Renaud Snanoudj

Primary brain lymphomas after kidney transplantation: presentation and outcome.

Background. Non-Hodgkin’s lymphoma is the second most frequent neoplasia following solid-organ transplantation. The objective of this study is to describe the clinical, histologic, and radiologic features of primary posttransplantation brain lymphomas (PTBL) in addition to their outcome. Methods. Twenty-five kidney transplant patients with histologically proven PTBL from 11 French centers were retrospectively investigated. Results. Immunosuppressive regimen included induction with antithymocyte globulins (ATG) in 20 patients. Median overall delay between transplantation and lymphoma was 18 months (4–264). Six of 10 patients with late posttransplantation brain lymphomas (PTBL) occurrence (>3 years) had been recently switched from azathioprine to mycophenolate mofetil (median switch lymphoma delay 14 months). Cerebral computed tomography (CT) scans and magnetic resonance imaging (MRI) revealed multifocal lesions (n=18), with a ring contrast enhancement (n=20) similar to cerebral abscesses, as observed in HIV-related brain lymphomas. Histology showed large B-cell non-Hodgkin’s lymphoma in 87.5% of cases; Epstein-Barr virus (EBV) was detected in 95%. After lymphoma diagnosis, immunosuppressive treatment was reduced in all patients, and all but one received complementary treatment by surgery (n=2), anti-CD21 antibodies (n=2), chemotherapy including high-dose intravenous methotrexate (n=7), encephalic radiotherapy (n=5), or chemotherapy plus radiotherapy (n=8). Median overall survival was 26 months. Patients with a radiotherapy-based regimen seemed to have a longer survival (36 vs. 7 months, P <0.005). Conclusions. Our study showed that PTBL are EBV-induced large B-cell lymphomas, which mimic cerebral abscesses on imaging and whose occurrence may be influenced by immunosuppression modifications. Treatment by radiotherapy is associated with better survival.

Impact of Norovirus/Sapovirus-Related Diarrhea in Renal Transplant Recipients Hospitalized for Diarrhea

Background. Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients. Methods. We undertook a retrospective study (2008–2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea. Results. Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty-one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stools clearance exhibited a prolonged viral shedding period with a median time of 289 days (107–581 days). Conclusions. Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment.

Intensive and prolonged treatment of focal and segmental glomerulosclerosis recurrence in adult kidney transplant recipients: a pilot study.

No treatment has consistently induced long‐term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an open‐label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18‐month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high‐dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 ± 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05–0.3 g/day) and 0.19 g/day (range 0.05–1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE‐dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.

Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS)

UNLABELLED Introduction. Recurrence of nephrotic-range proteinuria in patients with idiopathic nephrotic syndrome (INS) and focal and segmental glomerulosclerosis (FSGS) on native kidneys is associated with poor graft survival. Identification of risk factors for recurrence is therefore an important issue. In 2004, Columbia University introduced a histological classification of FSGS that identifies five mutually exclusive variants. In non-transplant patients, the Columbia classification appears to predict the outcome and response to treatment better than clinical characteristics alone. However, the predictive value of this classification to assess the risk of recurrence after transplantation has not been addressed. METHODS We retrospectively studied 77 patients with INS and FSGS on native kidneys who underwent renal transplantation. Of these, 42 recipients experienced recurrence of nephrotic range proteinuria. RESULTS At time of recurrence, minimal-change disease (MCD) was the main histological feature. On serial biopsies, the incidence of MCD decreased over time, while the incidence of FSGS variants increased. The variant type observed in the native kidneys was not predictive of either recurrence or type of FSGS seen on the allograft. Patients with complete and sustained remission did not developed FSGS. CONCLUSION In conclusion, the Columbia classification is of no help in predicting recurrence after renal transplantation or histological lesions in the case of recurrence of proteinuria.

Candida albicans arteritis transmitted by conservative liquid after renal transplantation : A report of four cases and review of the literature

Background. Mycotic arteritis and/or aneurysms are infrequent complications of renal transplantation. They are mostly secondary to bacterial infection and rarely to Candida albicans. We report four cases of mycotic arteritis due to C. albicans after renal transplantation but which have been inoculated during organ harvesting or conservation. Methods. In all the four cases corresponding to two independent donors, C. albicans was isolated few days later in the systematic culture of the conservative liquid. We also review the clinical features and outcomes of 13 cases previously reported in the literature. Results. In two cases, the diagnosis of fungal arteritis was confirmed only during autopsy after the patient’s death due to massive bleeding. In the other two cases, the diagnosis was made on the arterial section of the anastomotic wall after detransplantation for massive bleeding for arterial leakage although an immediate antifungal treatment with fluconazole and caspofungin was given and was found to be inefficient. Conclusion. This is a serious complication of renal transplantation because it leads to graft loss in the majority of the cases and even to death in a few cases despite an efficient and rapid treatment. Routine fungal cultures of preservation media are important for early diagnosis and timely surgical interventions are life-saving.

Costimulation blockade and its possible future use in clinical transplantation.

The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death of patients. As an immune‐specific alternative to conventional immunosuppressants, new biotechnology tools can be used to block the costimulation signals of T‐cell activation. Many experimental studies – particularly preclinical studies in nonhuman primates – have focused on blocking the ‘classical’ B7/CD28 and CD40/CD40L pathways, which are critical in primary T‐cell activation. Here, we review the limitations, the recent advances and the first large‐scale clinical application of the CTLA4‐Ig fusion protein to block the B7/CD28 costimulation pathway. We also focus on new B7/CD28 and tumor necrosis factor (TNF)/TNF‐R family costimulatory molecules that can deliver positive or negative costimulation signals regulating the alloimmune response. Strategies that use single agents to block costimulation have often proved to be insufficient. Given the diversity of the different costimulation molecules, future strategies for human transplantation may involve the simultaneous blockade of several selected pathways or the simultaneous use of conventional immunosuppressants.

