Claire Presne

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 <30×109/L (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 3.4–24.2, P<.001), serum creatinine level ≤200 µmol/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.

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.

Pulse wave velocity and vascular calcification at different stages of chronic kidney disease.

Background Increased arterial stiffness and vascular calcification have been recognized as important predictors of cardiovascular mortality in patients with chronic kidney disease. Method In order to examine the precise temporal link between aortic stiffness and cardiovascular risk at the earliest stages of chronic kidney disease, we studied a cohort of 150 patients with chronic kidney disease (52 stage 2/3 patients, 51 stage 4/5 patients and 47 stage 5D patients). Each patient underwent a plain, lateral lumbar radiograph and an abdominal and thoracic multislice spiral computer tomography scan in order to identify and quantify aortic and coronary calcifications. Pulse wave velocity was used as a measure of arterial stiffness. Results Regardless of the disease stage, patients with chronic kidney disease had higher adjusted pulse wave velocity than controls with preserved renal function (14.6 ± 3.8 vs. 10.7 ± 1.7 m/s, respectively; P < 0.0001). Regarding aortic calcification, there was a gradual but significant rise in later chronic kidney disease stages. A similar trend was found for coronary calcification. In a multivariate analysis only age, mean arterial pressure, diabetes and the aortic calcification score were independent determinants of higher pulse wave velocity. Conclusion We found that both vascular stiffness and vascular calcification appear early in patients with chronic kidney disease, but only vascular calcification worsens as the disease progresses. The increase of vascular stiffness in adult patients with chronic kidney disease seems to be more related to age, systolic blood pressure, diabetes and vascular calcification than to uremic toxicity.

Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis

The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.

Thalidomide in patients with multiple myeloma and renal failure

treatment. Our own experience with rFVIIa and reports in the literature on the use of rFVIIa in treating this group of patients involve small numbers of patients. Systematic data collection as recommended by the international registry on rFVIIa and congenital platelet disorders group (Poon & d’Orion, 2000) are therefore important in providing useful information on dosing regimes, efficiency and safety in these rare disorders.

Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

Background Acquired thrombotic thrombocytopenic purpura is still associated with a 10–20% death rate. It has still not been possible to clearly identify early prognostic factors of death. This study involved thrombotic thrombocytopenic purpura patients with acquired severe (<10% of normal activity) ADAMTS13 deficiency and aimed to identify prognostic factors associated with 30-day death. Design and Methods The study involved a prospective cohort of patients and was carried out between October 2000 and August 2010. A validation cohort of patients was set up from September 2010 to August 2011. Altogether, 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency were enrolled. The study evaluated 30-day mortality after treatment initiation according to characteristics at inclusion. Results Non-survivors (11%) were older (P=10−6) and more frequently presented arterial hypertension (P=5.10−4) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (P=0.004). On presentation, cerebral manifestations were more frequent in non-survivors (P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables determining death were age, severe cerebral involvement and LDH level 10 N or over. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death. Conclusions A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and identify patients with a worse prognosis.

Viewpoint: How Do Calcimimetics Fit Into the Management of Parathyroid Hormone, Calcium, and Phosphate Disturbances in Dialysis Patients?

As suggested by its American brand name (Sensipar), the calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing parathyroid hormone (PTH) release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore cinacalcet decreases the risk of hypercalcemia and hyperphosphatemia in contrast to 1α‐OH vitamin D derivatives. Compared with calcium‐containing oral phosphate binder (OPB), it increases the risk of hypocalcemia and may decrease the PTH‐mediated phosphaturia in predialysis patients. This justifies its combined use with calcium‐containing OPB in order to prevent hypocalcemia and enhance the hypophosphatemic effect of the latter, while improving PTH suppression. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day, a recommendation that we believe should be revised. No pathophysiologic or randomized trial data have yet evidenced the absolute necessity for systematically using 1α‐OH vitamin D derivatives and noncalcium‐containing OPB rather than higher doses of calcium‐containing OPB alone in uremic patients without vitamin D insufficiency. In patients with hyperparathyroidism as severe as in the “Treat to Goal Study,” the Durham study showed that a calcium carbonate dose more than three times the K/DOQI limit could decrease PTH into the recommended range, with the advantage of a lower calcium‐phosphate product compared with the combination of calcitriol and noncalcium OPB. Besides the efficient PTH suppression associated with lower calcium‐phosphate product and a good gastrointestinal tolerance, long‐term data suggest that cinacalcet may decrease the risk of parathyroidectomy and fracture, while high bone turnover lesions are improved. However, no long‐term data on bone mineral density and cardiovascular calcification and complications are yet available. Such studies, along with those comparing cinacalcet and 1α‐OH vitamin D‐based approaches to hyperparathyroidism, are needed.

Localized Amyloidosis of the Genitourinary Tract: Report of 5 New Cases and Review of the Literature

Primary localized amyloidosis of the genitourinary tract is a rare entity characterized by small pseudotumors localized in the renal pelvis, ureters, or bladder. Amyloid fibrils are derived from immunoglobulin light chains, but no systemic plasma cell proliferation is detected. The clinical and radiologic features mimic urinary tract cancer, and local treatment is indicated. The prognosis is excellent in most cases, although disease recurrence is possible.We report 5 new cases of localized amyloidosis of the urinary tract, with lambda (4/5), or kappa (1/5) chain amyloid protein, involving the bladder (5/5), and the ureter and renal pelvis (1/5), with multiple, bilateral lesions in 1 case. The presenting complaint was painless hematuria in 4 cases. All cases were of primary (AL)-type amyloidosis. All patients underwent extensive investigation, and none presented any signs of generalized amyloidosis. A favorable outcome was observed in every case. We performed a comprehensive review of the literature, and summarize the data.Abbreviations: AA = secondary amyloidosis, AL = primary amyloidosis, CT = computed tomography, KMnO4 = potassium permanganate, MGUS = monoclonal gammopathy of unknown significance, MRI = magnetic resonance imaging, SAA = serum amyloid A, TTR = transthyretin.

Rituximab for minimal-change nephrotic syndrome in adulthood: predictive factors for response, long-term outcomes and tolerance

BACKGROUND Minimal-change nephrotic syndrome (MCNS) is a common cause of steroid sensitive nephrotic syndrome (NS) with frequent relapse. Although steroids and calcineurin inhibitors (CNIs) are the cornerstone treatments, the use of rituximab (RTX), a monoclonal antibody targeting B cells, is an efficient and safe alternative in childhood. METHODS Because data from adults remain sparse, we conducted a large retrospective and multicentric study that included 41 adults with MCNS and receiving RTX. RESULTS Complete (NS remission and withdrawal of all immunosuppressants) and partial (NS remission and withdrawal of at least one immunosuppressants) clinical responses were obtained for 25 and 7 patients, respectively (overall response 78%), including 3 patients that only received RTX and had a complete clinical response. After a follow-up time of 39 months (6-71), relapses occurred in 18 responder patients [56%, median time 18 months (3-36)]. Seventeen of these received a second course of RTX and then had a complete (n = 13) or partial (n = 4) clinical response. From multivariate analysis, on-going mycophenolate mofetil (MMF) therapy at the time of RTX was the only predictive factor for RTX failure [HR = 0.07 95% CI (0.01-0.04), P = 0.003]. Interestingly, nine patients were still in remission at 14 months (3-36) after B-cell recovery. No significant early or late adverse event occurred after RTX therapy. CONCLUSIONS RTX is safe and effective in adult patients with MCNS and could be an alternative to steroids or CNIs in patients with a long history of relapsing MCNS.

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center

Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP.