Potential biomarkers in pediatric Familial Mediterranean Fever-related nephropathy: KIM-1 and NGAL

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Abstract
Introduction: Familial Mediterranean Fever (FMF) is an autoinflammatory disease which exhibits an autosomal recessive inheritance manner and is characterized by inflammation of serosal membranes including pleurae, synovia, and peritoneum, usually with accompanying fever and pain, and presents with symptomatic episodes. Kidney Injury Molecule-1 (KIM-1) is a novel biomarker of acute renal injury (ARI) which is secreted by the proximal tubule cells after occurrence of kidney damage, which shows tubule damage sensitively and is easily detectable by urinary biochemistry analysis. Neutrophil Gelatinase Associated Lipocalin (NGAL) is a novel biomarker that can be identified in the distal tubules and collecting ducts after development of ARI. Besides some traditional parameters like glomerular filtration rate, there is no specific biomarker to predict kidney injury or failure in FMF. There is very scant data regarding role of NGAL and KIM-1 in predicting FMF-related nephropathy and kidney failure. Our objective was to shed some light on whether urinary KIM-1 and/or NGAL levels can be used as biomarkers of renal injury in FMF patients.Methods: This prospective study included patients with clinical diagnosis of FMF who were admitted to our Pediatric Emergency Clinic between January 2018 and January 2019, and healthy children of similar gender and age as controls. Urine samples were collected for urinary KIM-1 and NGAL analyses. When a sufficient number of patients were reached, KIM-1 and NGAL levels were measured from the samples. Urinary KIM-1 levels were determined using an ELISA kit. Urinary KIM-1 levels were standardized for urine creatinine (ng/mg). NGAL enzyme activities were measured spectrophotometrically using commercial kits.Results: A total of 56 children, 51.8% (n=29) Familial Mediterranean Fever patients and 48.2% (n=27) controls, were recruited. Kidney injury molecule-1 levels in pediatric FMF patients were elevated than those noted in the controls (p=0.003), while KIM-1/creatinine ratios were similar (p=0.500). Pediatric FMF patients had elevated NGAL levels than those of the controls (p<0.001). Mean NGAL/creatinine ratio of FMF patients (5.24±4.19) were also higher than that of the control group (0.03±0.03) (p<0.001).Conclusion: While findings indicating acute tubular damage such as proteinuria and hematuria have not developed, high KIM-1 and NGAL levels may indicate that these biomarkers are likely to be used as reliable, non-invasive, and early predictors of renal injury. Larger multicenter clinical studies are necessary for urinary levels of these molecules to be routinely used for earlier recognition of FMF-related renal injury.

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