Angiotensin converting enzyme gene polymorphism in idiopathic nephrotic syndrome

Nephrotic syndrome is a common renal disease in children and it is defined as proteinuria, hypolbuminemia, hyperlipidemia and edema. According to the study from International Study of Kidney Disease in Children, 76.6% showed minimal change disease in nephrotic syndrome in children. Most patients with minimal change proven by renal biopsy have a good response after a standard course of prednisolone treatment. A complete remission is induced in about 80% cases and 40-50% of these relapse frequently. According to the biopsy results, patients with focal segmental glomerulosclerosis (FSGS) respond poorly to steroid therapy and tend to progress end-stage renal failure compared with patients with minimal change nephrotic syndrome (MCNS). In patients with steroid-dependent nephrotic syndrome (SDNS), in addition to high dosage of steroid therapy, some patients may need immunosuppressants to improve proteinuria. Glomerulosclerosis, leading to progressive loss of renal function in various kidney diseases, is analogous in some aspects of atherosclerosis including a regulatory role of the renin-angiotensin system (RAS), especially in angiotensin-converting enzyme (ACE) gene polymorphism.
The variable steroid response of children with idiopathic nephrotic syndrome has not been explained. Angiotensin II may induce proteinuria, while angiotensin converting enzyme (ACE) inhibitors may reduce proteinuria and even get remission in nephrotic syndrome. Whether angiotensin II related to steroid threshold in difficult steroid dependent and steroid resistant nephrotic syndrome remains undetermined. The genotypes in ACE gene polymorphism can influence plasma and tissue angiotensin II levels.
ACE gene insertion/deletion (I/D) polymorphism with DD genotype is a risk factor for cardiovascular disease and renal disease. ACE gene has been identified I/D polymorphism on the ACE locus on chromosome 17q23 of a 287-basepair fragment on intron 16. Lee et al. reported a markedly different distribution of ACE genotypes in FSGS and MCNS in their Korean patients in which the DD genocypte was significantly associated with FSGS. Al-Eisa et al. described that an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation in nephrotic syndrome in Kuwaiti children. The purpose of this study was to examine the association between the ACE I/D genotype distribution in children with nephrotic syndrome and the response to steroid therapy. We used the newly developed automatic denaturing high performance liquid chromatography system (DHPLC) instead of gel electrophoresis to analyze PCR amplicons.
A total of 59 children diagnosed as nephrotic syndrome at the age of 1 to 10 year-old were recruited in this study. Eighty children without renal diseases were also recruited as control group in genetic analysis. The patients were divided into 2 groups according to their clinical response to steroid: SS group including infrequent and frequent relapsers and non-SS group including steroid resistant (SR) and steroid dependent (SD) patients. Clinical parameters including the age of onset, systolic and diastolic blood pressure, renal function, albumin and C3 level showed no difference between two groups except for significantly elevated triglyceride in the non-SS group. In genetic study for ACE I/D genotype distribution, patients had significantly higher percentage to have DD genotype (DD vs. non-DD; p<0.001) and D-allele (D-allele + vs. D-allele -; p<0.001) than control group. Furthermore, patients also had significantly higher percentage to have DD genotype than ID or II genotype than control group. Among 59 patients with nephritic syndrome, the distribution of DD, ID and II genotype was 52.5% (31/59), 10.2% (6/59) and 37.3% (22/59), respectively. DD genotype showed significantly higher in the non-SS group than SS group (p=0.026). And non-SS group also had significantly higher incidence in D-allele presentation than SS group (p=0.024).
Our data shows that patients with nephrotic syndrome had higher rate to have DD genotype and D allele than control group. Among these patients, SD and SR patients had higher percentage of D-allele and DD genotype in ACE gene polymorphism. This finding suggests that DD genotype may indeed be a risk factor for steroid dependence and steroid resistance, and angiotensin II may be involved in the steroid response of idiopathic nephrotic syndrome.