Evaluation of association between UMOD gene variants, clinical findings and renal outcomes in children with idiopathic nephrotic syndrome

Nephrotic syndrome (NS) is a renal disease characterised by nephrotic proteinuria, hypoalbuminemia, edema and hyperlipidemia resulting from damage to glomeruli and increased glomerular filtration barrier permeability. Approximately 10-35% of patients with NS develop chronic kidney disease (CKD) and late age of onset, resistance to steroids and immunosuppressive agents, focal segmental glomerulosclerosis (FSGS) and underlying genetic podocytopathies have been associated with poor prognosis and CKD. Although the genetic etiology of NS has been elucidated, there are few data on the genetic factors involved in the association between NS and CKD. The aim of this study was to determine the factors associated with renal prognosis in children with NS and to evaluate the association of UMOD gene variants with clinical findings and renal function. Patients who were followed up with the diagnosis of NS in our clinic were included in the study according to the order of outpatient clinic admission. Demographic, clinical and laboratory data were obtained from the hospital's medical record system. UMOD NG_008151.1:g.1348C>A (rs12917707) and NC_000016.10:g.20389517C>T (rs11864909) variants were analyzed. Patients were clinically divided into 3 groups. Group 1 (ESRD) included patients on hemodialysis and transplantation, group 2 (CKD) included patients with a GFR below 90 or with a GFR above 90 and proteinuria, and group 3 included patients with a GFR above 90 and no proteinuria, that is, in remission with or without medication. The study included 120 patients with NS and 48 healthy children. The mean age at diagnosis was 5,49±3,75 years and the mean follow-up period was 6.91±4.58 years. 73 of the patients were male (60.8%), 47 were female (39.2%). Of the patients, 61 were diagnosed as steroid-resistant NS, 35 as steroid-sensitive NS, 16 as steroid-dependent NS, and 8 as frequent relapse NS. During the follow-up period, 12 of 61 steroid-resistant patients went into remission, 14 developed CKD, 2 went to dialysis and 33 went to kidney transplantation. Of the 16 steroid-dependent patients, 14 went into remission, 1 developed CKD and 1 underwent renal transplantation. All 35 steroid sensitive patients and 8 patients with frequent relapses went into remission. At the last outpatient clinic visit, 36 patients were included in the ESRD group (group 1), 15 patients in the CKD group (group 2), 42 patients in remission without medication and 27 patients in remission with medication, totaling 69 patients in group 3. In the group with ESRD, the mean age was older, the follow-up period was longer, the rate of consanguineous marriage between parents was higher, and the rate of NS in the family was more frequent (p<0.05). Family history of CKD was more frequent both in the ESRD group and in the CKD group compared to the other group (p<0.05). The rate of HT at the time of diagnosis was higher, creatinine and cystatin c values at baseline were higher, and GFR values were lower in the ESRD group (p<0.05). In the 3rd group, complications such as coinfection, thrombosis, osteoporosis, dyslipidemia, developmental delay, acute kidney injury were found to be lower (p<0.05). Pathologic allele distributions of UMOD rs12917707 and rs11864909 variants were found to be similar in steroid resistant, steroid sensitive, steroid dependent, steroid dependent, frequent relapse and complete remission groups. When those who developed ESRD were compared with those who did not develop ESRD and those with ESRD among steroid-resistant patients were compared with those without ESRD, the rate of CT heterozygous type of UMOD rs11864909 variant was found to be higher in the ESRD group (p<0.05). When all patients; steroid resistant patients and patients with hematuria at the time of diagnosis were divided into 3 groups, the rate of UMOD rs11864909 variant CT heterozygote type distribution was higher in the ESRD group compared to the CKD group (p<0.05). The frequency of rs11864909 variant pathologic T allele was higher in the group with hematuria at the time of diagnosis compared to the group without hematuria (p<0.05). The results of our study suggest that UMOD rs12917707 variant is not associated with NS, whereas UMOD rs11864909 variant is associated with ESRD in NS. In previous studies, these variants have been found to be associated with ESRD, glomerular filtration rate and renal function; however, they have never been investigated in the patient population with NS and our study is unique in this respect.