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Background: Posttransplant lymphoproliferative disorders (PTLD) still represent a major preoccupation after renal transplantation, even in the most recent years., Methods: We analyzed the incidence, risk, and prognostic factors of PTLD in a cohort of kidney recipients using the United States Renal Data System., Results: Among 25,127 Medicare patients transplanted between 1996 and 2000, 344 developed a PTLD defined as a non-Hodgkin lymphoma (1.4%). History of pretransplant malignancy (adjusted hazard ratio [AHR]=3.54, CI 2.31-5.43), younger age (AHR=1.91, CI 1.18-3.1), fewer HLA matches (AHR=1.32, CI 1.1-1.59) and treatment by ATG (AHR=1.55, CI 1.2-1.99) and OKT3 (AHR=1.37, CI 1-1.76), especially if given for rejection therapy were associated with an increased risk of PTLD. Mycophenolate and azathioprine were associated with a lower risk of PTLD (AHR=0.6, CI 0.47-0.78 and AHR=0.66, CI 0.46-0.95, respectively). IL2-receptor inhibitors and sirolimus did not modify the risk of PTLD. Patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine) have a lower risk of PTLD than those without. Patients with PTLD had poor survival (64% vs. 80% at 5 years). Older age, pretransplant malignancy and OKT3 were risk factors for death whereas treatment with mycophenolate was associated with a better survival (AHR=0.49, CI=0.28-0.82)., Conclusions: Our study highlights the contribution of patient history and immunosuppression in the risk of PTLD in the era of modern immunosuppression.

Sirolimus (SRL) is suspected to induce proteinuria. We retrospectively studied proteinuria in a population of liver (n = 29) and kidney transplant (n = 30) recipients switched to SRL with progressive diminution or withdrawal of calcineurin inhibitors (CNI). We also observed estimated glomerular filtration rate (GFR), modification of treatment with antiproteinuric drugs, and changes in concentration of SRL. Collection of data started 3 months before SRL introduction at a mean follow-up of 21 months. Following SRL introduction, proteinuria was not detected in the 28 liver transplant patients, and was stable in the two others. In the kidney transplant group, proteinuria did not occur in 12 patients, remained stable in three, and was slightly increased in 14 (0.57 +/- 0.93 g/d vs 1.83 +/- 1.26 g/d). For all patients, eGFR remained stable; there was no difference in management of antiproteinuric drugs. As suspected, cyclosporin (CsA) and tacrolimus (FK) serum concentrations were decreased. We observed a significant correlation between the variation of proteinuria and the variation of serum concentration of CsA or FK (respectively, P = .001 and P = .007). On the other hand, we did not find any correlation between variation in proteinuria and concentration of SRL. This retrospective study suggests that in our cohort of liver transplant patients without previous renal damage, SRL did not provoke proteinuria. On the other hand, the slight aggravation of proteinuria in a subgroup of kidney transplant patients seems to be linked to the hemodynamic renal effects due to CNI withdrawal.

Until recently, human cytomegalovirus (hCMV) infection and anti-CMV treatment in transplanted patients have been monitored essentially by pp65 antigenemia, which is time-consuming and requires experienced operators. For the last two years, pp65 antigenemia levels have tended to be lower than previously in our laboratory, which could be due to better monitoring of CMV-related risk. Results obtained by real-time PCR with a LightCycler instrument or by pp65 antigen assay were compared on 145 serial samples from bone marrow or kidney transplant recipients under the usual conditions of our laboratory. CMV DNA was extracted from plasma and quantified by using primers and probes directed to HXFL4 gene. The plasma CMV DNA load was measured by using a standard curve constructed with a commercially available quantified CMV DNA suspension. Among the 145 samples, 139 showed a pp65 antigen which was negative or lower than 20 positively stained cells per 200,000 leukocytes. In the patients with positive pp65 antigenemia, the corresponding values of CMV DNA copy number/ml were significantly higher than those observed in patients without antigenemia (P < 0.001). CMV DNA was detected from 4 up to 52 days before pp65 antigen. Elsewhere, between two dates at which pp65 antigen was positive, intermediate PCR results could be positive while the pp65 antigen was negative. This real-time quantitative PCR assay is a rapid technique adapted to monitor plasma CMV DNA in transplant setting, even for low viremia., (Copyright 2005 Wiley-Liss, Inc.)

Background: Posttransplant lymphoproliferative disorders (PTLD) occur in 0.5% to 2.5% of cases in renal-transplant recipients. Epstein-Barr virus (EBV) is usually detected in the tumor cells, suggesting a role for this virus as an agent of B-cell proliferation. It is unusual for patients receiving allografts from the same donor to develop PTLD simultaneously., Methods: we describe two patients who received renal allografts from the same donor and developed PTLD simultaneously. The presence of EBV in both tumors was confirmed. In this report, the origin of tumor cells was determined by immunohistochemical human leukocyte antigen (HLA) typing and microsatellite analysis. Clonality was studied by immunoglobulin gene rearrangement analysis., Results: Our results suggest that the tumor originated from donor cells in both patients but, because immunoglobulin gene rearrangements were different, this could mean that lymphoid cells proliferate independently in each recipient., Conclusions: We propose the following pathogenesis: immortalization of passenger B lymphocytes by EBV, proliferation of these cells, and development of PTLD by means of immunosuppression, antigenic stimulation, and HLA mismatch.

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.

