Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Hot Spot of Complement Factor I Rare Variant p.Ile357Met in Patients With Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease due to a dysregulation of the complement alternative pathway. Complement factor I (CFI) negatively regulates the alternative pathway and CFI gene rare variants have been associated to aHUS with a low disease penetrance. We report 10 unrelated cases of HUS associated to a rare CFI variant, p.Ile357Met (c.1071T>G). All patients with isolated p.Ile357Met CFI missense variant were retrospectively identified among patients included between January 2007 and January 2022 in the French HUS Registry. We identified 10 unrelated patients (70% women; median age at HUS diagnosis, 36.5 years) who carry the same rare variant p.Ile357Met in the CFI gene. Seven patients (cases 1-7) presented with aHUS in the native kidney associated with malignant hypertension in 5 patients. None received a C5 inhibitor. Two of these cases occurred in the peripartum period with complete recovery of kidney function, while 5 of these patients reached kidney failure requiring replacement therapy (KFRT). Four patients with KFRT subsequently underwent kidney transplantation. Three later developed C3 glomerulopathy in their kidney graft, but none had aHUS recurrence. Three other patients (cases 8-10) experienced de novo thrombotic microangiopathy after kidney transplantation, precipitated by various triggers. The rare CFI variant p.Ile357Met appears to be a facilitating genetic factor for HUS and for some forms of secondary HUS.

Urine Protein/Creatinine Ratio in Thrombotic Microangiopathies: A Simple Test to Facilitate Thrombotic Thrombocytopenic Purpura and Hemolytic and Uremic Syndrome Diagnosis.

BACKGROUND: Early diagnosis of thrombotic thrombocytopenic purpura (TTP) versus hemolytic and uremic syndrome (HUS) is critical for the prompt initiation of specific therapies. OBJECTIVE: To evaluate the diagnostic performance of the proteinuria/creatininuria ratio (PU/CU) for TTP versus HUS. PATIENTS/METHODS: In a retrospective study, in association with the "French Score" (FS) (platelets < 30 G/L and serum creatinine level < 200 µmol/L), we assessed PU/CU for the diagnosis of TTP in patients above the age of 15 with thrombotic microangiopathy (TMA). Patients with a history of kidney disease or with on-going cancer, allograft or pregnancy were excluded from the analysis. RESULTS: Between February 2011 and April 2019, we identified 124 TMA. Fifty-six TMA patients for whom PU/CU were available, including 35 TTP and 21 HUS cases, were considered. Using receiver-operating characteristic curves (ROC), those with a threshold of 1.5 g/g for the PU/CU had a 77% sensitivity (95% CI (63, 94)) and a 90% specificity (95% CI (71, 100)) for TTP diagnosis compared with those having an 80% sensitivity (95% CI (66, 92)) and a 90% specificity (95% CI (76, 100) with a FS of 2. In comparison, a composite score, defined as a FS of 2 or a PU/CU ≤ 1.5 g/g, improved sensitivity to 99.6% (95% CI (93, 100)) for TTP diagnosis and enabled us to reclassify seven false-negative TTP patients. CONCLUSIONS: The addition of urinary PU/CU upon admission of patients with TMA is a fast and readily available test that can aid in the differential diagnosis of TTP versus HUS alongside traditional scoring.

Immunoglobulin A nephropathy in association with inflammatory bowel diseases: results from a national study and systematic literature review.

BACKGROUND: Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). METHODS: We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. RESULTS: Crohn's disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9 years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100 mg/mmol in 70.8% of patients (mean 254 mg/mmol). Estimated glomerular filtration rate (eGFR) was >60 mL/min/1.73 m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1-2 and 38% C1-2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2 years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n = 3) or a >50% decrease in eGFR from initial values (n = 1). A similar evolution was observed in patients with primitive IgAN. CONCLUSIONS: This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes.

Apheresis in Adult With Refractory Idiopathic Nephrotic Syndrome on Native Kidneys.

