Leflunomide has been shown to be very effective in preventing and curing several autoimmune animal diseases. Further, this agent is as effective as cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several cytokines and is cytostatic for certain cell types. In this light, we could show that tyrosine phosphorylation of the RR-SRC peptide substrate and the autophosphorylation of the epidermal growth factor (EGF) receptor were, dose dependently, inhibited by leflunomide. EGF activates the intrinsic tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of peptides, the amino acid residue in all cases is tyrosine. These results indicate that much of leflunomide's activity could be due to the inhibition of tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus, leflunomide, which is effective against autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs.

Background and purpose: Until recently clinical diagnosis of chronic renal allograft dysfunction could only be established invasively by renal biopsy. Given the risks of that procedure, a non-invasive, diagnostic test would be very advantageous. Novel ultrasound-based elasticity tools, using "Acoustic Radiation Force Impulse (ARFI)" technology are now available. Previously this technique has been utilised to quantify liver fibrosis. First results of these studies are promising. The purpose of our study was to investigate correlation between stiffness values obtained by ARFI-quantification and histological fibrosis score in renal transplants.Methods: We employed "Virtual Touch TM tissue quantification" (Siemens Acuson, S2000) to quantitatively measure tissue stiffness in the cortex of transplant kidneys.Eighteen patients were included in this prospective study, recording close temporal ARFI-quantification and fibrosis measurements. All patients undergoing renal transplant biopsy were examined with ARFI-quantification (15 measurements per transplant kidney). Resistive indices were also calculated from pulsed-wave Doppler ultrasound. Transplant biopsies were histologically evaluated by a reference nephropathologist and graded according to the percentage of fibrosis and to the BANFF-score. Due to the non-normal distribution of the data the Spearman-correlation-coefficient (rho) was used to assess the bivariate relationship of ARFI and fibrosis in the transplant kidney.Results: There was a significant positive moderate correlation between mean ARFI-values and the grade of fibrosis (rho = +0.465; p = 0.026). This correlation was also valid for the mean ARFI-values and the BANFF-category (rho = +0.468; p = 0.025). There was no significant correlation between the mean ARFI-values and the resistive indices in the transplant kidney (rho = +0.034; p = 0.904). Nevertheless, a positive correlation between the mean RI-values of the kidney and the grade of fibrosis was established (rho = +0.563; p = 0.015). Conclusion:The mean values of ARFI measurements and the resistive indices are potentially independent explanation variables for evaluating the grade of fibrosis in transplant kidneys.

Rationale : Patients with end-stage renal disease are characterized by increased cardiovascular and all-cause mortality because of advanced remodeling of the macrovascular and microvascular beds. Objective : The aim of this study was to determine whether retinal microvascular function can predict all-cause and cardiovascular mortality in patients with end-stage renal disease. Methods and Results : In the multicenter prospective observational ISAR study (Risk Stratification in End-Stage Renal Disease), data on dynamic retinal vessel analysis were available in a subcohort of 214 dialysis patients (mean age, 62.6±15.0; 32% women). Microvascular dysfunction was quantified by measuring maximum arteriolar dilation and maximum venular dilation (vMax) of retinal vessels in response to flicker light stimulation. During a mean follow-up of 44 months, 55 patients died, including 25 cardiovascular and 30 noncardiovascular fatal events. vMax emerged as a strong independent predictor for all-cause mortality. In the Kaplan-Meier analysis, individuals within the lowest tertile of vMax showed significantly shorter 3-year survival rates than those within the highest tertile (66.9±5.8% versus 92.4±3.3%). Univariate and multivariate hazard ratios for all-cause mortality per SD increase of vMax were 0.62 (0.47–0.82) and 0.65 (0.47–0.91), respectively. Maximum arteriolar dilation and vMax were able to significantly predict nonfatal and fatal cardiovascular events (hazard ratio, 0.74 [0.57–0.97] and 0.78 [0.61–0.99], respectively). Conclusions : Our results provide the first evidence that impaired retinal venular dilation is a strong and independent predictor of all-cause mortality in hemodialyzed end-stage renal disease patients. Dynamic retinal vessel analysis provides added value for prediction of all-cause mortality and may be a novel diagnostic tool to optimize cardiovascular risk stratification in end-stage renal disease and other high-risk cardiovascular cohorts. Clinical Trial Registration : URL: http://www.clinicaltrials.gov . Unique identifier: NCT01152892.

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