Réal Noël

Mycophenolate mofetil, an alternative to cyclosporine A for long-term immunosuppression in kidney transplantation?

Background. Mycophenolate-mofetil (MMF) is a nonnephrotoxic immunosuppressant most often used in combination with cyclosporine A (CsA) and prednisone (Pred).This study reports the outcome of 17 adult renal recipients whose immunosuppressive regimen was changed from CsA-Pred to MMF-Pred because of CsA nephrotoxicity. Methods. CsA nephrotoxicity was diagnosed in all patients based on suggestive histopathological lesions on a renal biopsy. Sixteen patients had deteriorating graft function and 1 had isolated persistent proteinuria. Immunosuppressive therapy was changed 57±32 months posttransplant. Results. After replacement of CsA by MMF, a reduction in serum creatinine was observed in all patients (mean 26±17%). This reduction was maintained 20±8 months after the change in therapy without any episodes of acute rejection. Serum lipids and blood pressure also decreased significantly. Conclusion. This study demonstrates that MMF-Pred can be an effective long-term immunosuppressive treatment alternative for renal transplant patients experiencing CsA nephrotoxicity. Such treatment may result in improved graft function, and better control of hypertension and hyperlipidemia.

Monitoring of cytomegalovirus infections by the CD8+CD38+ T-cell subset in kidney transplant recipients.

BACKGROUND The CD8+CD38+ T-cell subset can predict progression to acquired immune deficiency syndrome among human immunodeficiency virus-positive subjects. This T-cell subset usually increases during other active viral infections (cytomegalovirus [CMV], Epstein Barr virus). We report on its usefulness in the early detection of CMV infection in kidney transplant recipients. METHODS Quantitation of CD8+CD38+ T cells was monitored by dual-color flow cytometry analysis on 77 patients during the posttransplantation period. Seventeen of the 52 patients at risk for CMV disease (33%) had primary infection or reactivation and three patients had herpes simplex virus infection only. RESULTS In every patient with CMV disease, high values for the CD8+CD38+ subset were detected with a 90% positive predictive value for the primary infections. Elevated values were observed at the very first clinical signs of the viral disease or within the few preceeding days. Acute rejection episodes did not provoke false-positive results. CONCLUSION This immunologic marker is sensitive and easily obtainable on a daily basis. It may help to direct therapy during rejection or serve as a tool for early detection of clinical viral diseases.

Chronic Interstitial Nephritis due to 5-Aminosalicylic Acid

Nephrotoxicity has recently been reported with the use of 5-aminosalicylic acid (5-ASA) which has structural similarities to phenacetin and aspirin. The present paper describes 2 cases of interstitial nephritis and 1 case of end-stage failure associated with 5-ASA treatment. The first patient presented with severe renal failure which was partially reversed with 5-ASA discontinuation and steroid therapy. The second had severe renal failure (serum creatinine 469 mmol/l) but renal function stabilized with 5-ASA withdrawal. The third patient had end-stage renal failure and underwent hemodialysis and a successful kidney transplant.

Dual-kidney transplants as an alternative for very marginal donors: long-term follow-up in 63 patients.

Background. Organ shortage has led to the use of dual-kidney transplant (DKT) of very marginal donors into a single recipient to increase the use of marginal organs. To date, few data are available about the long-term outcome of DKT and its usefulness to increase the pool of available organ. Methods. We conducted a single-center cohort study of DKTs with longitudinal follow-up over an 8-year period. Between 1999 and 2007, 63 DKTs were performed. All kidneys from donors younger than 75 years refused by all centers for single transplantation, and kidneys from donors aged 75 years or older were routinely evaluated based on preimplantation glomerulosclerosis. Renal function, patient or graft survival, and perioperative complications were compared with 66 single kidneys from expanded criteria donors (ECD) and 63 ideal kidney donors. Results. After a median follow-up of 56 months, patient or graft survival was similar between the three groups. Twelve-, 36-, and 84-month creatinine clearance were similar for DKT and ECD (12 months: 58 and 59 mL/min; 36 months: 54 and 60 mL/min; and 84 months: 62 and 51 mL/min, respectively). For the study period, the routine evaluation of very marginal kidneys for DKT in our center has led to an increase of 47% in the transplants from donors aged 50 years or older, which represent 12% at the level of our organ procurement organization. Conclusions. DKT patients can expect long-term results comparable with single kidney ECD. The implementation of a DKT program in our unit safely increased the pool of organs from marginal donors.

Donor-specific antibodies, C4d and their relationship with the prognosis of transplant glomerulopathy.

Background Transplant glomerulopathy (TG) is a diagnostic criterion for chronic active antibody-mediated rejection (CAABMR), with C4d, donor-specific antibodies (DSA) and other lesions of chronic tissue injury. However, TG often presents without C4d or DSA. Until recently, such cases were termed suspicious for CAABMR, and their prognosis remains unclear. Methods To better understand the contribution of TG, C4d, and DSA on outcomes, we retrospectively studied 61 patients with late TG for the composite endpoint of death-censored graft failure or doubling of serum creatinine. Cases were matched to controls based on age, year and number of transplant, type of donor, and the availability of an indication biopsy during the same time after transplantation. Analyses were performed using proportional hazards models. Results Compared to matched controls, patients with TG had a more than fivefold increased risk of reaching the endpoint (adjusted hazard ratio (aHR), 5.3; 95% confidence interval (95% CI), 1.5-18.4). The proportion of patients with isolated TG, TG suspicious for CAABMR (C4+/DSA− or C4d−/DSA+) and TG with definite CAABMR (C4d+/DSA+) were 63%, 20%, and 17%, respectively. Suspicious and definite CAABMR showed a similar prognosis, significantly worse than isolated TG (aHR, 4.5; 95% CI, 1.1-18.9 and aHR, 5.9, 95% CI, 1.1-31.3 respectively). Conclusion Transplant glomerulopathy is associated with poor prognosis, independent of the level of graft dysfunction and other chronic histologic changes. This prognosis is similar whether there is evidence of tissue or peripheral alloantibody reactivity. These findings are relevant to the development of clinically meaningful criteria for CAABMR, for its clinical management, and in the future selection of population for clinical trials.

2013 Banff Criteria for Chronic Active Antibody-Mediated Rejection: Assessment in a Real-Life Setting

Significant changes in the criteria for chronic active antibody‐mediated rejection (CAABMR) were made in the Banff 2013 classification. These modifications expanded the number of patients diagnosed with CAABMR, with undetermined clinical significance. We compared the 2007 and 2013 criteria for the composite end point of death‐censored graft failure or doubling of serum creatinine in 123 patients meeting the criterion related to the morphologic evidence of chronic tissue injury. In all, 18% and 36% of the patients met the 2007 and 2013 criteria, respectively. For the criterion related to antibody interaction with endothelium, only 25% were positive based on the 2007 definition compared with 82% using the 2013 definition. Cox modeling revealed that a 2013 but not a 2007 diagnosis was associated with the composite end point (adjusted hazard ratio 2.5 [95% confidence interval (CI) 1.2–5.2] vs. 1.6 [95% CI 0.7–3.8], respectively). The 2013 criterion based on both the C4d score and the glomerulitis plus peritubular capillaritis score (g+ptc) was more strongly associated with the end point than the 2007 criterion based only on C4d; however, when dissected by component, only the C4d component was significant. The association with clinical outcomes improved with the 2013 criteria. This is related to the new C4d threshold but not to the g+ptc ≥2 component.

Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor‐specific anti‐HLA antibodies: a cohort study

The development of de novo anti‐HLA donor‐specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. Despite this, antibody screening post‐transplant is not widespread, largely because the optimal management of patients with dnDSA remains undetermined. We hypothesized that in this population, calcineurin inhibitor blood levels would be an independent predictor of graft loss. We analyzed a cohort of unsensitized patients for whom anti‐HLA antibody screening was performed prospectively post‐transplant. During the screening period between January 2005 and April 2016, 42 patients developed dnDSA. There was no difference in the clinical characteristics or the histological scores of patients biopsied for clinical indication versus those biopsied solely due to detection of dnDSA. Cox modeling revealed a strong relationship between mean tacrolimus levels following dnDSA detection and graft loss, with a hazard ratio of 0.49 (95% CI, 0.33–0.75), which persisted following adjustment for established independent predictors (HR, 0.52, 95% CI, 0.30–0.89). Kaplan–Meier analysis by tertiles of tacrolimus levels and receiver operating curve analysis concurred to show that a threshold of 5.3 ng/ml could be predictive of graft loss. These data suggest that anti‐HLA antibody monitoring post‐transplant could guide maintenance immunosuppression and improve graft outcomes.