BACKGROUND: Apheresis is the gold standard for idiopathic nephrotic syndrome (INS) relapse after transplantation, but it remains unknown whether such treatment is useful for adults with refractory INS on native kidneys. METHODS: This retrospective study included patients older than 16 years with biopsy-proven refractory (persistent nephrotic syndrome on corticosteroids plus at least 1 immunosuppressive drug) INS treated by apheresis and followed for at least 3 months. RESULTS: Between September 1997 and January 2020, 21 patients (focal segmental glomerulosclerosis: 12, minimal change nephrotic syndrome: 9, men: 67%, median age: 34 years) were identified. At last follow-up (12 months), 7 of 21 patients were in complete or partial remission. Remission was associated with older age (51 vs. 30 years, P = 0.05), lower proteinuria (3.9 vs. 7.3 g/d, P = 0.03), and lower estimated glomerular filtration rate (eGFR) (28.0 vs. 48.5 ml/min per 1.73 m2, P = 0.05) at apheresis. The need for dialysis before apheresis (odds ratio [OR] 22.0 [1.00-524], P = 0.026), age ≥50 years (OR: 22.6 [1.00-524], P = 0.006), a marked (>4.5 g/d) decrease in proteinuria (OR: 9.17 [1.15-73.2], P = 0.041), and a short (<12 months) time between diagnosis and apheresis (OR: 10.8 [1-117], P = 0.043) were significantly associated with remission. Three of 7 patients in remission who were initially on dialysis became dialysis-free; by contrast, none of the 14 patients without remission was initially on dialysis, but 5 of 14 had become dialysis-dependent (P = 0.01). CONCLUSION: Apheresis may result in remission in adult patients with refractory INS, particularly in those at risk of renal failure, with limited sensitivity to medical treatments, if apheresis is initiated within a year of diagnosis.

Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors.

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.

Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort.

BACKGROUND: Hemolytic uremic syndrome due to Shiga toxin-producing E. coli (STEC-HUS) is the main cause of acute kidney injury in young children. Most fully recover kidney function; however, some develop long-term sequelae. We aimed to determine whether kidney injury 1 year after HUS onset is associated with long-term kidney outcome in pediatric STEC-HUS. METHODS: A retrospective population-based study of children < 15 years with STEC-HUS between 1992 and 2012 was performed. Mixed effects logistic regression was used to investigate associations between kidney injury at 1 year and long-term kidney outcome. RESULTS: Ninety-eight STEC-HUS cases were reported. Of 96 patients who survived acute phase, 84 were evaluated at 1-year follow-up of whom 42 (44% of survivors) showed ≥ 1 signs of kidney injury. Data from 81 patients were collected after median follow-up of 8.7 (IQR 3.5-12.7) years. At last follow-up, 42 (44% of survivors) had ≥ 1 signs of kidney injury including decreased estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 (n = 30), proteinuria (n = 17), or hypertension (n = 5). Among 42 patients with kidney injuries at 1-year follow-up, only 22 (52%) still had kidney disease at last follow-up. Conversely, of 33 patients without kidney injury at 1-year and available long-term outcome data, 11 (33%) had proteinuria or decreased GFR at last follow-up. There was no statistically significant association between kidney injury at 1 year and long-term kidney outcome. CONCLUSIONS: Since kidney sequelae may appear at variable time intervals after acute HUS, all patients need lifelong follow-up to detect early signs of chronic kidney disease and propose measures to slow progression.

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.

BACKGROUND: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab. STUDY DESIGN: Case series of C3 glomerulopathy. SETTING & PARTICIPANTS: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada. OUTCOMES: Global or partial clinical renal response. MEASUREMENTS: Evolution of serum creatinine and proteinuria values. RESULTS: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders. LIMITATIONS: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases. CONCLUSIONS: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.

Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.

The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment.

