Philippe Vanhille

Adult Faconi Syndrome Secondary to Light Chain Gammopathy: Clinicopathologic Heterogeneity and Unnsual Features in 11 Patients

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et als description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

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.

Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis

PURPOSE To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis. PATIENTS AND METHODS Forty-three patients with histologically proven vasculitis (21 with Wegeners granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination. RESULTS Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegeners granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegeners granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies. CONCLUSION The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.

Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls

OBJECTIVE Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence. METHODS Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls. RESULTS Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died. CONCLUSIONS Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.

Renal Lesions Associated with IgM-Secreting Monoclonal Proliferations: Revisiting the Disease Spectrum

BACKGROUND AND OBJECTIVES Since the first description of pathology of the kidney in Waldenström disease in 1970, there have been few reports on kidney complications of IgM-secreting monoclonal proliferations. Here, we aimed to revisit the spectrum of renal lesions occurring in patients with a serum monoclonal IgM. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fourteen patients with a circulating monoclonal IgM and a kidney disease related to B cell proliferation were identified retrospectively. Demographic, clinical, and laboratory data were assessed for each patient at the time of kidney biopsy. RESULTS Seven patients had a nephrotic syndrome. Patients without nephrotic syndrome all had impaired renal function. Mean serum creatinine was 238 micromol/L. For five patients, the diagnosis of monoclonal IgM preceded the kidney disease by 28.8 mo (range 12 to 60). Seven patients had Waldenström disease, two had a small B cell non-Hodgkin lymphoma, one had an IgM-excreting multiple myeloma, one had a marginal zone B cell lymphoma, and three had an IgM-related disorder. Renal lesions included (1) intracapillary monoclonal deposits disease with granular, electron-dense IgM thrombi occluding capillary lumens (5); (2) atypical membranoproliferative glomerulonephritis (3); (3) lambda light chain amyloidosis (2) associated with mu deposits in one patient; (4) acute tubular necrosis (1); and (5) CD20(+) lymphomatous infiltration (3). Remission of the nephrotic syndrome was attained in three of seven patients, and renal function improved after chemotherapy. CONCLUSIONS Although renal complications of IgM proliferations are rare, a wide spectrum of kidney lesions is observed, without correlation with the type of hematologic disorder.

Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection.

Hepatitis C virus (HCV) infection represents, by far, the major cause of mixed cryoglobulinemia (MC). The renal disease associated with this pathological condition is now well described. By contrast, renal involvement in patients with MC not associated with HCV has been only poorly described, and few cases have been reported. We analyzed the demographic, clinical, and laboratory features and outcome in patients presenting with renal disease associated with MC not related to HCV infection. Records of 20 patients with MC and renal disease, with no evidence of HCV by serology and polymerase chain reaction analysis, were retrospectively analyzed. Renal biopsies and extensive searches for lymphoproliferative disorder were performed in all patients at presentation. MC was related to primary Sjögren Syndrome (pSS) in 9 patients, and to non-Hodgkin lymphoma in 1 patient, while MC was classified as essential in the remaining 10 cases. Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min per 1.73 m2). Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens. Skin vasculitis was the main extrarenal manifestation. In all patients, cryoglobulinemia was classified as type II MC, characterized by monoclonal IgM&kgr; and polyclonal IgG. Most patients (17/20) were treated with steroids or immunosuppressive agents, or both. Initial renal remission was observed in 94% of patients. However, renal relapse occurred in most patients, with 10% reaching end-stage renal disease. Three patients with essential MC developed B-cell lymphoma 36-48 months after the diagnosis of MC. Unexpectedly, B-cell lymphoma induced by Epstein-Barr virus infection occurred in only 1 of the 9 pSS patients. Forty percent of patients died as a result of extrarenal causes. Renal disease associated with MC unrelated to HCV is characterized by the high prevalence of pSS (45%), the finding of CD20+ B-lymphocyte nodular infiltrates in the kidney interstitium, and a high incidence of overt B-cell lymphoma during follow-up. These findings emphasize the need for repetitive clinical evaluation in those patients. Abbreviations: GFR = glomerular filtration rate, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus-1, MC = mixed cryoglobulinemia, pSS = primary Sjögren syndrome.

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.

Treatment of Systemic Necrotizing Vasculitides in Patients Aged Sixty‐Five Years or Older: Results of a Multicenter, Open‐Label, Randomized Controlled Trial of Corticosteroid and Cyclophosphamide–Based Induction Therapy

To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegneners] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg‐Strauss] [EGPA]).

Acalculous ischemic gallbladder necrosis in the catastrophic antiphospholipid syndrome.

A 29-year-old woman was referred for abdominal pain. Results of tests for lupus anticoagulant and antibodies to phosphatidylserine and to beta2-glycoprotein I were positive, but the patient had no features of systemic lupus erythematosus (SLE). Abdominal ultrasonography showed a thickening of the gallbladder wall without cholelithiasis. A surgical procedure revealed necrotic areas of the gallbladder wall, and a cholecystectomy was performed. Histologic examination of the gallbladder showed multiple thrombi and no vasculitis. Despite full-dose heparin, the patient developed a catastrophic antiphospholipid syndrome (APS) and subsequently died. Among connective tissue disorders, acute acalculous cholecystitis has been reported in patients with polyarteritis nodosa and/or SLE. APS should be considered as a possible cause of acalculous cholecystitis.