Activated intrarenal transcription of CTL-effectors and TGF-β1 in children with focal segmental glomerulosclerosis

Abstract

The pathogenesis of childhood nephrotic syndrome (NS), whether the lesion is minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), remains elusive. Based on the presence of elevated cytokine levels in peripheral blood, a T cell-induced injury could be postulated. To test the hypothesis that infiltrating T cells actively contribute to the glomerular injury in children with NS, we studied the intrarenal transcription of various T cell-related chemokines, cytokines and cytotoxic T-lymphocyte (CTL) effector molecules in the renal biopsy tissue of 52 nephrotic children with a variety of histologic lesions. Intrarenal gene expression was studied using reverse transcription (RT)-assisted-polymerase chain reaction (PCR). Interleukin-2 (IL-2) and IL-4 transcripts were not observed in any of the specimens. IL-2 receptor alpha mRNA was detected in 24 of 40 proteinuric patients, but also in 6 of 10 patients in remission and showed no significant differences with regard to steroid response. Intrarenal gene expression of CTL mediators and transforming growth factor-beta1 (TGF-beta1) was noted particularly in patients with progressive disease leading to chronic renal failure. TGF-beta1 gene expression was noted in 23 of 29 steroid resistant (SR) children with NS not caused by lupus nephritis and in 18 of 20 FSGS patients. In contrast TGF-beta1 gene expression was detected in only 3 of 14 steroid-sensitive patients (P < 0.001). Two of these patients later developed FSGS. In patients with steroid-resistant NS, intrarenal TGF-beta1 gene expression showed a positive predictive value of 90% and a negative predictive value of 88% to identify FSGS (P < 0.0001). These results support the notion that immunologically mediated events contribute to the progressive renal damage seen in children with FSGS.