Clinical and genetic characteristics of Dent's disease type 1 in Europe.

BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.

Epidemiology of granulomatosis with polyangiitis and microscopic polyangiitis in adults in France.

BACKGROUND: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare systemic necrotizing vasculitis. The national incidence and prevalence of GPA/MPA and patient mortality remain unknown in France. A real-life study using retrospective data from the French National Health Data System was set up to describe the epidemiology and demographic characteristics of hospitalized GPA and MPA patients, overall and by disease. METHODS: All adult patients (≥18 years of age) hospitalized for GPA (ICD-10 M31.3) or MPA (ICD-10 M31.7) between 01 and 01-2010 and 31-12-2017 and affiliated to the General health insurance Scheme (covering 76% of the French population) were included in this national retrospective observational study. Descriptive analyses, univariate and multivariable logistic models, Kaplan-Meier survival analysis, and Cox models were performed. RESULTS: The study involved 4445 prevalent GPA patients (including 1578 incident patients) and 1833 prevalent MPA patients (878 incident patients). Distinction between GPA and MPA diagnosis could not be made for 303 patients (149 incident patients). In people aged over 20 years, the age-standardized incidence rates of GPA and MPA were 0.5 and 0.3/100,000 person-years, respectively and the age-standardized prevalence rates were 10 and 4/100,000 person-years, respectively. The standardized mortality ratios in GPA and MPA patients aged over 20 years were 2.0 and 2.7, respectively, and remained constant. Renal failure, pulmonary and urinary tract infections, as well as coronary disease were more frequent among MPA than GPA patients. One-year survival rates among GPA and MPA patients were 96% (95%CI 94%-97%) and 94% (92%-95%), respectively. Five-year survival rates among GPA and MPA patients were 81% (95% CI 79%-83%) and 72% (68%-75%), respectively. After adjusting for comorbidities, the risk of death was still higher in MPA (hazard ratio 1.26 [95%CI 1.06-1.50]) than in GPA patients. CONCLUSIONS: Despite advances in the therapeutic management of patients, mortality rates are still high and stable over time, highlighting the need for improved management.

Hepatocyte nuclear factor-1ß shapes the energetic homeostasis of kidney tubule cells.

Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1ß (HNF-1ß) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1ß deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b-/- ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1ß in metabolism. Hnf1b-/- cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b-/- cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b-/- cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1ß. HNF-1ß shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.

Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Immune thrombotic thrombocytopenic purpura in older patients: prognosis and long-term survival.

Older age is associated with increased mortality in immune thrombotic thrombocytopenic purpura (iTTP). Yet, data are scarce regarding iTTP occurring among older patients. To assess clinical features and long-term impact of iTTP on mortality in older patients (>60 years old), characteristics and prognoses of adult iTTP patients enrolled in the French Reference Center for Thrombotic Microangiopathies registry between 2000 and 2016 were described according to age (<60 years old or ≥60 years old). Long-term mortality of iTTP older survivors was compared with that of non-iTTP geriatric subjects. Comparing, respectively, older iTTP patients (N = 71) with younger patients (N = 340), time from hospital admission to diagnosis was longer (P < .0001); at diagnosis, delirium (P = .034), behavior impairment (P = .045), renal involvement (P < .0001), and elevated troponin level (P = .025) were more important whereas cytopenias were less profound (platelet count, 22 × 103/mm3 [9-57] vs 13 × 103/mm3 [9-21], respectively [P = .002]; hemoglobin level, 9 g/dL [8-11] vs 8 g/dL [7-10], respectively [P = .0007]). Short- and mid-term mortalities were higher (P < .0001) and increased for every 10 years of age range. Age ≥60 years, cardiac involvement, increased plasma creatinine level, and total plasma exchange volume were independently associated with 1-month mortality. Compared with a non-iTTP geriatric population, older survivors showed an increased long-term mortality (hazard ratio = 3.44; P < .001). In conclusion, older iTTP patients have atypical neurological presentation delaying the diagnosis. Age negatively impacts short-term but also long-term mortality.

Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura.

