liquid chromatography (HPLC)], we could not show abnormal amount of microalbuminuria.
The mean values of GFR of the study group were still in the normal range as per CKD classification. However, the values were relatively lower compared to the mean values of the control group. Lower GFR values in the study group compared to control group may indicate that even mild ATN might result in a relatively lower GFR.
The mean values of FeMg and FENa of the study group were mostly in high ranges. Considering the duration of follow-up of our patients (12-30 months), the high values of these parameters may reflect early stages of CKD or even residual tubular damage from a resolving ATN. However, overcoming the problem of shortness of follow-up time, we selected patients with a history of only mild ATN to demonstrate whether FEMg and FENa increased at or after 12 months of resolving ATN.
The higher value of FEMg and FENa in the study group compared to control group showed that even mild ischemic ATN might cause tubular damage, especially in hypoxia sensitive parts of tubules. Since magnesium reabsorption predominantly occurs in an ischemic sensitive section of the tubule, FEMg can be used as a good index to determine early stages of tubular dysfunction or as an indicator of residual tubular damage. The small number of patients in each group is the limitation of our study. Whether changes of FEMg and FENa really reflect early stages of CKD needs more longitudinal and prolonged studies on a larger study group.
| References|| |
|1.||Albright,RC Jr, DO. Acute Renal Failure : a practical update. Mayo Clin Proc 2001;76:67-74. |
|2.||Santos WJ, Zanetta DM, Pires AC, Lobo SM, Lima EQ, Burdmann EA. Patients with ischemic, mixed and nephrotoxic acute tubular necrosis in intensive care unit- a homogenous population? Crit Care 2006;10(2):R68. |
|3.||Khan IH, Catto GR, Edward N, Macleod AM. Acute renal failure: Factors influencing nephrology referral and outcome. QJM 1997;90: 781. |
|4.||Stevens PE, Tamimi NA, Alhasani MK, et al. Non-specialist management of acute renal failure. QJM 2001;94:533. |
|5.||Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: Results of a community-based study. Br Med J 1993;306: 481. |
|6.||Liano F, Pascual J. Epidemiology of acute renal failure: A prospective, multicenter, community based study. Madrid Acute Renal Failure Study Group. Kidney Int 1996;50:811. |
|7.||Waikar SS, Curhan GC, Wald R, et al. Declining mortality in patients with acute renal failure, 1988 to 2002. J Soc Nephrol 2006;17: 1143. |
|8.||Myers BD, Moran SM. Hemodynamically mediated acute renal failure. N Engl J Med 1986;314:97. |
|9.||Liango O, Jaber BL. Renal and patients outcomes after acute tubular necrosis, [internet]. 2008[update 2008 May23; cited 2008 October 23].Available from http://www.uptodate.com |
|10.||Futrakul P, Yenrudi S, Futrakul N, et al. Tubular function and tubulointerstitial disease. Am J Kidney Dis 1999;33(5):886-91 |
|11.||Andreoli SP. Clinical Evaluation and Management. In: Avner DE, Harmon EW, Niaudet P (eds), Pediatric Nephrology, 5 th edn. Lippincott Williams & Wilkins, Philadelphia PA 2004; 1233-51. |
|12.||Gheissari A, Haghighi M. Diagnostic value of doppler ultrasound in differentiating prerenal azotemia from acute tubular necrosis in children. Saudi J Kidney Dis Transplant 2006; 17(2):168-70. |
|13.||Clarkson MR, Friedwald JJ, Eustace JA, Rabb H. Acute kidney injury. In: Brenner and Rectors′ eds. The Kidney, 8 th edition. Saunders (Elsevier) Philadelphia 2008;943-86. |
|14.||Topf JM, Murray PT. Hypomagnesemia and Hypermagnesemia. Rev Endocr Metab Disord 2003;4:195-206. |
|15.||Otukesh H, Hoseini R, Hooman N, Chalian M, Chalian H, Tabarroki A. Prognosis of acute renal failure in children. Pediatr Nephrol 2006;21:1873-8. |
|16.||Arora P, Kher V, Rai PK, Singhai MK, Gulati S, Gupta A. Prognosis of acute renal failure in children: A multivariate analysis. Pediatr Nephrol 1997;11:153-5. |
|17.||Loza R, Estremadoyro L, Loza C, Cieza J. Factors associated with mortality in acute renal failure (ARF) in children. Pediatr Nephrol 2006;21:106-9. |
|18.||Uchino S, Kellum AJ, Bellomo R, et al. Acute renal failure in critically ill patients-A multinational,multicenter study. JAMA 2005;294: 813-8. |
|19.||Spurney Rf, Fulkerson WJ, Schwab SJ. Acute renal failure in critically ill patients: Prognosis for recovery of kidney function after prolonged dialysis. Crit Care Med 1991;19(1):8-11. |
|20.||Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30(9):2051-8. |
|21.||Bagshaw SM, George C, Dinu I, Bellomo R. A multi-center evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23(4): 1203-10. |
|22.||Filler G. Acute renal failure in children: aetiology and management. Pediatric Drugs 2001;3(11): 783-92. |
|23.||Ghani AA, Al Helal B, Hussain N. Acute renal failure in pediatric patients: Etiology and predictors of outcome. Saudi J Kidney Dis Transpl 2009;20:20-9 |
|24.||Schiffl H. Renal recovery from acute tubular necrosis requiring renal replacement therapy: a prospective study in critically ill patients. Nephrol Dial Transplant 2006;21:1284. |
|25.||Askenasi DJ, Feig DI, Graham NM, Hui- Stickle, Goldstein SL. 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006;69:184-9. |
|26.||Geogaki-Angelaki NH, Steed BD, Chantler C, Haycock BG. Renal function following acute renal failure in childhood: A long term follow up study. Kidney Int 1989;35:84-9. |
|27.||Liano F, Felipe C, Tenorio MT, et al. Longterm outcome of acute tubular necrosis: a contribution to its natural history. Kidney Int 2007;71:679-86. |
|28.||Abdulkhader R, Liborio AB, Malheiros D MA. Histological Features of Acute tubular necrosis in native kidneys and long-term renal function. Renal Failure 2008;30(7):667-73. |
|29.||Futrakul N, Tosukhowong P, Valyapongpichit Y, Tipprukmas N, Futrakul P, Patumraj S. Oxidative stress and hemodynamic maladjustment in chronic renal disease: a therapeutic implication. Ren Fail 2002;24:433-45. |
|30.||Green J, Abbasi Z, Winaver J, Skorecki KL. Acute Renal failure: Clinical and pathophysiologic aspects. In: Seldin D, Giebisch G (eds). The Kidney,Physiology and Pathophysiology, 3 rd edn. Lippincot Williams and Wilkins, Philadelphia 2000;2329-73. |
|31.||Quamme GA, de Rouffignac C. Renal Magnesium Handling. In: Seldin D, Giebisch G (eds). The Kidney, Physiology and Pathophysiology, 3 rd edn. Lippincot Williams and Wilkins, Philadelphia 2000;1711-29. |
|32.||Poujeol P, Chabardes D, Roinel N, de Rouffignac C. Influence of extracellular fluid volume expansion on magnesium, calcium and phosphate handling along the rat nephron. Pflugers Arch 1976;365:203-11. |
|33.||de Rouffignac C, Quamme GA. Renal magnesium handling and its hormonal control. Physiol Rev 1994;74: 305-322. |
Department of Pediatric Nephrology, Isfahan University of Medical Sciences, St. AlZahra Hospital, Isfahan
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