BACKGROUND: Eculizumab is approved for atypical hemolytic uremic syndrome (aHUS). Guidelines discuss the importance of prompt treatment. We report a post hoc analysis investigating the effect of baseline factors, including patient characteristics and time from the latest aHUS manifestation to eculizumab initiation, on change from baseline in estimated glomerular filtration rate (eGFR) and other outcomes. METHODS: Data were pooled from four phase 2, open-label, single-arm, prospective clinical studies of eculizumab for patients with aHUS. Multivariate regressions identified predictors of eGFR change from baseline. The proportion of patients achieving sustained eGFR increase (defined: ≥15 ml/min/1.73 m2 for ≥28 days) and platelet count normalization were evaluated 1 year post-treatment. Baseline characteristics and eGFR outcomes were summarized by time to treatment from last aHUS manifestation [≤7 days (n = 21) versus >7 days (n = 76)]. RESULTS: Baseline eGFR were similar between groups. Multivariate regression analysis demonstrated time from aHUS manifestation to eculizumab treatment, age, baseline lactate dehydrogenase (LDH) and baseline hemoglobin were independently predictive of eGFR change from baseline. Mean eGFR change from baseline at 1 year was significantly higher in patients treated in ≤7 days than >7 days (57 vs. 23 ml/min/1.73 m2, p = 0.0098). After 1 year, 17/21 and 36/76 patients in the ≤7 and >7 day groups, respectively, achieved a sustained increase in eGFR. Mean time to platelet count normalization was similar between groups. CONCLUSIONS: Younger age, higher baseline LDH and lower baseline hemoglobin were associated with greater eGFR improvements. Early eculizumab initiation led to improved renal recovery, demonstrating the importance of rapid diagnosis and treatment of patients with aHUS.

Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy.

BACKGROUND: Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity <10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation. METHODS: Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686. FINDINGS: We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients). INTERPRETATION: Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder. FUNDING: Assistance Publique-Hôpitaux de Paris.

Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys. STUDY DESIGN: A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 µmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included. SETTING & PARTICIPANTS: 19 patients were identified through a query sent to all French nephrology centers. OUTCOMES & MEASUREMENTS: Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy. RESULTS: All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls. LIMITATIONS: Retrospective study and use of historical controls. CONCLUSIONS: Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.

Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency.

A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. METHODS: We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. RESULTS: We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. CONCLUSIONS: Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

USPIO-enhanced MR imaging of macrophage infiltration in native and transplanted kidneys: initial results in humans.

The purpose of this study was to evaluate the detection and characterization of macrophage infiltration in native and transplanted kidneys using ultrasmall superparamagnetic iron oxide particles (USPIO). Among 21 patients initially enrolled, 12 scheduled for renal biopsy for acute or rapidly progressive renal failure (n = 7) or renal graft rejection (n = 5) completed the study. Three magnetic resonance (MR) sessions were performed with a 1.5-T system, before, immediately after and 72 h after i.v. injection of USPIO at doses of 1.7-2.6 mg of iron/kg. Signal intensity change was evaluated visually and calculated based on a region of interest (ROI) positioned on the kidney compartments. Histological examination showed cortical macrophage infiltration in four patients (>5 macrophages/mm(2)), two in native kidneys (proliferative extracapillary glomerulonephritis) and two in transplants (acute rejection). These patients showed a 33 +/- 18% mean cortical signal loss on T2*-weighted images. In the remaining eight patients, with <5 macrophages/mm(2), there was no cortical signal loss. However, in three of these, presenting with ischemic acute tubular necrosis, a strong (42 +/- 18%) signal drop was found in the medulla exclusively. USPIO-enhanced MR imaging can demonstrate infiltration of the kidneys by macrophages both in native and transplanted kidneys and may help to differentiate between kidney diseases.

Post-allogeneic haematopoietic stem cell transplantation membranous nephropathy: clinical presentation, outcome and pathogenic aspects.

