Glucocorticoid resistance in dialysis patients may impair the kidney allograft outcome

Abstract

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.

Dynamics of salivary cortisol in chronic kidney disease patients at stages 1 through 4

“…Our data suggest that a subpopulation of CKD patients has a disordered feedback control of the HPA axis as reported in ESRD . Other authors observed in vitro a diminished affinity of cytoplasmatic GC receptors to dexamethasone in ESRD . It is also possible that the requirements for a higher dose of dexamethasone to adequately suppress cortisol reflected a greater stimulatory (“stress”) input to the hypothalamus in some CKD patients .…”

“…It is also possible that the requirements for a higher dose of dexamethasone to adequately suppress cortisol reflected a greater stimulatory (“stress”) input to the hypothalamus in some CKD patients . So, a combination of increased central activation and the decreased GR affinity may have resulted in the need for a higher dose of dexamethasone to adequately suppress cortisol secretion”. It would be interesting to ascertain if a single 2 mg overnight oral dexamethasone dose can rule out false positive 1 mg DST results in a larger population of patients with renal disease.…”

In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis

“…Conversely, our observations concerning the K D of the GRs are in contrast to other reports [7,33]. In this perspective, it is important to note that higher numbers of GRs were accompanied by lower affinity of the receptor (that is, a higher K D ) in several other conditions [7,33-37]. …”

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

“…Variability in glucocorticoid sensitivity can be observed in several conditions, such as chronic inflammatory and autoimmune diseases, including rheumatoid arthritis (12), pemphigus (13), idiopathic nephrotic syndrome (14), dialysis patients (15), and asthma (16). In addition, there is a considerable variability in the sensitivity to glucocorticoids across individuals (17,18) and some of these differences have been related to polymorphisms, some of which relatively frequent in the GR gene (19)(20)(21)(22).…”