Introduction
Acute pyelonephritis (PN) is a serious renal bacterial infection, which is associated with significant morbidity rate and higher incidence rate in women compared to men (1). This bacterial infection involves the lower urinary tract and results in a tubular dysfunction. This serious infection can lead to hospitalization of the majority of cases. Urinary tract is known as a common site of infection and acute pyelonephritis is recognized as the most severe type of urinary tract infection (UTI). High fever, malaise, dehydration, vomiting, stomach pain, irritability, and poor feeding are proposed as the clinical symptoms and systemic characteristics of this kidney infection. Escherichia coli is the major etiological agent in almost 80% of the cases (2). Early recognition and treatment of the infection are indispensable to avoid the late sequelae. Diagnosis and differentiation of pediatric pyelonephritis is a challenging issue. Several diagnostic strategies have been used to assess the kidney involvement in children with urinary tract infections such as urine culture, nuclear imaging dimercaptosuccinic acid (DMSA), renal scan and erythrocyte sedimentation (ESR) and C-reactive protein (CRP) measurements as blood inflammation indices (3). In almost 15% of children with acute pyelonephritis, renal parenchymal scarring has been recognized by DMSA scans as a long-term consequence of acute pyelonephritis and associated vesicoureteral reflux, which can eventually lead to other problematic consequences such as hypertension and proteinuria (4).
Evaluating various types of biomarker levels might be also supportive during the detection process of urinary tract infection in children such as urinary matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) (5). Low molecular serum proteins are found in urine in an extremely low concentration, however during the damage processes of proximal tubules, these small proteins will be excreted into the urine. Increased levels of urinary alpha-1-microglobulin (A1M), procalcitonin, and chemokine IL-8 have been also suggested to be associated with the incidence of acute urinary tract infection and vesicoureteral reflux (6,7). Nevertheless, the exact role of these biomarkers is not certainly revealed in detecting the pediatric pyelonephritis.
A1M is a low molecular weight protein measured in patients with pyelonephritis as a significant indicator of proximal tubular dysfunction. A specific characteristic of A1M, its stability even in room temperature, made it a good candidate to be studied for the diagnosis of pyelonephritis in children. Sensitivity and specificity of A1M in distinguishing pediatric with pyelonephritis is not sufficiently investigated.
In this paper, we aim to provide a systematic review of articles in PubMed and Scopus, evaluating the prognostic value of alpha-1-microglobulin in detecting the children with pyelonephritis with or without vesicoureteral reflux and renal scarring.
Methods
PubMed and Scopus were searched to obtain the relevant articles with the following search terms: acute pyelonephritis AND microglobulin. Last search was done in December 2014. No language and date limitations were included in our search strategy. Children with pyelonephritis or outflow disease of the upper urinary tract were included in our study, while patients with hydronephrosis or renal atrophy, patients without any proven UTI, those with UTI but without fever and patients with high fever of non-renal origin encompassed the exclusion criteria.

Results
A total of 39 articles were retrieved according to the search strategy (16 articles from PubMed and 23 articles form Scopus). After studying the abstracts of the articles, majority of them were omitted due to the irrelevant renal diseases to the purpose of our study or studying B2-microgolobulin. Only five articles were related to the subject of our study (Figure 1).
Applicable information and data of one relevant article written in Russian could not be retrieved due to inaccessibility to the full text of the article. Information regarding studies conducted on pediatrics with pyelonephritis is summarized in Table 1.

Discussion
Evaluating urinary microproteins is a noninvasive method that might have the diagnostic potential for early detection and differentiation of renal abnormalities.
Based on the literatures, beta 2-microglobulin has been a detecting urinary protein marker or index for many years and a considerable number of studies have investigated its diagnostic features (8-13). However, due to its weak constancy in acid PH, its diagnostic potential is questionable and impaired. In one study, Konda et al. revealed that these markers were not considerably predictive of renal function compared with A1M; however the concentration of beta 2-microglobulin, N-acetyl-beta-D-glucosaminidase, and microalbumin increased in children with reflux neuropathy. A1M can even indicate the presence of unusual renal function in reflux nephropathy in pediatrics before the incidence of proteinuria (14).
In 2000, Mantur et al. revealed that evaluating the urinary A1M/creatinine ratio was a useful means with the diagnostic advantages of proximal tubule damage during pediatric infection of urinary tract with E. coli (15). Pyelonephritis is known as a bacterial infection condition, which could result in parenchymal scarring and life-treating consequences.
Nowadays, alpha-1-microglobulin (A1M) as a multifunctional and immunomodulatory protein has shown a wide range of clinical use and has become a considerable alternative test for evaluating tubular function; this might be due to its constancy.

