CD40/SCD40 imbalance in hemodialysis patients.

We read with great interest the paper by Pawlak et al. [1] recently published in Clinical Biochemistry. The authors demonstrated that the serum levels of soluble CD40 (sCD40), a natural antagonist of CD40/CD40L system, are high in patients on hemodialysis (HD) and are strictly related to renal residual function (RRF). Elevated sCD40 serum levels have been reported in the clinical setting of chronic kidney disease, peritoneal dialysis, and HD and have been related to the deficient response to hepatitis B vaccination found in those patients [2] and [3]. In addition, it has been recently described that, in HD patients, the reduction of sCD40 levels by a treatment with a high permeability dialytic membrane is associated to a significant increase of anti-HBs antibody titer [4]. Therefore, a role for sCD40 in uremic immunodeficiency has been hypothesized and it is currently under investigation. In order to evaluate the CD40/sCD40 balance in HD patients, we performed an observational study comparing CD40 B-cell membrane expression and sCD40 serum levels among HD patients, uremic patients not on HD (UR) and, also, healthy subjects (HS). Fourteen stable patients (mean ± SD; age, 65.1 ± 13.6 years) on regular thrice-weekly bicarbonate HD for at least 6 months were enrolled. Patients affected by conditions influencing the immune response, such as acute infections, active immunological diseases, immunosuppressive therapy, previous transplantation, or history of malignancies, were excluded from the study. Control samples were taken from 7 UR (age, 68.8 ± 8.5 years) and 8 HS (age, 47.9 ± 11.5 years). Blood samples were collected before HD treatment. sCD40 serum levels were measured by an enzyme-linked immunosorbent assay (Bender MedSystems). CD40+ B lymphocytes were defined by CD20 and CD40 cell membrane co-expression, analyzed by flow cytometry using anti-CD20 and anti-CD40 mAbs (BD Biosciences). Demographic factors, RRF, and dialytic adequacy, evaluated by a single-pool urea kinetic model (spKt/V) and Charlson comorbidity index (CI), were recorded. Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease (MDRD) formula (eGFR) [5]. sCD40 serum levels resulted significantly higher in HD than in HS and UR (Table 1). In the group of patients undergoing HD, serum sCD40 concentrations were significantly higher in anuric patients (N = 5) compared to those with RRF (N = 9) (1392.3 ± 633.3 vs. 507.9 ± 290.5, P < 0.05, respectively), whereas they did not correlate with spKt/V and CI. Similarly, in UR patients, serum sCD40 levels were indirectly correlated with eGFR (UR eGFR = 16.5 ± 6.6 mL/min; r2 = 0.93; P = 0.03). Moreover, CD40 B-cell membrane expression was also impaired in UR and HD patients, who presented a significantly lower number of CD20+CD40+ cells, expressed as both absolute number and percentage of total lymphocytes, compared to HS (Table 1). Our data confirm and further reinforce Pawlak's findings, highlighting the fact that uremic patients show an imbalance in the CD40 co-stimulatory pathway. In particular, HD patients present a modified CD40/sCD40 pattern with a lower number of CD40+ B-cells associated to higher sCD40 serum levels, when compared to HS. The clinical impact of this imbalance is still unknown, but it could well explain those humoral and cellular immune dysfunctions described in uremic patients [6] and [7]. The loss of renal function plays a key role in this CD40/sCD40 imbalance, as proven by the relationship between sCD40 serum levels and renal function in both UR and HD patients. However, the influence of other factors, such as biocompatibility of dialytic devices and inflammatory state, cannot be ruled out and should be investigated in larger, specifically designed studies.