Preemptive rituximab infusions prevent relapses in immune thrombotic thrombocytopenic purpura (iTTP) by maintaining normal ADAMTS13 activity. However, the long-term outcome of these patients and the potential adverse events of this strategy need to be determined. We report the long-term outcome of 92 patients with iTTP in clinical remission who received preemptive rituximab after identification of severe ADAMTS13 deficiency (activity <10%) during the follow-up. Thirty-seven patients had >1 iTTP episode, and the median cumulative relapse incidence before preemptive rituximab was 0.33 episode per year (interquartile range [IQR], 0.23-0.66). After preemptive rituximab, the median cumulative relapse incidence in the whole population decreased to 0 episodes per year (IQR, 0-1.32; P < .001). After preemptive rituximab, ADAMTS13 activity recovery was sustained in 34 patients (37%) during a follow-up of 31.5 months (IQR, 18-65), and severe ADAMTS13 deficiency recurred in 45 patients (49%) after the initial improvement. ADAMTS13 activity usually improved with additional courses of preemptive rituximab. In 13 patients (14%), ADAMTS13 activity remained undetectable after the first rituximab course, but retreatment was efficient in 6 of 10 cases. In total, 14 patients (15%) clinically relapsed, and 19 patients (20.7%) experienced benign adverse effects. Preemptive rituximab treatment was associated with a change in ADAMTS13 conformation in respondent patients. Finally, in the group of 23 historical patients with iTTP and persistently undetectable ADAMTS13 activity, 74% clinically relapsed after a 7-year follow-up (IQR, 5-11). In conclusion, persistently undetectable ADAMTS13 activity in iTTP during remission is associated with a higher relapse rate. Preemptive rituximab reduces clinical relapses by maintaining a detectable ADAMTS13 activity with an advantageous risk-benefit balance.

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

BACKGROUND: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. METHODS: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. RESULTS: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients. CONCLUSION: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems.

Plasma exchange and thrombotic microangiopathies: From pathophysiology to clinical practice.

Thrombotic microangiopathy (TMA) brings together many diseases that have a commonality in the apparition of mechanical hemolysis with consuming thrombopenia. In all cases, these diseases can be life threatening, thereby justifying the implementation of treatment as an emergency. First-line treatment represents plasma exchange. This treatment has proven efficiency in improving the vital patient's and functional prognosis. However, the administration methods of plasma exchange can be redefined in light of the understanding of the pathophysiology of TMA. The aim of this review is to try to define, from pathophysiology, the place of plasma exchanges in the modern therapeutic arsenal of TMA.

The factor VIII:C/VWF:Ag ratio as a useful tool to predict relapse in patients with acquired haemophilia A: A retrospective cohort study.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of autoantibodies against coagulation factor VIII (FVIII). The mortality rate remains high. International recommendations define complete remission as undetectable inhibitor (<0.6 Bethesda Units [BU]) and normal FVIII activity (FVIII:C) that persists after immunosuppressive therapy stopped. For patients achieving remission, the risk of relapse reaches 20%. The risk factors for this relapse are not well known. AIM: In this study, we examined the accuracy of the FVIII/W ratio (FVIII:C/von Willebrand Factor Antigen (VWF:Ag) ratio) to predict relapse in 64 consecutive patients with AHA. RESULTS: In this cohort, all patients had a very low FVIII/W ratio at the time of diagnosis, and this value progressively increased in the first weeks of immunosuppressive treatment. In our study, 9/55 (14%) did not achieve complete remission. Twenty-seven patients were followed long enough (more than a year) to show that in the 22 patients who did not relapse, the FVIII/W ratio remained durably normalized. By contrast, in the five patients who relapsed during follow-up, we noted either no normalization of the FVIII/W ratio, or a secondary decrease to an abnormal value of <0.7 after initial normalization. In all patients who relapsed, the ratio was the first abnormal biological result to be observed, always preceding changes in the activated partial thromboplastin time (aPTT), FVIII:C and anti-FVIII reappearance. CONCLUSION: These data suggest that the FVIII/W ratio could be considered a sensitive biological marker to predict recovery and/or relapse in AHA.

The Effectiveness of Topical Cerium Nitrate-Silver Sulfadiazine Application on Overall Outcome in Patients with Calciphylaxis.

BACKGROUND: Calciphylaxis (CPX) is a rare and life-threatening disease characterized by vascular calcification and development of painful and necrotizing skin lesions with a challenging management. Mechanisms of CPX are complex and include an imbalance between vascular calcification promoters and inhibitors, and frequently vitamin K deficiency. OBJECTIVES: To describe the various presentations and identify predictive factors of death in patients with CPX. METHODS: In this multicenter retrospective study, we included 71 CPX patients followed in South-West France (n = 26) and in French Polynesia (n = 45), and who all received sodium thiosulfate (25 g thrice weekly for a median of 61 days). RESULTS: Characteristics at presentation significantly differed between metropolitan and Polynesian French patients. Polynesians were less frequently on regular dialysis at the onset of CPX, had a higher incidence of diabetes mellitus and obesity, more disturbances of calcium-phosphorus metabolism, and received vitamin K antagonists less frequently than patients from South-West France. Despite intensive management, the 1-year mortality rate was 66% and median time to death was 200 days (IQR, 40; 514). The number of body areas involved (i.e., three: OR 2.70 [1.09; 6.65], p = 0.031; four: OR 8.79 [1.54; 50.29], p = 0.015) was the only predictive factor for death, whereas application of topical cerium nitrate-silver sulfadiazine was protective (OR 0.44 [0.20; 0.99], p = 0.046). Surgical debridement, hyperbaric oxygenation therapy, and geographical origin were not associated with overall outcomes. CONCLUSIONS: Cerium nitrate may lead to vascular decalcification and chelation of reactive oxygen species, and prevent infection. Cerium nitrate-silver sulfadiazine was associated with better outcomes and should be tested in a prospective comparative trial in CPX patients.

Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults.

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history. Strict clinical criteria included lack of response to glucocorticoids and cyclosporine, and no recurrence after kidney transplantation. Mutations in SRNS genes were detected using a targeted gene panel. Sixteen of 135 tested participants (11.8%) carried pathogenic mutations in monogenic SRNS genes, and 14 others (10.4%) carried two APOL1 high-risk alleles. Autosomal recessive disease was diagnosed in 5 participants, autosomal dominant disease in 9, and X-linked disease in 2. Four participants carried a de novo heterozygous mutation. Among the 16 participants with identified mutations in monogenic SNRS genes, 7 (43.7%) had type IV collagen mutations. Mutations in monogenic SNRS genes were identified primarily in participants with proteinuria onset before 25 years of age, while the age at disease onset was variable in those with APOL1 high-risk genotype. Mean age at diagnosis was lower and renal survival was worse in participants with identified mutations in SNRS genes than in those without mutations. We found a significant rate of pathogenic mutations in adults with SRNS, with Type IV collagen mutations being the most frequent. These findings may have immediate impact on clinical practice.

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists.

OBJECTIVES: The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. METHODS: This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. RESULTS: We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. CONCLUSION: Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.

Bendamustine plus rituximab for indolent B-cell lymphoma of renal significance.

Treatment of indolent B-cell non-Hodgkin lymphomas (iNHL) of renal significance is challenging given the need for deep and prolonged hematological response to restore and control renal function overtime, yet to be balanced with the risk of adverse drug-related events. This prospective single-center study included 20 patients with iNHL of renal significance (tubulointerstitial presentation [n = 8], glomerulopathy with or without monoclonal Ig deposits [n = 12]) who received a steroid-sparing regimen of rituximab plus bendamustine (BR), with either no or <1 month of steroid intake (as a first line therapy in 80%). Seventeen patients (85%) achieved a complete (CHR, n = 12) or a partial (PHR, n = 5) hematological response. Nine out of the 12 patients (75%) with iNHL-related glomerulopathy had a complete (CRR) or a partial (PRR) renal response. Among the six patients with glomerulopathy and CHR, five had a CRR (83%) compared to 1/6 (17%) that did not reach CHR. eGFR increased from 38 to 58 mL/min/1.73 m2 , and returned to baseline in five patients. Among the eight patients with a tubulointerstitial presentation, six (75%) had a renal response (5 CRR), and eGFR increased from 29 to 48 mL/min/1.73 m2 . One patient with a PHR had a renal relapse. Mortality rate was 10% at 12 months. The BR regimen was well tolerated overall. Thus, despite severe renal disease at presentation, a relapsing iNHL in 20% of patients and several comorbidities, the BR regimen was efficient and safe in our series. It should be further assessed as a first line therapy for patients with iNHL of renal significance.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Incidence and outcome of lupus nephritis in French Polynesia
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OBJECTIVE: Outcomes of systemic lupus erythematosus (SLE) and lupus nephritis (LN) are highly heterogeneous among some populations because of interactions between genetic, epigenetic, environmental, and socioeconomic factors. A better characterization of social and ethnic disparities in mixed populations may thus help to develop individualized treatment regimens. MATERIALS AND METHODS: Retrospective observational study including all patients with LN diagnosed between January 1993 and January 2014 in the only Nephrology Department of French Polynesia. RESULTS: The annual incidence of SLE and LN in French Polynesia was 3.6 and 0.96 per 100,000, respectively. Among the 45 patients with biopsy-proven LN (pediatric onset, 26.7%), LN occurred during the first SLE flare-up in 68.8%. At presentation, median eGFR was 72 mL/min/1.73m2 (31 - 105), 32 patients had class-III/IV active glomerulonephritis (GN), and 10 had pure or mixed class-V GN. During the follow-up, 5 patients died (11.1%) and 2 reached end-stage renal disease (4.4%). Cumulative incidences of complete and partial renal responses were 31.1% and 40% at 12 months. Complete renal response (CR) was only predicted by renal presentation (lack of leukocyturia, low proteinuria). Among the 36 patients with renal response, 18 relapsed. Maintenance treatment (mycophenolate mofetil) and place of residence (Windward Islands as compared to remote islands) were the only factors that protected from relapse. CONCLUSION: Renal presentation was the main predictive factor for a renal response whereas geographical residence and maintenance-treatment regimen were predictive of LN relapses in patients from French Polynesia, an area characterized by a specific genetic background and including several isolated islands that have limited access to healthcare.
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Hepatocyte Nuclear Factor-1ß Controls Mitochondrial Respiration in Renal Tubular Cells.

AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A), a coactivator of the transcription factor PPAR-γ that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1ß (HNF-1ß) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1ß transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-γ and TNF-α led to inhibition of HNF-1ß transcriptional activity. Moreover, inhibition of HNF-1ß significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1ß binding to the Ppargc1a promoter in mouse kidneys. We also demonstrated downregulation of renal PPARGC1A expression in a patient with an HNF1B germinal mutation. Thus, we propose that HNF-1ß links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly via PPARGC1A signaling. Our findings further strengthen the view of HNF1B-related nephropathy as a mitochondrial disorder in adulthood.

The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits.

Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS.

Alternative complement pathway hemolytic assays reveal incomplete complement blockade in patients treated with eculizumab.

Eculizumab is a monoclonal anti-C5 antibody used in the treatment of atypical hemolytic uremic syndrome (aHUS). We monitored complement inhibition in 16 eculizumab-treated patients suffering from HUS or transplant rejection (not aHUS patients). Blood samples were obtained one to four weeks after the last eculizumab injection. We observed that eculizumab efficiently blocked the terminal pathway (TP) through classical pathway (CP) activation measured by kinetic hemolytic assay (HA) (<10%) but incompletely blocked the TP through alternative pathway (AP) activation measured by rabbit (APH50>23%) or chicken erythrocytes HA (AP100>15%). Conversely, functional ELISA revealed a complete blockade of TP through AP activation in all patients (<10%). C5a and sC5b9 levels were not correlated with residual APH50 or AP100. Similar results were obtained after in vitro addition of increasing amounts of eculizumab to a control serum (in vitro APH50>60% and AP100>20%). We also showed that ELISA was less sensitive than HA.

Thrombotic thrombocytopenic purpura misdiagnosed as autoimmune cytopenia: Causes of diagnostic errors and consequence on outcome. Experience of the French thrombotic microangiopathies reference centre.

Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (<10%) acquired ADAMTS13 deficiency-associated TTP from our National database that included 423 patients, who had an initial misdiagnosis (20% of all TTP). Main diagnostic errors were attributed to autoimmune thrombocytopenia, associated (51%) or not (37%) with autoimmune hemolytic anemia. At admission, misdiagnosed patients were more frequently females (P = .034) with a history of autoimmune disorder (P = .017) and had organ involvement in 67% of cases; they had more frequently antinuclear antibodies (P = .035), a low/undetectable schistocyte count (P = .001), a less profound anemia (P = .008), and a positive direct antiglobulin test (DAT) (P = .008). In multivariate analysis, female gender (P = .022), hemoglobin level (P = .028), a positive DAT (P = .004), and a low schistocytes count on diagnosis (P < .001) were retained as risk factors of misdiagnosis. Platelet count recovery was significantly longer in the misdiagnosed group (P = .041) without consequence on mortality, exacerbation and relapse. However, patients in the misdiagnosed group had a less severe disease than those in the accurately diagnosed group, as evidenced by less organ involvement at TTP diagnosis (P = .006). TTP is frequently misdiagnosed with autoimmune cytopenias. A low schistocyte count and a positive DAT should not systematically rule out TTP, especially when associated with organ failure.

Asymptomatic circulating T-cell clone cause renal polymorphic inflammatory fibrosis.

BACKGROUND: Renal complications of non-Hodgkin lymphoma encompass a wide spectrum of monoclonal Ig-related pathologies. Clonal circulating T cells can also be associated with non-renal autoimmune disorders induced by overproduction of specific patterns of cytokines or unbalanced lymphocytes sub-populations. METHODS: Immunophenotyping of circulating T cells and TCR gene restriction analysis using Biomed-2 protocol. NF-κB staining and mRNA quantification of inflammatory genes in HK-2 epithelial renal cells exposed to supernatants of peripheral blood mononuclear cells with clonal T-cell population. RESULTS: Here, we could identify a persistent clonal T-cell population, only characterized by in-depth immunophenotyping of circulating lymphocytes and using multiplex PCR analysis of TCR gene rearrangements, in two patients with polymorphic inflammatory renal fibrosis of unknown origin. Using an in vitro approach, we could demonstrate that peripheral blood mononuclear cells including the clonal population can trigger a phenotype switch of epithelial renal cells from a quiescent state to a pro-inflammatory state characterized by NF-κB nuclear translocation and overexpression of inflammatory cytokine or chemokine. CONCLUSION: These preliminary data suggest that circulating T-cell clones may directly activate epithelial renal cells or promote a T-/B-cell population with autoimmune reactive properties against kidney cells, which, in the absence of overt renal lymphoma infiltration, lead to the subsequent inflammatory renal fibrotic phenotype.