Yvon Lebranchu

Epidemiology of Posttransplant Lymphoproliferative Disorders in Adult Kidney and Kidney Pancreas Recipients: Report of the French Registry and Analysis of Subgroups of Lymphomas

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten‐year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47–60 years and >60 years (vs. 33–46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22–2.86 and AHR = 2.80, CI = 1.73–4.55, respectively, p < 0.0001), simultaneous kidney–pancreas transplantation (AHR = 2.52, CI = 1.27–5.01 p = 0.008), year of transplant 1998–1999 and 2000–2001 (vs. 2006–2007, AHR = 3.36, CI = 1.64–6.87 and AHR = 3.08, CI = 1.55–6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36–8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0–4, AHR = 1.54, CI = 1.12–2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1–2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

Correction of Postkidney Transplant Anemia Reduces Progression of Allograft Nephropathy

Retrospective studies suggest that chronic allograft nephropathy might progress more rapidly in patients with post-transplant anemia, but whether correction of anemia improves renal outcomes is unknown. An open-label, multicenter, randomized controlled trial investigated the effect of epoetin-β to normalize hemoglobin values (13.0-15.0 g/dl, n=63) compared with partial correction of anemia (10.5-11.5 g/dl, n=62) on progression of nephropathy in transplant recipients with hemoglobin <11.5 g/dl and an estimated creatinine clearance (eCrCl) <50 ml/min per 1.73 m(2). After 2 years, the mean hemoglobin was 12.9 and 11.3 g/dl in the normalization and partial correction groups, respectively (P<0.001). From baseline to year 2, the eCrCl decreased by a mean 2.4 ml/min per 1.73 m(2) in the normalization group compared with 5.9 ml/min per 1.73 m(2) in the partial correction group (P=0.03). Furthermore, fewer patients in the normalization group progressed to ESRD (3 versus 13, P<0.01). Cumulative death-censored graft survival was 95% and 80% in the normalization and partial correction groups, respectively (P<0.01). Complete correction was associated with a significant improvement in quality of life at 6 and 12 months. The number of cardiovascular events was low and similar between groups. In conclusion, this prospective study suggests that targeting hemoglobin values ≥13 g/dl reduces progression of chronic allograft nephropathy in kidney transplant recipients.

Five-Year Results of a Randomized Trial Comparing De Novo Sirolimus and Cyclosporine in Renal Transplantation: The Spiesser Study

Calcineurin inhibitors improve acute rejection rates and short‐term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5‐year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL‐ or CsA‐based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent‐to‐treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on‐treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.

Genetic study of a new X-linked recessive immunodeficiency syndrome.

Seven forms of X-linked (XL) immunodeficiency have been described (XL agammaglobulinemia, XL severe combined immunodeficiency [SCID], Wiskott-Aldrich syndrome, XL chronic granulomatous disease, XL hyper-IgM syndrome with low IgG and IgA, and XL lymphoproliferative syndrome), and properdine deficiency. Although there are (some) phenotypic variants, diagnosis is relatively simple on the basis of clinical, immunological, and genetic characteristics. We studied a family in which several males were affected by severe infections and whose pedigree suggested recessive XL inheritance of an immunodeficiency. Immunologic and genetic studies (X inactivation patterns in females and restriction fragment length polymorphism [RFLP] segregation) were performed in order to characterize the immunodeficiency. The propositus, a 5-yr-old boy, was found to have a severe and progressive T- and B-cell functional immunodeficiency characterized by defective antigen-specific responses. No lymphocyte subsets or membrane anomalies were detected and the immunodeficiency did not correspond to usual XL forms. Studies of DNA from two of the informative females, the mother and one sister revealed nonrandom X chromosome inactivation of T cells and, partially, B cells but not PMN, a pattern similar to that observed in XL SCID carriers. RFLP studies identified a haplotype segregating with the abnormal locus that may be localized in the proximal part of the long arm of the X chromosome. We thus report the characterization of a new XL immunodeficiency that may correspond either to another XL locus or to an attenuated phenotype of XL SCID.

The role of Thymoglobulin induction in kidney transplantation: an update.

The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte‐depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T‐cell surface antigens as well as natural killer‐cell antigens, B‐cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long‐lasting T‐cell depletion. Randomized studies have established the anti‐rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6–7.5 mg/kg, with vigilant short‐ and long‐term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high‐risk patients, in those at increased risk of DGF and to maintain efficacy in low‐risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance.

Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency

Background —STAT3 deficiency is responsible for autosomal dominant hyper-IgE syndrome characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyper-IgE and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics and etiology of these features have yet to be described. Methods and Results —We prospectively screened 21 adult STAT3-deficient patients (median age: 26 years; range 17 - 44) for vascular abnormalities. They were explored with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography and echo-tracking-based imaging of the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, murine models of aortic aneurysm were studied in the presence and absence of inhibitors of STAT3-dependent signaling. Brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, atrophy) were found in 95% of patients. Peripheral and brain artery abnormalities were reported in 84% of patients, whereas coronary artery abnormalities were detected in 50%. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.n Conclusions —Vascular abnormalities are highly prevalent in STAT3-deficient patients. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.Background— Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. Methods and Results— We prospectively screened 21 adult patients with STAT3 deficiency (median age, 26 years; range, 17 to 44) for vascular abnormalities. We explored the carotid arteries with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking–based imaging. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Conclusions— Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

Prognostic significance of graft Foxp3 expression in renal transplant recipients: a critical review and attempt to reconcile discrepancies

A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.

Sirolimus-based regimen is associated with decreased expression of glomerular vascular endothelial growth factor

BACKGROUNDnSirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression.nnnMETHODSnUsing immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF).nnnRESULTSnA total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036).nnnCONCLUSIONSnThere is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation.

Renal resistive index as a new independent risk factor for new‐onset diabetes mellitus after kidney transplantation

Pulse pressure and urinary albumin excretion were recently identified as risk factors of new‐onset diabetes after renal transplantation (NODAT), suggesting that microvascular injury may be implicated in NODAT. However, the relationship between of microvascular injury and NODAT is unknown. In the present long‐term (median follow‐up: 5.7u2003years; observation period: 4908 patient‐years) retrospective study in 656 renal transplant recipients, the association between baseline renal resistance index (RI, used as a marker of widespread microvascular damage) and the incidence of NODAT was assessed. The incidence of NODAT was 11.2% and 14.6% at 5 and 10u2003years, respectively, after transplantation. RI at 3u2003months was a risk factor for NODAT [hazard ratio (HR) per 0.1: 2.19 (1.55–3.09), Pu2003<u20030.0001]. RI >0.75 (vs. 0u2003≤u20030.75) was a potent a predictor of NODAT [HR: 3.29 (1.91–5.67), Pu2003<u20030.0001], even after adjustments [HR: 3.29 (1.50–7.24), Pu2003=u20030.0030] on age, weight, glucose, nephropathy, and arterial pressure. Similar results were observed when RI was measured at 1u2003month [HR per 0.1:1.74 (1.33–2.27), Pu2003<u20030.0001] and 12u2003months [HR per 0.1:1.74 (1.33–2.27), Pu2003<u20030.0001] after transplantation. High RI early after renal transplantation is a long‐term risk factor for NODAT, and could be used to refine the individual risk of NODAT.

Kidney Transplant with Multiple Renal Artery Grafts from Deceased Donors: Are Long-Term Graft and Patient Survival Compromised?:

Background— Kidneys with multiple arteries are often transplanted. However, the long-term outcome of such kidneys recovered exclusively from deceased donors is not clear. Objective— To determine whether use of renal grafts with multiple arteries affects long-term graft survival and function. Methods— The outcomes of 259 consecutive kidney transplants between 1996 and 2000 were retrospectively reviewed. Patients were divided into 2 groups, multiple renal artery graft recipients (n = 70) and single renal artery graft recipients (n = 189). Short-term complications and long-term outcomes (survival rates, blood pressure after transplant, creatinine clearance, and proteinuria levels at 1, 3, 5, and 7 years after transplant) were compared between the 2 groups. Results— Early vascular complications were more common (P = .02) in multiple artery graft recipients (18.6%) than in single artery graft recipients (7.9%), mainly because of occlusion of a polar artery in grafts with multiple renal arteries (7.1%). Urologic complications were no more frequent in one group than in the other (5.7% vs 5.3%; P = .89). The 2 groups did not differ significantly (P = .33) in long-term graft survival, with a median follow-up of 9.05 years (range, 0.1–12.7 years). Mean (SD) for creatinine clearance (59.4 [22.6] vs 55.9 [20.3] mL/min; P = .47), proteinuria (0.77 [2.1] vs 0.4 [0.8] g/24 h; P = .19), and systolic blood pressure (133.6 [14.5] vs 133.7 [17.5] mm Hg; P = .85) did not differ significantly between the 2 groups 7 years after transplant. Conclusions— Kidney transplant with grafts containing multiple renal arteries rather than grafts with a single renal artery does not significantly influence patient and graft outcomes.