The main objective of our study was to detect early renal impairment in our CF patients by comparing the usual renal assessment through kidney function tests (urea, creatinine) GFR, A/C ratio, urine analysis, renal u/s to urinary NAG enzyme level.
As CFTR expression and function have been demonstrated in the kidney, abnormalities in renal tubular function along with an increased risk of renal injury due to a propensity for dehydration are both well described in CF. In addition, the need to use potentially nephrotoxic antibiotics or anti-rejection drugs (post lung transplantation) may lead to acute or chronic renal injury. This raises concerns regarding renal dysfunction in the CF population .
This study shows a significant elevation of urinary NAG enzyme level in CF cases compared to the healthy control group. On the contrary, the usual kidney function tests (serum urea and creatinine) were normal in all cases. While estimated GFR and recorded A/C ratio were only abnormal in 35.0% and 17.5%, respectively, of cases.
This goes in line with the study done by Nazareth and Walshaw, 2013 which shows that GFR is also insensitive in the detection of early renal dysfunction as up to 30% of nephrons can cease to function before GFR alters, since the remainder compensates by increasing their filtration rate. It is only with a further loss of renal tissue that GFR will reduce . The glomerular filtration rate though estimated by different formulae that are simple to use in daily practice but none has been formally validated in CF  due to the possibility of overestimation of these formulae to the GFR in children with CF because they are not reliable when the serum creatinine is unstable , as many of CF patients are in a hypermetabolic state have diminished muscle mass, and have limited exercise capacity, all of which can influence creatinine production. In addition, measurement of GFR may lead to variability or bias depending on the conditions of each patient (hydration status, protein intake) .
The same was observed in measuring serum creatinine in our patients as 100% had normal serum creatinine levels; this goes in correlation with a study done by Boer et al., 2010, which showed that serum creatinine levels can vary widely with age, gender, muscle mass, muscle metabolism, medications, and hydration status .
Hence recently, attention has been directed towards the evaluation of urinary enzymes as non-invasive biomarkers of renal tubular damage that is useful in the early diagnosis of acute renal injury before conventional laboratory assays become deranged [11,12,13], and they reflect sub-clinical toxicity. They may also indicate the site of primary tubular damage because of their localization in tubular lysosomes (N-acetyl-β-D-glucose-aminidase [NAG]) and the brush border (alanine amino-peptidase [AAP]) [14, 15].
N-Acetyl-β-Dglucosaminidase is a lysosomal enzyme that leaks into urine which is mainly originated from the proximal tubular cells. This enzyme is defined as being more specific and sensitive to renal tubular injury than creatinine especially with its isoenzymes and when combined with other renal biomarkers, for example, Neutrophil gelatinase-associated lipocalin (NGAL) and Kim-1 .
In our study, there was a significant elevation of urinary NAG levels in the case group than control group (P value < 0.001). This also was reported in a study of Liangos et al., 2007, where the urinary NAG enzyme has a high sensitivity for acute kidney injury (AKI) .
In addition, there was a positive correlation of urinary NAG levels with the duration of the disease and its severity with P value 0.019 and 0.001, respectively. This also was reported in a study by Glass et al., 2005, in which the correlation between urinary NAG enzyme elevation and duration of disease in CF children was significant .
Aminoglycosides target the lysosomal system within the proximal tubule. The drug initially binds to the brush border membranes and is then transferred to the tubular cell lysosomes, which may subsequently leak and rupture. Advanced toxicity is characterized by tubular cell necrosis and eventually renal failure .
Our study reported a statistically significant elevation of urinary NAG enzyme level in CF patients with positive intake of nephrotoxic medication to those with negative intake (P value = 0.005) Also, there was a significant correlation of urinary NAG enzyme with the duration of nephrotoxic medications intake (P value = 0.008).
Few previous studies assessed urinary NAG excretion in patients with CF during inhaled aminoglycoside treatment. Steinkamp et al. reported a significant increase in mean urinary NAG excretion in 10 patients treated with intravenous tobramycin, while inhaled tobramycin produced no alteration in urinary NAG activity , on the other side Ring et al. demonstrated in those patients receiving gentamicin inhalation a positive correlation between urinary NAG and the cumulative dose of nebulized gentamicin .