Presentation and Outcome of Patients with Systemic Amyloidosis Undergoing Dialysis

BACKGROUND AND OBJECTIVES Light chain (AL) and secondary (AA) amyloidosis usually present as a systemic disease frequently involving the kidney and leading to ESRD. Data regarding patients with AA or AL amyloidosis undergoing dialysis remain scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We retrospectively studied patients with AA or AL amyloidosis who started dialysis in five French centers between January 1, 1995 and December 31, 2005. RESULTS We identified 19 patients with AL and 20 patients with AA amyloidosis undergoing dialysis. Patients with AL amyloidosis had shorter time from diagnosis to dialysis (25.2 versus 69.3 mo, P < 0.05) and more extrarenal amyloidosis, especially cardiac (63.2 versus 5%, P < 0.0001). Mean duration of follow-up was 37.4 and 31.8 mo for patients with AL and AA amyloidosis, respectively. Fifteen patients (78.9%) with AL and three patients (15%) with AA amyloidosis died on dialysis. Median survival was shorter in patients with AL (26 mo) than AA amyloidosis [not definable (ND)] (P < 0.02). Sepsis and cardiac deaths were the main causes of mortality. Prognosis factors for death at 1 yr were AL type (P < 0.01), cardiac amyloidosis [odds ratio (OR) = 18, P < 0.01], heart failure (OR = 8, P < 0.04), and shorter time from diagnosis to dialysis (6.1 versus 56 mo, P < 0.03). Multivariate analysis indicated that AL type (P = 0.02), but not cardiac amyloidosis was independently associated with global mortality. CONCLUSIONS Survival of patients with amyloidosis undergoing dialysis, especially AL type, is probably better than previously reported. However, mortality is higher in AL than AA type, especially in the setting of cardiac involvement.

Immunological strategies targeting B cells in organ grafting.

After delayed-type hypersensitivity and T cell cytotoxicity, the production of alloantibodies is the third effector mechanism contributing to graft injury. Histological characterization of antibody-mediated rejection and the detection of donor-reactive antibodies have highlighted the role of humoral immunity in acute and chronic rejection. A potential way of achieving central B cell tolerance is to induce complete chimerism with a myeloablative regimen and bone marrow transplant. However, nonmyeloablative regimens have been developed to create a state of “mixed chimerism” in patients without hematologic malignancies. Other strategies targeting B cells have been developed for the management of “high risk” clinical situations, including highly sensitized patients and transplantation with a positive crossmatch. These strategies have been extended to ABO incompatible transplantations and xenotransplantations. We will review therapeutic regimens that allow the removal or neutralization of pathogenic antibodies (immunoadsorption, plasmapheresis, intravenous globulins) and the blockade of memory B cell proliferation and differentiation into plasmocytes, including cyclophosphamide, the tacrolimus/mycophenolate mofetil combination, and anti-CD20 antibodies.

Early conservative intervention for candida contamination of preservative fluid without allograft nephrectomy

BACKGROUND Fungal contamination of kidney allograft preservative fluid can lead to renal arteritis and arterial wall rupture. METHODS We have evaluated a conservative management strategy based onearly antifungal therapy, rigorous morphological monitoring of the graft artery and surgical second look (SSL). Since November 2004, preservative fluid was routinely cultured on specific media for all kidney transplant recipients. RESULTS In 8/474 cases, results were positive for Candida (albicans 5, glabrata 2, tropicalis 1). Two patients also had candida infection of drainage fluid leading to the diagnosis of operative site infection. Radiological and surgical examinations of the renal graft artery were normal in all cases and nephrectomy was not required. At 12 months, all patients were alive with a functioning allograft. CONCLUSION Early antifungal therapy with microbiological and morphological follow-up should be recommended as soon as contamination is detected, but SSL is advised only in patients with risk factors for arterial anomalies.

Peripheral B-cell phenotype and BAFF levels are associated with HLA immunization in patients awaiting kidney transplantation.

Background The role of B-cell subsets in human leukocyte antigen (HLA)-specific humoral responses in patients with end-stage renal disease is poorly documented. The objective of this study was to analyze the potential association between B-cell subsets distribution and anti-HLA antibodies before kidney transplantation. Methods The authors studied by flow cytometry peripheral B-cell subsets and serum levels of BAFF, the main homeostatic cytokine for peripheral B cells, in 101 consecutive end-stage renal disease patients admitted for transplantation. Results In patients with HLA antibodies detected with Luminex single antigen, the proportion of activated naive B cells (Bm2) was significantly higher (64.4±15.1% vs. 52.5±19.1% in HLA antibody-negative patients, P=0.0008) at the expense of memory B cells, as were BAFF serum levels (1,651±1,297 vs. 1,139±693 pg/mL, P<0.0001). Proportion of Bm2 and BAFF levels were positively associated with the diversity of anti-HLA antibodies. In multivariate analysis, besides HLA-immunizing events (pregnancy and previous transplantation), proportion of Bm2 cells but not of other B-cell subsets or BAFF levels was independently associated with the presence and diversity of anti-HLA antibodies. High proportion of Bm2 cells before transplantation was associated with an increased risk of developing de novo donor-specific antibodies during the first year posttransplant. The authors did not find any association between the frequency of antibody-mediated rejection and pretransplant proportion of any B-cell subset or BAFF serum levels. Conclusion Increased proportions of activated naive B cells are linked with pretransplant HLA immunization and the development of posttransplant donor-specific antibodies.