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).


CONCLUSIONS
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.
Harris
Shelley
S
The Renal Research Laboratories, Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, UK. shelly.harris@cmmc.nhs.uk
Coupes
Beatrice M
BM
Roberts
Stephen A
SA
Roberts
Ian S D
IS
Short
Colin D
CD
Brenchley
Paul E C
PE
D000208:Acute Disease; D000328:Adult; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006084:Graft Rejection / Q000150:complications; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014184:Transplantation, Homologous
D053773:Transforming Growth Factor beta1