BACKGROUND: Post-allogeneic haematopoietic stem cell transplantation (HSCT) membranous nephropathy (MN), a rare complication of HSCT, remains an ill-defined entity. We describe the clinical and biological characteristics and outcome of five patients with post-HSCT MN, review the previously reported cases and discuss the pathogenic aspects of this nephropathy. METHODS: Cases were identified by using a questionnaire sent to nephrologists and pathologists in French university and general hospitals. Medical records and kidney biopsy specimens were reviewed and relevant data were collected. Moreover, the IgG subclasses in glomerular deposits and the presence of chimeric renal cells were studied. RESULTS: Five patients were identified. All had a history of chronic graft-vs-host disease (cGVHD) and all had active manifestations of cGVHD at MN diagnosis. Mean time between HSCT and diagnosis of MN was 24.4 months. Renal insufficiency was present in four patients. Renal biopsy examination showed typical features of MN in all patients. IgG1 and IgG4 were the predominant IgG subclasses in the glomerular deposits. No chimeric glomerular cell was detected. Initial treatment for MN consisted in corticosteroids and immunosuppressors (ciclosporin, mycophenolate mofetil, rituximab, chlorambucil) in all patients. Complete remission of nephrotic syndrome (NS) occurred in two patients, partial remission in one patient, while treatment was inefficacious in one (data not available for one patient). Most interestingly, the evolution of NS paralleled the evolution of cGVHD in all patients. CONCLUSION: Our data suggest an association between cGVHD and post-HSCT MN. Treatment, mainly steroids and ciclosporin, should be aimed at the control of acute manifestations of cGVHD.

MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy.

PURPOSE: To assess renal glomerular homing of intravenously injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) at in vivo and ex vivo magnetic resonance (MR) imaging in an experimental rat model of mesangiolysis. MATERIALS AND METHODS: Animal procedures were performed in accordance with protocols approved by Institutional Animal Care and Use Committee. Fourteen rats were divided into two groups: one pathologic (n = 10), with persistent mesangiolysis following simultaneous injection of OX-7 monoclonal antibody and puromycin aminonucleoside in which 10(7) SPIO- and DiI-labeled MSCs were injected, and one control (n = 4). In vivo and ex vivo MR imaging examinations were performed with 4.7- and 9.4-T spectrometers, respectively, and T2*-weighted sequences. In vivo signal intensity variations were measured in the liver and kidney before and 6 days after MSC injection. Intrarenal signal intensity variations were correlated with histopathologic data by means of colocalization of DiI fluorescence, alpha-actin, and Prussian blue stain-positive cells. Histologic differences between the glomerular homing of MSCs in different kidney portions were correlated to the areas of MR signal intensity decrease with nonparametric statistical tests. RESULTS: On in vivo images, signal intensity measurements of pathologic kidneys following MSC injection did not show any signal intensity decrease (P = .7), whereas a 34% +/- 14 (mean +/- standard deviation) signal intensity decrease was observed in the liver (P < .01), where a substantial number of labeled cells were trapped. On ex vivo images, pathologic kidneys showed focal cortical (glomerular) areas of signal intensity loss, which was absent in controls. The areas of low signal intensity correlated well with alpha-actin and Prussian blue stain- and DiI-positive areas (P < .01), which indicates that MSCs specifically home to injured tissue. No MSCs were detected in the kidneys of control animals. CONCLUSION: Intravenously injected MSCs specifically home to focal areas of glomerular damage and can be detected at ex vivo MR imaging.

Activation of mesangial cells by platelets in systemic lupus erythematosus via a CD154-dependent induction of CD40.

BACKGROUND: Platelets are potential contributors to glomerular injury via the release of chemotactic and/or mitogenic mediators upon activation or through direct CD154/CD40-dependent interaction with cell components of the glomerulus. We examined whether platelets could activate mesangial cells and the potential role of the platelet-associated CD154. METHODS: Thrombin-activated platelets from systemic lupus erythematosus (SLE) patients or from disease or healthy controls were grown with human mesangial cells in the presence or not of a neutralizing anti-CD154 antibody either in contact or in a noncontact setting, the platelets and mesangial cells being separated by a pore size semipermeable membrane. The induction of mesangial cell surface antigens was assayed by flow cytometry. The quantification of mesangial cell proliferation was performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the production of transforming growth factor-beta1 (TGF-beta1), platelet-derived growth factor (PDGF) and soluble CD40 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Activated platelets from patients with SLE could induce an up-regulation of the expression of CD40 on mesangial cells with a concomitant release of soluble CD40. This induction required a direct contact between platelets and mesangial cells and was dependent upon the platelet-associated CD154. Pathologic consequences of the up-regulation of CD40 were a CD40-dependent stimulation of the proliferation of mesangial cells and a CD40-dependent increased production of TGF-beta1 by these cells. CONCLUSION: Platelets from patients with SLE can activate mesangial cells through CD40/CD154 interactions, leading to an induction of proliferation of the mesangial cells and an enhanced production of TGF-beta1, a profibrotic cytokine.

