VLITL is a major cross-ß-sheet signal for fibrinogen Aα-chain frameshift variants.

The first case of hereditary fibrinogen Aα-chain amyloidosis was recognized >20 years ago, but disease mechanisms still remain unknown. Here we report detailed clinical and proteomics studies of a French kindred with a novel amyloidogenic fibrinogen Aα-chain frameshift variant, Phe521Leufs, causing a severe familial form of renal amyloidosis. Next, we focused our investigations to elucidate the molecular basis that render this Aα-chain variant amyloidogenic. We show that a 49-mer peptide derived from the C-terminal part of the Phe521Leufs chain is deposited as fibrils in the patient's kidneys, establishing that only a small portion of Phe521Leufs directly contributes to amyloid formation in vivo. In silico analysis indicated that this 49-mer Aα-chain peptide contained a motif (VLITL), with a high intrinsic propensity for ß-aggregation at residues 44 to 48 of human renal fibrils. To experimentally verify the amyloid propensity of VLITL, we generated synthetic Phe521Leufs-derived peptides and compared their capacity for fibril formation in vitro with that of their VLITL-deleted counterparts. We show that VLITL forms typical amyloid fibrils in vitro and is a major signal for cross-ß-sheet self-association of the 49-mer Phe521Leufs peptide identified in vivo, whereas its absence abrogates fibril formation. This study provides compelling evidence that VLITL confers amyloidogenic properties to Aα-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of Aα-chain amyloidosis.

Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study.

BACKGROUND: Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. RESULTS: Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. CONCLUSION: Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.

Progression of pulse pressure in kidney recipients durably exposed to CsA is a risk factor for epithelial phenotypic changes: an ancillary study of the CONCEPT trial.

In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year.

[Angiotensin-2 type 1 receptors (AT1R) and cancers]. / Récepteurs de type 1 à l'angiotensine-2 (AT1R) et cancers.

Recently, several meta-analysis suggested an increased risk of cancers linked to the use of antagonists of angiotensin-2 receptors or inhibitors of angiotensinogen converting enzyme. The results of epidemiological studies are conflicting. Meta-analysis as well as retrospective studies are not reliable and biased, since they have never been designed to explore any pro- or antitumoral effect. We lack of prospective studies that could take off the doubt on these drugs. Nevertheless, all experimental researches pointed out potent antitumoral properties. Indeed, direct antiproliferative and neo-angiogenic inhibition have been described on tumor cell cultures as well as on animal models. Moreover, we are convinced that the use of antagonists of angiotensin-2 receptors and inhibitors of angiotensinogen converting enzyme may be then of clinical use in the near future in association with classical antitumor drugs. In this review, we proposed to explore these data by a thorough analysis of recent literature associating epidemiological and experimental studies.

Aspergillus arthritis and organ transplantation.

We report a case of a kidney and pancreas transplanted patient, hospitalized for septic hip arthritis. The whole diagnostic work-up including synovial and bone biopsies remained negative. After inefficient empirical anti-bacterial antibiotic treatment, femoral head resection was performed and tissue analysis revealed Aspergillus fumigatus hyphae. Treatment with voriconazole along with hip replacement led to complete recovery. However, drug interaction between immunosuppressive and anti-fungal drugs was complicated by cellular acute graft rejection. Aspergillus fumigatus arthritis is an uncommon and serious infection that should be evoked especially in the case of resistance to anti-microbial antibiotics and/or an atypical clinical picture.

Three kidneys, two diseases, one antibody?

Anti-factor H antibody has been recently described as responsible for thrombotic microangiopathies (TMA) as well as membranoproliferative glomerulonephritis (MPGN). We report here, for the first time, the case of a woman with an anti-factor H antibody, who developed MPGN on native kidney, rapid recurrence on first graft, and TMA on second graft despite immunosuppressive therapy and plasma exchanges. This case supports the hypothesis that MPGN and TMA are closely linked by common pathogenic mechanisms and the need for complete exploration of complement pathway including factor H activity and autoantibody in front of any MPGN.

Renal biopsies after 70 years of age: a retrospective longitudinal study from 2000 to 2007 on 150 patients in Western France.

The elderly are more often referred to nephrologists and questions about indications for renal biopsy are increasing. The vascular lesions that appear with aging make the diagnosis of additional nephropathy more difficult. The purpose of our study is to investigate the characteristics of renal biopsies in the elderly in order to evaluate the indications and their use in guiding specific therapeutic interventions. Patients over 70 years who underwent a renal biopsy between 2000 and 2007 in Rennes University Hospital were retrospectively analyzed for biopsy complications, clinical features, diagnosis, therapy and its complications, evolution and mortality. Among the 150 renal-biopsied patients, 60% had a glomerulopathy and 30% had nephrotic syndrome. Biopsy complications occurred in 3.3%. 64% of nephrotic patients received immunosuppressive treatment and 62% of them developed drug-associated complications. In the treated group, there was more remission and survival at day 1000 was improved. Renal biopsy may be indicated in the elderly, because it often gives a therapeutically useful diagnosis and complications are rare if contra-indications are respected. Kidney biopsy revealed histological diagnoses that were not usually suspected by the clinical presentation. In addition, immunosuppressive therapy did not alter the mortality rate, but did increase survival at 3 years.

