Relationship between atrial scar on cardiac magnetic resonance and pulmonary vein reconnection after catheter ablation for paroxysmal atrial fibrillation.

INTRODUCTION: Pulmonary vein (PV) reconnection is frequent in patients showing atrial fibrillation (AF) recurrence after PV isolation (PVI). Its detection with cardiac magnetic resonance (CMR) may help predict outcome and guide redo procedures. We assessed the relationship between scar on CMR and PV reconnection after catheter ablation for paroxysmal AF. METHODS AND RESULTS: Fifty-one patients with paroxysmal AF underwent CMR before PVI using either a conventional single-electrode catheter (N = 28) or a circular multielectrode catheter (N = 23). At 3 months, a second CMR study was performed, followed by a systematic electrophysiological procedure to look for PV reconnection, regardless of AF recurrence. Preablation fibrosis and postablation scar were quantified and mapped from late gadolinium-enhanced CMR. CMR results were compared to the distribution and extent of PV reconnection. CMR and electrophysiological findings were compared between catheter types. Three months after successful PVI, scar gaps were found in 39 (76%) patients, and 78 (39%) veins. Electrical PV reconnection was detected in 45 (88%) patients, and 99 (50%) veins. The extent of PV reconnection related closely to the number of gaps (R = 0.55; P < .001), and to scar burden (R = -0.63; P < .001). However, the agreement was only fair for the localization of PV reconnection (k = 0.37; P < .001), scar gaps particularly lacking sensitivity in areas of pre-existing fibrosis. The circular catheter was associated with shorter procedures (P < .001), more scar (P = .01), less gaps (P = .01), and less reconnected veins (P = .03). CONCLUSION: PV reconnection is extremely frequent after PVI. CMR scar imaging accurately predicts its extent, but poorly predicts its location. Multielectrode circular catheters induce more complete ablation.

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.

C3 nephritic factor associated with C3 glomerulopathy in children.

BACKGROUND: C3 glomerulopathy (C3G) is characterized by predominant C3 deposits in glomeruli and dysregulation of the alternative pathway of complement. Half of C3G patients have a C3 nephritic factor (C3NeF). C3G incorporated entities with a range of features on microscopy including dense deposit diseases (DDD) and C3 glomerulonephritis (C3GN). The aim of this work was to study children cases of C3G associated with C3NeF. METHODS: We reviewed 18 cases of C3G with a childhood onset associated with C3NeF without identified mutations in CFH, CFI, and MCP genes. RESULTS: Clinical histories started with recurrent hematuria for seven patients, nephrotic syndrome for four, acute post-infectious glomerulonephritis for three and acute renal failure for four. Twelve patients had a low C3 at first investigation. Kidney biopsy showed ten C3GN and eight DDD. Twenty-three percent of the patients tested presented elevated sC5b9. Seven patients relapsed 3 to 6 years after the onset. At the end of follow-up, two patients were under dialysis, 11 had a persistent proteinuria, five had none; four patients did not follow any treatment. Steroids were first used in 80 % of cases. CONCLUSIONS: C3NeF associated C3G has a heterogeneous presentation and outcome. Anti-proteinuric agents may control the disease during follow-up, even after nephrotic syndrome at the onset. The efficiency of immunosuppressive therapy remains questionable.

Interferon gamma licensing of human dendritic cells in T-helper-independent CD8+ alloimmunity.

The high frequency of allogeneic reactive CD8(+) T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8(+) T-cell responses have led to disparate findings. Recent studies have reported CD8(+)-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8(+) T cells independently of CD4(+) T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8(+) T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-ß. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8(+) T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.

Autosomal dominant polycystic kidney disease: risk factor for nonmelanoma skin cancer following kidney transplantation.

Nonmelanoma skin cancers (NMSC) are the most common malignant tumors following solid organ transplantation. Risk factors for NMSC mainly include immunosuppression, age, sun exposure and patient phototype. Recent findings have suggested that autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of developing NMSC. We performed a monocenter retrospective study including all kidney recipients between 1985 and 2006 (n = 1019). We studied the incidence of NMSC, solid cancers and post-transplantation lymphoproliferative disease (PTLD), and analyzed the following parameters: age, gender, phototype, time on dialysis, graft rank, immunosuppressive regimen, history of cancer and kidney disease (ADPKD versus others). Median follow-up was 5.5 years (range: 0.02-20.6; 79 838 patient-years). The cumulated incidence of NMSC 10 years after transplantation was 12.7% (9.3% for solid cancers and 3.5% for PTLD). Autosomal dominant polycystic kidney disease and age were risk factors for NMSC (HR 2.63; P < 0.0001 and HR 2.21; P < 0.001, respectively) using univariate analysis. The association between ADPKD and NMSC remained significant after adjustments for age, gender and phototype using multivariate analysis (HR 1.71; P = 0.0145) and for immunosuppressive regimens (P < 0.0001). Autosomal dominant polycystic kidney disease was not a risk factor for the occurrence of solid cancers after transplantation (HR 0.96; P = 0.89). Our findings suggest that ADPKD is an independent risk factor for developing NMSC after kidney transplantation.

Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.

Nephronophthisis is an autosomal recessive chronic tubulointerstitial disease that progresses to end-stage renal disease (ESRD) in about 10% of cases during infancy. Mutations in the INVS (NPHP2) gene were found in a few patients with infantile nephronophthisis. Mutations of NPHP3, known to be associated with adolescent nephronophthisis, were found in two patients with early-onset ESRD. Here we screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations. In this cohort there were 16 families with NPHP2 mutations and NPHP3 mutations in seven. Three patients carried only one heterozygous mutation in NPHP3. ESRD arose during the first 2 years of life in 16 of 18 patients with mutations in NPHP2, but in only two patients with mutations in NPHP3. Renal morphology, characterized by hyper-echogenic kidneys on ultrasound and tubular lesions with interstitial fibrosis on histology, was similar in the two patient groups. The kidney sizes were highly diverse and ultrasound-visualized cysts were present in a minority of cases. Extra-renal anomalies were found in 80% of the entire cohort including hepatic involvement (50%), cardiac valve or septal defects (20%) and recurrent bronchial infections (18%). We show that NPHP3 mutations in both infantile and adolescent nephronophthisis point to a common pathophysiological mechanism despite their different clinical presentations.

[Renal transplantation in patients with autosomal dominant polycystic kidney disease: pre-transplantation evaluation and follow-up]. / Transplantation rénale pour polykystose rénale autosomique dominante: spécificités de la préparation et du suivi des patients.

Autosomal dominant polycystic kidney disease (ADPKD) which accounts for 15% of all renal transplantations emerges as the third cause of kidney transplantation in France. In addition to routine evaluation before transplantation, the ADPKD patient requires special assessment of three aspects: should potential kidney complications (recurrent upper tract infection or haemorrhage) or kidney size assessed by computed tomography require nephrectomy prior to transplantation? Is it advisable to detect intracranial aneurysm (ICA) in patients with a relative having experienced ruptured ICA? When transplantation from a living relative is considered, the existence of ADPKD in the donor should be formally ruled out by imaging or genetic studies. The risk of recurrence of ADPKD post-transplantation does not exist. Nevertheless other complications may occur. Thus, an increased incidence of colonic perforation has been reported. In addition, as compared to non-ADPKD patients, an increased risk for both skin cancer and new-onset post-transplant diabetes mellitus has been reported recently after kidney transplantation. Finally, because these patients suffer from an inherited syndrome, physicians should carefully consider the personal and familial history before and after transplantation in order to respond to fatalism in some cases, or to attenuate excessive enthusiasm in the others. Altogether, it apears that a specific approach is needed for ADPKD patients when considering renal transplantation.

High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations.

Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes--AHI1, NPHP1, and NPHP6--have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.

Occupational exposure in ANCA-positive patients: a case-control study.

BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA) are valuable biomarkers for the diagnosis and follow-up of small vessel vasculitis. The role of ANCA has not yet been fully established, but genetic, infectious, and/or environmental factors may increase susceptibility to these diseases. We performed an epidemiologic study to investigate whether the presence of ANCA was associated with silica or any other form of occupational exposure, regardless of the underlying disease. METHODS: All consecutive ANCA-positive patients recorded at the institution's Laboratory of Immunology between 1990 and 2000 were included. Patients hospitalized in a unit of internal medicine matched for age and gender were selected as controls (two controls/case). Qualitative and semiquantitative professional exposure and smoking habits were analyzed by five experts blind to the diagnosis. RESULTS: Univariate analysis showed that patients who reported dust exposure had a 2.6 greater risk of being ANCA-positive (P= 0.007) (odds ratio 2.6; 95% CI 1.3 to 5.3) and individuals with professional exposure to silica had a 3.4 higher risk of being ANCA-positive (P= 0.03) (odds ratio 3.4; 95% CI 1.1 to 9.9). None of the other environmental factors or smoking habits were different between ANCA-positive patients and controls. There was no difference in silica exposure between patients with cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), or atypical ANCA. Semiquantitative analysis showed a dose effect of silica exposure with a nearly sevenfold greater risk of being ANCA-positive compared to controls (P= 0.02) (odds ratio 6.9; 95% CI 1.3 to 35.1). CONCLUSION: These results support the hypothesis that the presence of ANCA in plasma might at least partially be related to occupational exposure.

Living with a functioning kidney transplant at 74 yr or older: a national epidemiological study.