[Platelet-associated CD154: a new interface in haemostasis and in the inflammatory reaction]. / Le CD154 plaquettaire: une nouvelle interface dans l'hémostase et la réaction inflammatoire.

Blood platelets play a crucial part in the blood clotting process by forming the platelet plug. Recent evidence indicates that they are likely to play a key role in the inflammatory reaction via CD154/CD40 interactions. CD40 was known to be widely expressed, for instance on cells of the vasculature including endothelial cells, smooth muscle cells and macrophages. It was also known that the triggering of CD40 on these cells led to the acquisition of an activated pro-inflammatory and pro-coagulant phenotype. It was subsequently shown that platelets express CD154 which is cryptic in unstimulated platelets but is expressed at the platelet surface upon platelet activation. When expressed at the platelet surface and exposed to CD40-expressing vascular cells, the platelet-associated CD154 triggers a variety of pro-inflammatory and pro-coagulant responses including induction of adhesion receptors, release of cytokines and chemokines, induction of tissue factor and of metalloproteinases. Platelet-associated CD154 is also involved in platelet/platelet interactions during platelet aggregation. Furthermore, in vivo models have emphasized the critical role of the platelet-associated CD154 in the progression of atherosclerotic disease and in the stabilization of arterial thrombi. Recent data show that CD40-bearing cells involved in fibrosis such as hepatic stellate cells and glomerular mesangial cells also respond to platelet-associated CD154, thus suggesting a new mechanism by which platelets may be instrumental in the inflammatory diseases of the liver or the kidney. Finally, platelet-associated CD154 has been shown to have immune competence both in vitro and in vivo, observations that open new fields of research on the potential implications of platelets in the immune response and auto-immune diseases.

In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver.

PURPOSE: To evaluate in vivo magnetic resonance (MR) imaging with a conventional 1.5-T system for depiction and tracking of intravascularly injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs). MATERIALS AND METHODS: This study was conducted in accordance with French law governing animal research and met guidelines for animal care and use. Rat MSCs were labeled with SPIO and transfection agent. Relaxation rates at 1.5 T, cell viability, proliferation, differentiation capacity, and labeling stability were assessed in vitro as a function of SPIO concentration. MSCs were injected into renal arteries of healthy rats (labeled cells in four, unlabeled cells in two) and portal veins of rats treated with carbon tetrachloride to induce centrolobular liver necrosis (labeled cells and unlabeled cells in two each). Follow-up serial T2*-weighted gradient-echo MR imaging and R2* mapping were performed. MR imaging findings were compared histologically. RESULTS: SPIO labeling caused a strong R2* effect that increased linearly with iron dose; R2* increase for cells labeled for 48 hours with 50 microg of iron per milliliter was 50 sec(-1) per million cells per milliliter. R2* was proportional to iron load of cells. SPIO labeling did not affect cell viability (P > .27). Labeled cells were able to differentiate into adipocytes and osteocytes. Proliferation was substantially limited for MSCs labeled with 100 microg Fe/mL or greater. Label half-life was longer than 11 days. In normal kidneys, labeled MSCs caused signal intensity loss in renal cortex. After labeled MSC injection, diseased liver had diffuse granular appearance. Cells were detected for up to 7 days in kidney and 12 days in liver. Signal intensity loss and fading over time were confirmed with serial R2* mapping. At histologic analysis, signal intensity loss correlated with iron-loaded cells, primarily in renal glomeruli and hepatic sinusoids; immunohistochemical analysis results confirmed these cells were MSCs. CONCLUSION: MR imaging can aid in monitoring of intravascularly administered SPIO-labeled MSCs in vivo in kidney and liver.