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Abstract. The prevalence of chronic kidney diseases (CKD) in children has risen rapidly in
worldwide due to congenital anomalies of the kidney and urinary tract (CAKUT). Urine
NGAL has become a biomarker which has been demonstrated to be associated with poor
prognosis of CKD. The aim of this study was to analyzed urine NGAL on long term CKD in
patients CAKUT. This is a cohort study, involving 120 patients with CAKUT, who were
divided into two groups: the obstructive type and non obstructive type. The primary follow-up
end-point was a composite of halving of eGFR or recurrent urinary tract infection. Secondary
follow-up end-point was eGFR of less than 15 mL/min or death caused by renal. The mean
age of the patients was 7.5 ± 4.1 years and 60% were boys. Sixty two point five percents of
patients had obstructive CAKUT. In bivariate analysis there was strong association between
concentration of urine NGAL and progressivity of CKD (p=.0.001) After regression, urin
NGAL continued to be associated with progressivity of CKD (AUC 74%). Therefore, we
suggest that urine NGAL could be considered in predicted severe CKD in CAKUT patients.
1. Introduction
These CAKUT anomalies are the spectrum of malformations that occur in the kidney and urinary tract,
result from defective development of the kidney and urinary tract.[1,2] The most common post natal
manifestation of CAKUT include palpable abdominal mass or decreased urinary output (obstructive
type), meanwhile in those without urinary tract symptoms (non obstructive type), detection of CAKUT
is not easy, as an incidental finding during a routine examination or while the child is undergoing
investigation for an unrelated complaint. [3,4] Almost all infants and children with CAKUT have
higher chance to develop urinary tract infection (UTI) and or obstruction that are risk to renal
impairment (chronic kidney disease).
Most CAKUT cases in developing countries lack of ante/post natal screening, delay treatment
and progress from chronic kidney disease (CKD) to end stage renal disease (ESRD). In CAKUT with
CKD, the tubulointerstitial disease is an important step that leads to nephron loss and in turn leads to
interstitial inflammation and fibrosis.[1,5,6] In response to injury, tubular epithelial cells produce
cytokines, such as NGAL. The production of urin NGAL is increased occurring in states of tubular
injury [7,8] Aim of this article is to describe role of urin NGAL to predict severity of CAKUT .
1
2. Material and Methods
This was a cohort study carried out in the Department of Pediatric Nephrology, University of
Sumatera Utara, Medan, Indonesia. This study was done over a period of 4 years from February 2014-
February 2017. After written informed consent and ethical clearance from University of Sumatera
Utara, patients with CKD due to CAKUT with stable kidney function for at least for 6 months were
enrolled in the study. All the new cases aged between 1 and 17 years with CKD stage II-IV were
enrolled as per KDIGO (Kidney Disease: Improving Global Outcomes) guidelines [9]
A total of 122 subjects were enrolled in the study, 120 subjects completed the study up to end-
point and 2 subjects dropped out from the study. After enrollment these patients were followed for 18
months. The diagnostic criteria of CAKUT were defect of the renal parenchyma and or urinary tract
malformation documented by renal ultrasonography and voiding cystoureterogram. In our study
disease progression was decided on the basis of declining eGFR or progression of CKD stage, ie,
progression from stage II to stage III or stage III to stage IV. The Schwartz formula was used to
calculate the eGFR.[10] The staging criteria for CKD were defined as: stage II renal damage with
eGFR of 60–89 mL/min per 1.73 m2; stage III eGFR of 30–59 mL/min per 1.73 m2 and stage IV
eGFR of 15–29 mL/min per 1.73 m2 [9] Patients with non-syndromic vesicoureteral reflux (VUR),
malignant renal tumor, sepsis, massive proteinuria, being treated with steroids or immunosuppressive
agents were excluded from the study. Because of CAKUT is life-long disease, so chronologic age was
used as the index date instead. To ensure the validity of the index date, the patients were followed-up
for at least 6 months and those with incomplete observation were not included in this study.
Biochemistry, urinalysis, and urine protein measurements were performed as per study protocols.
2
Table 1. Baseline demographic data
All CAKUT Non Obstructive Obstructive
(n=120) (n= 45) (n=75)
Gender (Males, n) 72 20 52
Age, years (SD) 7.5(4.1) 7.7(3.8) 8.1(4,3)
GFR (n)
Stage II 32 9 23
Stage III 18 5 13
Stage IV 70 31 39
Findings from this study (indicate that NGAL represents a novel risk marker of CKD progression.
Urinary NGAL showed predictive power progression CKD into ESRD. In adult CKD patients, urinary
NGAL just not a simple surrogate index of baseline GFR, because after adjust to GFR, urinary NGAL
still have power to predict CKD progression.[12] Urinary NGAL might be particularly useful in the
evaluation of kidney recovery in patients with low-grade proteinuria. Proteinuria is an important direct
mediator of tubular epithelial cell injury and urinary NGAL increased in paralel with degree of
proteinuria [13]. In CAKUT, commonly found low grade proteinuria and after treatment of CAKUT
also found the same situation. In these circumstances, urine NGAL continues to increase especially in
CAKUT with CKD stage 3 and 4.
In CAKUT children it is necessary to prolong the follow up after adolescence because risk of
severe CKD and ESRD (Figure 2 and Table 3). The ItaliKid study showed that children with moderate
and severe CKD, had risk to developing ESRD estimated at 70 and 97%, respectively.[14] This data
showed that predict to severe CKD is warranted. Children from milder CKD had risk to developing
3
ESRD. Role of urin NGAL to predict severity CKD in CAKUT patients found to be established, so
patient at risk severe CKD could be identified. This study had several limitations which may have
influenced the results. We included various types of CAKUT disease with varying severity of GFR.
Patients were administered according to obstructive or non-obstructive types of CAKUT but these
factors may affect the number of patients achieving “recovery” to evaluate the predictive value of
urine NGAL from the beginning of treatment.
References
[1] Palacios Loro ML, Sequra Ramirez DK, Ordonez Alvares FA, Santos Rodriguez F 2015. An Pediatr (Barc) 83(6)
442.e1-5.
[2] Song R, Yosypiv IV 2011. Pediatr Nephrol 26 353–64.
[3] Rodriguez MM 2014. Fetal Pediatr Pathol 33(5-6) 293-320
[4] Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J et al 2003. J Am Soc Nephrol 14(10) 2534-43
[5] Woodward M, Frank D 2002. BJU Int 89(2) 149–56
[6] Moritz KM, Singh RR, Probyn ME 2009. Am J Physiol Renal Physiol 296 F1–9.
[7] Seikaly MG, Ho PL, Emmett L, Fine RN, Tejani A 2003. Pediatr Nephrol. 18 796–804
[8] Schmidt-Ott KM, Mori K, Li YJ, Kalandadze A, Cohen DJ, Devarajan P et al 2007. J Am Soc Nephrol 18(2)
407-13
[9] National Kidney Foundation 2002. Am J Kidney Dis. 39 S1–S266.
[10] Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A 1976. Pediatrics 58 259-63.
[11] Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y et al 2009. Kidney Int 75 285-94
[12] Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR et al 2009. Clin J Am Soc Nephrol 4(2)
337-44.
[13] Sirisopha A, Vanavanan S, Chitamma A, Phakdeekitcharon B, Thakkinstian A, Lertrit A et al 2016. Int J of Nephrol
Article ID 4904502 1-9
[14] Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, et al 2003. Pediatrics 111 e382–7.