EGF-responsive C17 murine-derived neural stem cells (neurospheres) were grafted into the dentate gyrus of adult male rats after dentate granule cells lesions produced by colchicine injections. Behavioural performance was evaluated over two post-grafting periods, using tests sensitive to hippocampal dysfunctions. The first period began 1 month after grafting and testing conducted in the water maze and the radial maze distinguished working- and reference-memory performance. The second period began 9 months after grafting and learning performance was also evaluated in a Hebb-Williams maze, in addition to both other tests. The lesions induced lasting deficits in all tests. During the first period, the grafts had no effect in either test. Conversely, during the second period, grafted rats showed a weak improvement in the water maze and a significant increase of reference memory performance in the radial maze. In the Hebb-Williams maze, performance of grafted rats was close to normal. Strengthening the idea that dentate gyrus granule cells play an important role in the acquisition of new (perhaps more configural than only spatial) information, our results, moreover, suggest that neurosphere grafts may foster recovery after damage to point-to-point connection systems in the adult brain.

Patients with chronic renal diseases (CRD) have a high prevalence of lipid abnormalities. Elevated levels of total and low density lipoprotein cholesterol are associated with cardiovascular diseases in patients with CRD. The 3-hydroxy-methylglutaryl co-enzyme A reductase inhibitors appear to be the most effective agents to lower LDL cholesterol in this category of patients and are generally safe if used with caution. They should be drugs of first choice in CRD but dosage reduction and close monitoring may be required to avoid side effects in case of renal failure or in combination with calcineurin inhibitors. Moreover recent studies suggest that in addition to lowering plasma LDL cholesterol, theses compounds may modify several factors implicated in the development of atherosclerosis and the progression of chronic renal failure. Such newly defined effects may contribute to extend the use of statins in the management of renal patients.

New immunosuppressive therapies are currently being developed in renal transplantation and their relative risk in terms of posttransplant lymphoproliferative disorders (PTLD) must be carefully evaluated. For this purpose, a French registry of PTLD occurring after renal transplantation was set up. Among 10,000 patients presently followed up in 30 French renal transplantation centers, we prospectively identified 53 new PTLD (0.5%) since January 1998. Patients (34 male, 19 female) ranged from 3 to 72 years (mean age: 46 years), and the median time between grafting and diagnosis of PTLD was 63 months (2 months to 14 years). Ninety percent of recipients were Epstein-Barr virus (EBV) positive before transplantation. Most patients received a quadruple sequential therapy with polyclonal anti-lymphocyte globulin. Sites involved in PTLD were isolated lymph nodes in 13 cases, stomach or bowel in 10 cases, allograft in 14 cases, central nervous system in 6 cases, oropharynx in 4 cases, and skin or mucosa in 4 cases. Only three PTLD expressed markers of T lineage. Out of 40 studied tumors, 31 (78%) were EBV positive. Tumors were classified as polymorph in 26 cases and monomorph in 23 cases. Genotype studies in 18 PTLD showed a monoclonal pattern in 13 cases. In most patients, treatment consisted of reduction of immune suppression, 21 patients were given additional anti-viral therapy, 13 patients had anti-CD20, 23 patients underwent chemotherapy, and 4 patients were given cerebral radiotherapy. Five patients underwent transplantectomy. Sixteen patients (30%) died within the 1st year and 7 patients returned to dialysis (13%). The outcome of patients with PTLD remains poor, and the optimal approach to therapy is largely unknown. This ongoing registry is not only a national observatory but also a task force designed to improve the treatment strategy of PTLD.

Recent progress in molecular genetics have improved our understanding of the pathophysiology of several inherited diseases characterized by a renal hypokalemia. Some of these diseases result from inactivating mutations on the main cotransports involved in the reabsorption of sodium, namely the Gitelman and Bartter syndromes, that clinically mimics diuretic abuse with mild hypovolemia and low or normal blood pressure. Conversely some affections eventually lead to an increase in sodium reabsorption with hypervolemia and arterial hypertension: Liddle syndrome, apparent mineralocorticoid excess and dexamethasone suppressible hyperaldosteronism.

Post-transplant lymphoproliferative disorders (PTLD) are recognized as a devastating complication of organ transplantation. Their occurrence appears to vary according to the transplanted organ and the type and the level of administered immunosuppressive therapy. In kidney transplants the incidence is estimated between 1 and 2%. PTLD represent a clinically and morphologically heterogeneous group of lymphoid proliferations. They have been closely associated with Epstein-Barr virus (EBV), and the spectrum of manifestations after transplantation range from an infectious mononucleosis-like syndrome to more serious polyclonal or monoclonal lymphoproliferation, the treatment of which is not well defined and, relying on immuno- and chemotherapy. Oncogenicity of EBV is not yet completely understood, but may implicate latent viral gene expression of EBNA or LMP as well as Th2 cytokines. Detection and monitoring of EBV induced lymphoid abnormalities are necessary to start early efficient antiviral treatment. Prophylactic antiviral therapy has to be considered.

The treatment of severe lupus nephritis remains problematic. We have analysed retrospectively 17 patients with corticoresistant lupus nephritis treated with pulse cyclophosphamide. Single monthly doses (500 mg/m2) were given by intravenous infusion with a mean of 10.4 infusions per patient (3 to 18). A comparison of parameters at entry and at the end of the treatment revealed an improvement in proteinuria (4.8 vs 1.9 g/24 h; p < 0.013) whereas mean serum creatinine level and SLAM (Systemic Lupus Activity Measure) remained stable. The results were identical at follow up (mean: 14.5 months). Most of the therapeutic effect was achieved as soon as the 6th pulse. Further treatment was beneficial for four patients only. None of the studied parameters (serum creatinine level, renal biopsy, SLAM) was predictive of a response to an extended course of pulse cyclophosphamide. The infusions were definitively stopped in one patient and delayed in two others because of serious adverse effects. The data indicate that, in mean term, monthly intravenous cyclophosphamide was associated with a substantial amelioration of 24 hours urinary protein level. An amelioration of the renal function was however, uncommon.