Glucocorticoid resistance in dialysis patients reduces long-term graft survival after kidney transplantation.

Glucocorticoid (GC) resistance has been observed in chronic kidney disease (CKD) patients on dialysis. It can be evaluated by binding assays based on the dissociation constant (Kd), which is inversely proportional to ligand affinity. CKD patients with GC resistance had increased number of acute rejection episodes. We followed up 26 patients that underwent kidney transplantation to observe whether GC resistance could affect the response to acute rejection episode pulse therapy and the long-term allograft outcome. Using Kaplan-Meier survival curve, GC resistant patients showed lower acute rejection-free survival (p=0.03) and lower kidney allograft survival (p=0.008). No difference was found regarding number of deaths. Multivariate logistic regression showed that high Kd value was an independent predictor of lower kidney allograft survival (p=0.001). There was a negative Spearman correlation between Kd and kidney allograft survival (r=-0.88, p=0.03). In conclusion, our findings indicate the usefulness of binding assay performed previously to kidney transplantation to define GC resistance. In addition, the dissociation constant (Kd) is a reliable and independent predictive marker of higher frequency of acute rejection episodes, lower rejection-free graft survival, poor response of acute rejection episodes to methylprednisolone pulse therapy, and lower kidney allograft survival in a long-term follow-up.

Glucocorticoid resistance in dialysis patients may impair the kidney allograft outcome.

This study examines in vitro steroid sensitivity in chronic renal failure (CRF) patients and its influence on the allograft outcome. We determined the inhibitory effect of dexamethasone (DEX) on concanavalin A (Con-A)-stimulated peripheral blood mononuclear cell (PBMC) proliferation, and glucocorticoid receptor' (GR) number of binding sites (B(max)) and affinity (K(d)) in 28 CRF patients and 40 normal healthy controls. Based on K(d) values >95th percentile from controls, patients were divided into two groups: glucocorticoid resistant (n = 11) and glucocorticoid sensitive (n = 17). Patients were followed during 18 months post-transplantation observing acute rejection episodes (ARE), chronic allograft nephropathy (CAN), allograft failure and death. The DEX concentration that caused 50% inhibition of Con-A-stimulated PBMC proliferation (IC(50)) was higher in CRF than in healthy controls (2.2 x 10(-5) +/- 1.0 x 10(-5) versus 8.3 x 10(-6) +/- 4.2 x 10(-6) mol/L, P = 0.02). Values of K(d) (12.4 +/- 1.8 versus 7.2 +/- 0.9 nM) and B(max) (7.7 +/- 1.1 versus 4.1 +/- 0.3 fmol/mg protein) were higher in CRF patients (P = 0.02 and P = 0.001, respectively). There were higher incidences of ARE (P = 0.02) and CAN (P = 0.002) in the glucocorticoid-resistant group. Univariate and multivariate logistic regression showed that K(d) was an independent predictor of ARE (OR 8.8, P = 0.03) as well as of CAN (OR 16.5, P = 0.01). In conclusion, we observed glucocorticoid resistance in a subgroup of CRF patients undergoing dialysis, which led to a higher morbidity due to ARE and CAN in an 18-month follow-up period.