Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.

RATIONALE & OBJECTIVE: Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included. RESULTS: Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT. LIMITATIONS: Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants. CONCLUSIONS: Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants.

Primary hyperoxaluria in adults and children: a nationwide cohort highlights a persistent diagnostic delay.

Background: Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The primary objective of this study is to assess the current diagnostic delay for PH. Methods: This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis. Results: A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults [median (interquartile range)]: 1.2 (0.1-3.0) versus 30 (17-36) years, respectively (P < .0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases. Conclusion: This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis.

Fever control using external cooling in septic shock: a randomized controlled trial.

RATIONALE: Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. OBJECTIVES: To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. METHODS: In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. MEASUREMENTS AND MAIN RESULTS: Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). CONCLUSIONS: In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.

OBJECTIVE: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura. DESIGN: Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine. SETTING: Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France. PATIENTS: Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange. INTERVENTION: Add-on rituximab therapy, four infusions over 15 days. MEASUREMENTS AND MAIN RESULTS: One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred. CONCLUSIONS: Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.

Survey of caregiver opinions on the practicalities of family-centred care in intensive care units.

AIMS AND OBJECTIVES: To determine caregiver opinion on their intensive care unit's policies with regard to visiting hours, how families are informed and participate in patient care. BACKGROUND: Benefits of improving family access to the intensive care unit, information delivery and participation of families in care have been suggested. DESIGN: Survey of caregivers working in French-speaking intensive care units. METHODS: An e-mail invitation to complete an online, closed-ended questionnaire was issued to caregivers registered in the mailing list of the French society of intensive care. RESULTS: Caregivers (n = 731) working in 222 adult and 41 paediatric intensive care units completed the questionnaire. Unlike in paediatric intensive care units, 58% of adult intensive care unit had restricted visiting hours (< 4 hour). However, 63% of respondents would recommend extended visiting periods. A 24-hour policy existed in 7% of adult intensive care units; 10% of respondents from these intensive care units thought reducing visiting periods would be very useful or essential; 81% thought that a 24-hour policy contributed to improved relations with families; and only 9% thought that it was a hindrance to care. Over 90% of caregivers thought that families should be informed of patient progress in a designated room in the presence of the patient's nurse and that patient records should report family meetings. This policy was only implemented in half of the cases. Family participation in care procedures was strongly encouraged in only 0·5% of adult intensive care units. CONCLUSIONS: Intensive care unit caregivers are in favour of longer visiting hours, increased use of designated rooms for, and nurse participation in, meetings with families. Although caregivers do not associate families with care procedures, they considered that their presence during most interventions should be authorised. RELEVANCE TO CLINICAL PRACTICE: Our results could help in implementing intensive care unit policies concerning visiting hours, how families are informed and participate in patient care.

Cancer awareness in atypical thrombotic microangiopathies.

OBJECTIVE: To specify the clinical and biological characteristics of thrombotic microangiopathies (TMAs) associated with a recent diagnosis of cancer. PATIENTS AND Methods. Multicenter study involving 14 national centers. Cross-sectional analysis of 20 patients with cancer-associated TMAs included in our national registry from October 2000 to July 2007. Patients were also compared with 134 adult patients with an acquired idiopathic TMA by univariate analysis. RESULTS: Patients with a cancer-associated TMA typically displayed severe weight loss, dyspnea, bone pain, as well as disseminated intravascular coagulopathy and massive erythromyelemia (75%, 55%, 50%, 41%, and 85% of cases, respectively). By contrast, these features were observed with a much lower incidence in patients with an idiopathic TMA (8.9%, 19.7%, 0.8%, 7.1%, and 17.5%, respectively). Moreover, median platelet count was higher (48 x 10(9)/l; range, 21-73 x 10(9)/l versus 19 x 10(9)/l; range, 10-38 x 10(9)/l, respectively) and median serum creatinine level was lower (74 microM [range, 68-102] versus 113 microM [range, 80-225], respectively). The activity of the specific von Willebrand factor-cleaving proteinase ADAMTS13 was detectable in 14/17 studied patients. Platelet count improvement was observed in only seven patients and paralleled the response to chemotherapy. Prognosis of patients with cancer-associated TMAs was very poor, with a 30-day and 2-year mortality rate of 50% and 95%, respectively. CONCLUSION: Cancer-associated TMAs display specific features at onset that should prompt investigation of an underlying disseminated malignancy. In this context, chemotherapy rather than plasma is mandatory since TMA prognosis parallels that of cancer.

Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience.

Severe ADAMTS13 deficiency occurs in 13% to 75% of thrombotic microangiopathies (TMA). In this context, the early identification of a severe, antibody-mediated, ADAMTS13 deficiency may allow to start targeted therapies such as B-lymphocytes-depleting monoclonal antibodies. To date, assays exploring ADAMTS13 activity require skill and are limited to only some specialized reference laboratories, given the very low incidence of the disease. To identify clinical features which may allow to predict rapidly an acquired ADAMTS13 deficiency, we performed a cross-sectional analysis of our national registry from 2000 to 2007. The clinical presentation of 160 patients with TMA and acquired ADAMTS13 deficiency was compared with that of 54 patients with detectable ADAMTS13 activity. ADAMTS13 deficiency was associated with more relapses during treatment and with a good renal prognosis. Patients with acquired ADAMTS13 deficiency had platelet count < 30 x 10(9)/L (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 3.4-24.2, P<.001), serum creatinine level < or =200 micromol/L (OR 23.4, 95% CI 8.8-62.5, P<.001), and detectable antinuclear antibodies (OR 2.8, 95% CI 1.0-8.0, P<.05). When at least 1 criteria was met, patients with a severe acquired ADAMTS13 deficiency were identified with positive predictive value of 85%, negative predictive value of 93.3%, sensitivity of 98.8%, and specificity of 48.1%. Our criteria should be useful to identify rapidly newly diagnosed patients with an acquired ADAMTS13 deficiency to better tailor treatment for different pathophysiological groups.

Respective effects of end-expiratory and end-inspiratory pressures on alveolar recruitment in acute lung injury.

OBJECTIVE: A low tidal volume can induce alveolar derecruitment in patients with acute lung injury. This study was undertaken to evaluate whether this resulted mainly from the decrease in tidal volume or from the reduction in end-inspiratory plateau pressure and whether there is any benefit in raising the level of positive end-expiratory pressure (PEEP) while plateau pressure is kept constant. DESIGN: Prospective crossover study. SETTING: Medical intensive care unit of a university teaching hospital. PATIENTS: Fifteen adult patients ventilated for acute lung injury (PaO2/FiO2, 158 +/- 34 mm Hg; lung injury score, 2.7 +/- 0.6). INTERVENTIONS: Three combinations were tested: PEEP at the lower inflection point with 6 mL/kg tidal volume, PEEP at the lower inflection point with 10 mL/kg tidal volume, and high PEEP with tidal volume at 6 mL/kg, keeping the plateau pressure similar to the preceding condition. MEASUREMENTS AND MAIN RESULTS: Pressure-volume curves at zero PEEP and at set PEEP were recorded, and recruitment was calculated as the volume difference between both curves for pressures ranging from 15 to 30 cm H2O. Arterial blood gases were measured for all patients. For a similar PEEP at the lower inflection point (10 +/- 3 cm H2O), tidal volume reduction (10 to 6 mL/kg) led to a significant derecruitment. A low tidal volume (6 mL/kg) with high PEEP (14 +/- 3 cm H2O), however, induced a significantly greater recruitment and a higher Pao than the two other strategies. CONCLUSION: At a given plateau pressure (i.e., similar end-inspiratory distension), lowering tidal volume and increasing PEEP increase recruitment and PaO2.