A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients.

BACKGROUND: Induction therapy with antithymocyte globulin (ATG) reduces the incidence of acute rejection after transplantation. A study was undertaken to assess the efficacy and safety of ATG induction on tacrolimus-based and cyclosporine A (CsA)-based therapies compared with immediate tacrolimus triple therapy in kidney transplant recipients. METHODS: In a 6-month, open-label, randomized, prospective study conducted in 30 European centers, 555 renal transplant patients were randomly assigned to tacrolimus triple therapy (Tac triple, n=185), ATG induction with tacrolimus (ATG-Tac, n=186), or ATG induction with CsA microemulsion (ATG-CsA, n=184); all were combined with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection episode confirmed by biopsy. RESULTS: Patient demographics and clinical parameters at baseline were similar. Patient and graft survival rates were similar in all groups. The incidence of clinically apparent acute rejection was significantly higher (P=0.003) for Tac triple (33.0%) compared with ATG-Tac (22.6%) and the incidence for ATG-Tac was significantly lower (P=0.004) than for ATG-CsA (37.0%). The incidences of acute rejection confirmed by biopsy (primary endpoint) were 25.4%, 15.1%, and 21.2% for Tac triple, ATG-Tac, and ATG-CsA, respectively (Tac triple vs. ATG-Tac, P=0.004). The incidences of corticosteroid-resistant acute rejection were 7.0% (Tac triple), 4.8% (ATG-Tac), and 10.9% (ATG-CsA) (ATG-Tac vs. ATG-CsA, P=0.038). In the ATG groups, the incidences of leukopenia, thrombocytopenia, serum sickness, fever, and cytomegalovirus infection were significantly higher (P<0.05). CONCLUSIONS: Acute rejection was significantly lower in the ATG-Tac group compared with the ATG-CsA and Tac triple groups. Significantly more hematologic and infectious adverse events were observed in both ATG induction groups.

Management of vascular access for hemodialysis after successful kidney transplantation.

OBJECTIVE: There is a lack of data concerning the fate of arterio-venous fistulas (AVF) after successful kidney transplantation. The objective of this study was to assess the evolution of AVF in transplanted patients and to discuss the management of such vascular access once dialysis has been stopped. MATERIAL AND METHODS: We reviewed 160 renal transplant patients who had undergone an AVF 0 to 312 months (mean 29) before transplantation. 136 (85%) of AVF were created in the forearm/wrist region and 21 (13%) at the elbow. RESULTS: The mean follow-up was 69 months from renal transplantation and 95 months from constitution of the AVF. Vascular access had to be closed in 7.5% of cases. Thrombosis occurred in 31% of cases, mainly in distal fistulas (85%). AVF was still functional in 61% of patients at the end of follow-up. CONCLUSION: AVF remains functional in the majority of patients after renal transplantation and is not usually associated with any significant morbidity. Systematic closure of AVF does not seem warranted as it would deprive patients of a useful vascular access should dialysis become again necessary in the long term.

Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20mg day 0-day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin' group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a non-significant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients.

OBJECTIVE: Voriconazole is a broad-spectrum triazole antifungal agent under investigation for opportunistic infections that often target immunosuppressed patients. This study investigated the effect of voriconazole on the pharmacokinetics of cyclosporine (INN, ciclosporin). METHODS: This was a randomized, double-blind, placebo-controlled, crossover study in kidney transplant recipients with stable renal function who were receiving cyclosporine (150-375 mg/d). During the first study period (7.5 days), subjects in group A received concomitant voriconazole (200 mg every 12 hours); group B received a matched placebo. After a washout period (>or=4 days), subjects were crossed over to the other treatment regimen. RESULTS: In the 7 subjects who completed both regimens, concomitant administration with voriconazole resulted in a 1.7-fold increase in mean cyclosporine area under the plasma concentration-time curve within a dosage interval (AUC(tau); 90% confidence interval, 1.47 to 1.96). Cyclosporine maximum observed plasma concentration (C(max)) and the time to the first occurrence of C(max) (t(max)) were not affected in a clinically significant manner, but plasma trough concentration (C(min)) was higher in the presence of voriconazole than with placebo. The mean increase in cyclosporine C(min) in subjects who ceased to participate in the study was 2.48-fold (range, 1.88 to 3.03). There were 7 subjects who stopped participating in the study during voriconazole administration. Six of these subjects discontinued the study for reasons that were considered to be drug related, and the majority were attributable to increased cyclosporine levels. Although not serious, all causality-related adverse events were more frequent during voriconazole administration than during placebo administration. CONCLUSIONS: Mean cyclosporine AUC(tau) increased 1.7-fold in the presence of voriconazole. Therefore, when voriconazole is initiated in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be halved and that blood cyclosporine concentrations be carefully monitored. When voriconazole is discontinued, blood cyclosporine concentrations should be monitored and the cyclosporine dose increased, if necessary.