TGF-beta1 in chronic allograft nephropathy following renal transplantation.

BACKGROUND: Evidence from experimental models and clinical studies supports a major role for transforming growth factor-beta1 (TGF-beta1) in renal fibrosis. The aim of this study was to use repeated measurement of plasma TGF-beta1 as an indicator of persistent expression in a cohort of patients during the first 2 years post-renal transplantation and to correlate the findings with the development of chronic allograft nephropathy (CAN). METHODS: Active plasma TGF-beta1 was quantified in 100 consecutive renal allograft recipients (samples/patient = 35.6 +/- 12.9) under standard clinical management for a mean of 23 months (range 3.4-45 months). All patients were followed up for a minimum of 5 years. RESULTS: By 5 years, 23 patients had developed biopsy-proven CAN (CAN+), all of whom had been positive for plasma TGF-beta1. Demographic data were compared between patients who were CAN+ and CAN-negative (CAN-) and were not significantly different. TGF-beta1 exposure expressed as area under the curve / day (AUC/day) was correlated with the incidence of CAN. A Cox regression model was used to investigate the interrelationship of CAN, acute cellular rejection (ACR) and TGF-beta1 levels. ACR episodes were predictive of the development of CAN (log-rank test, p=0.003). After allowing for the effect of ACR (hazard ratio [HR]=3.6; 95% confidence ratio [95% CI], 1.5-8.7) between patients with and without ACR episodes, p=0.003), the independent effect of TGF-beta1 was confirmed (HR=1.7; 95% CI, 1.1-2.6; per quartile; p=0.008). CONCLUSION: The results demonstrate that episodes of ACR are highly predictive of chronic damage in the graft. Cumulative exposure to TGF-beta1 is identified as an independent predictor of CAN in the first 2 years posttransplantation.

VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5.

BACKGROUND: Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2). METHODS: Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions -460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-beta1 polymorphisms at positions -800, -509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). RESULTS: In cohort 1, there was a significant increase in frequency of the -460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94-58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21-4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF -460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease. CONCLUSION: In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.