Diagnostic importance of A1M
Studies on urinary excretion of A1M revealed successful results regarding the capability of this marker in the diagnosis of various urological diseases involved kidneys including patients with reflux and with outflow disease of the upper tract (19).
Due to the lack of specific symptoms in children with urinary tract infection, early diagnosis of pyelonephritis is extremely important. Acute phase of pyelonephritis might occur without any parenchymal inflammatory lesions, which are difficult and time-consuming to be diagnosed especially in children and infants (20). Early detection of bacterial infection and performing the appropriate treatment could reduce the possibility of parenchymal scarring. In normal condition, 99% of filtered low molecular weight proteins are absorbed in tubules, while urine excretion of these proteins is called tubular disease (21).
According to the study of Everaert et al. A1M was proposed as the most effective biomarker in differentiating acute prostatitis from acute pyelonephritis while compared with other biomarkers such as urinary gamma-glutamyltransferase, albumin, creatinine, and immunoglobulin A (IgA) (6). The urine excretion of A1M showed a statistically significant increased due to renal colic and chronic ureteral obstruction in PN patients (6). In this study, age and gender of patients have been investigated as possible risk factors of urinary excretion of A1M. They revealed that there was no relation between PN patients’ gender and A1M urinary excretion rate despite of the slight influence of age on A1M urinary excretion. Moreover, it was mentioned that urine production rate significantly increased the urine A1M/creatinine fraction. Immunonephelometry was used to evaluate the concentration of urinary A1M and their results were in concordance with DMSA image outcomes. Everaert et al. showed that in DMSA lesion-positive (acute pyelonephritis) patients, the urinary excretion of A1M was significantly higher compared with DMSA lesion-negative (cystitis) patients who had normal A1M excretion in urine (18). It was even revealed that the excretion of A1M was significantly different in patients with bilateral pyelonephritis compared to those with unilateral pyelonephritis (18).
Currently, checking of inflammatory lesions through Tc-99m dimercaptosuccinic acid (99mTc-DMSA) scintigraphy is considered “gold standard” in acute phase of pyelonephritis. Therefore, DMSA uptake is a marker of pyelonephritis. Assessing the concentration of proximal tubular dysfunction markers can be beneficial in the diagnosis of acute pyelonephritis. The concentration of urine biomarkers has been evaluated and compared with the 99mTc-DMSA results to measure their correlation. Everaert et al. observed a considerably high correlation between urinary A1M concentration and DMSA results. They reported the urinary A1M evaluation as a cheap, quick, and reliable screening method for the diagnosis of acute pyelonephritis and applying the appropriate and necessary antibiotic treatment (18). A1M is a sensitive and specific indicator of acute pyelonephritis and differentiator between upper and lower urinary tract infection. Furthermore, A1M might diagnose the incidence of acute pyelonephritis at the time of hospital admission and before obtaining urine culture results (19). Mentioned studies evaluated the concentration changes of urine biomarkers as a noninvasive and cost effective method; however this method might be very complicated due to the difficult comparisons. In the study of Puczko-Michalczuk, in 2008, nephrometric assay was used for the evaluation of A1M (17). Applying computer-based systems for urine protein differentiation could improve the quality of test interpretation. According to the study of Gonzalez Rodriguez et al. in 2009, A1M is more sensitive in the diagnosis of acute pyelonephritis compared with other renal diseases (16).
The small number of studies conducted on this issue, especially English language articles, limited the obtained data in this review.

Conclusion
A1M is not an acute phase protein but its concentration alters in several clinical conditions. Evaluating the urine concentration of A1M is a noninvasive and cost effective strategy with the diagnostic capability for urinary tract disorders such as early recognition of tubular damages during pyelonephritis.

Acknowledgement
We would like to thank Clinical Research Development Unit of Ghaem Hospital for their assistant in this manuscript.

Conflict of Interest
The authors declare no conflict of interest.