The number of older patients living with a functioning kidney graft is increasing. However the safety of the immunosuppressive treatment and quality of life in this population have not yet been determined. All patients grafted in France since 1969, born before the January 1 1926 and living with a functioning graft on January 1 2000 were included in this national study including all 34 French transplant centers. Renal function, immunosuppressive treatment, comorbid conditions and quality of life were assessed. From the initial population of 446 patients, 113 (26.2%) were still alive in 2000 (study population). Mean age was 76 yr (range: 74-80) with a mean post-transplant follow-up of 9.9 yr (0.1-28.7). Average serum creatinine level was 129 micromol/L (55-286). Immunosuppression was heterogeneous and included triple therapy (18.6%), dual therapy (41.6%) and monotherapy (40.8%). A history of cancer was noted in 36 of the 113 patients (32.1%) whereas hypertension was the most frequent co-morbid condition (80.3%). Estimated quality of life using the Karnofsky scale was between 80 and 100 in 78.4% of the patients. The immunosuppressive regimen in older renal transplant recipients living with a functioning graft varied widely among the 34 French transplant centers. Renal function in this group of patients was good and quality of life seemed excellent. Cardiovascular disease and malignancies were the main co-morbid conditions.

Death after withdrawal from dialysis: the most common cause of death in a French dialysis population.

BACKGROUND: Discontinuation of dialysis is a common cause of death in end-stage renal disease (ESRD) patients in North America and the UK, but appears to be unusual in the rest of Europe. The aim of this retrospective study was to characterize withdrawal from dialysis in a French population cohort. METHODS: We assessed the cause of death, and the medical and social characteristics of chronic dialysis patients in a French population who died in 2001. We compared patients who died after withdrawal from dialysis and patients continuing dialysis until death. We determined the decision-making process when dialysis was withdrawn. RESULTS: In a population cohort of 1436 dialysis patients, 196 died (13.9%). Of them, 40 patients (20.4%) died following withdrawal from dialysis. This was the most common cause of death, followed by cardio-vascular disease (18.4%). Patients withdrawing from dialysis had a significantly higher rate of dementia (17.5 vs 6.4%, P = 0.02), a poor general condition (55 vs 15.4%, P < 0.001), and were dependent in their life for everyday activities in comparison with patients who died from other causes. They were not different in age, sex, duration of dialysis treatment, dialysis technique, cardio-vascular disease, diabetes, stroke or cancer, but the sample size was small. Treatment was more often removed in patients with severe medical complications and/or cachexia (90%). The decision to stop dialysis was made most often by a physician (77.5%). CONCLUSION: Death after withdrawing from dialysis was the most common cause of death in ESRD patients in our French population cohort. The patients who died after discontinuation of treatment were more often in a poor general condition, near the end of life, and most often the physician decided to stop dialysis treatment.

Association of donor TNFRSF6 (FAS) gene polymorphism with acute rejection in renal transplant patients: a case-control study.

BACKGROUND: Genetic factors other than HLA have been reported to be associated with the outcome of organ transplantations. Because binding of FasL to its receptor Fas could play an important role in tubulitis and in the death of graft tubular epithelial cells during kidney allograft rejection, a gene polymorphism recently identified in position -671 in the promoter of the TNFRSF6 gene coding for Fas was investigated in donors. METHODS: A case-control study was performed within a cohort of non-hyperimmunized adult patients who had received cadaveric kidney transplants based on the occurrence or absence of acute cellular rejection in the first 6 months after renal transplantation. Each recipient from the acute rejection group (n = 35) was matched for age (+/- 5 years) and number of HLA-DR mismatches with two recipients within the non-acute rejection group (n = 70). RESULTS: The TNFRSF6-GG genotype was more frequent in donors in the group without rejection episodes. In contrast, patients who received a kidney from a TNFRSF6-A carrier were more likely to experience acute rejection episodes (relative risk nearly 2.1). CONCLUSION: This study suggests that donor TNFRSF6 polymorphism directly or indirectly influences acute kidney rejection episodes.

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.

The risk of hypertension in men: direct and indirect effects of chronic smoking.

OBJECTIVES: To assess the risk of hypertension associated with smoking status. DESIGN: A population-based cross-sectional study in 12 417 men screened for a routine medical and biological check-up provided by their medical insurance at the 'Institut inter-Régional pour la Santé' (IRSA, Regional Institute for Health), a group of 10 medical centres in Western and Central France. MAIN OUTCOME MEASURES: The prevalence and the relative risk of hypertension associated with smoking status. RESULTS: Overall, the prevalence of hypertension was higher in former smokers than in never smokers (13.5 versus 8.8%, P < 0.001). The risk of hypertension was higher [odds ratio (OR) 1.31 (1.13-1.52), P < 0.001] in former smokers than in never smokers, independently of age and alcohol intake. Both current and former smokers were at risk for systolic hypertension, especially those subjects aged 60 years and above. The risk of hypertension was associated with the number of cigarettes smoked [OR per 10 cigarettes smoked daily: 1.13 (1.05-1.21), P < 0.001] and the duration of smoking cessation [OR 0.99 (0.98-1.00), P = 0.01]. When body mass index was entered into the model, the risk of hypertension in former smokers was no longer significant; however, current smokers remained at risk for systolic hypertension. CONCLUSIONS: Former smokers are at risk for hypertension, probably because of the higher prevalence of overweight and obese subjects in this group. Current smokers are also at risk for systolic hypertension, especially in those subjects aged 60 years or older. However, this risk is independent of body mass index.