Background Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe ...end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. Study Design Open-label single-arm phase 2 trial. Setting & Participants Patients 18 years or older with aHUS (platelet count <150 × 103 /μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal ULN, and serum creatinine ≥ ULN) were included in this multicenter multinational study. Intervention Intravenous eculizumab (900 mg/wk for 4 weeks, 1,200 mg at week 5 and then every 2 weeks) for 26 weeks. Outcomes & Measurements Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 103 /μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. Results 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline ( P < 0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. Limitations Single-arm open-label design. Conclusions Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.
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 m2 ), 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.
C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the ...terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38 mL/min/1.73 m2 . Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits.
Summary The objective of the study was to investigate the role of endothelin-1 in the pathogenesis of scleroderma renal crisis in patients with systemic sclerosis. We used immunohistochemical ...analysis with anti–endothelin-1 and anti–von Willebrand factor antibodies in comparing kidney biopsies from patients with systemic sclerosis and scleroderma renal crisis (n = 14); from normal kidneys (n = 5); and from patients with typical hemolytic uremic syndrome and thrombotic microangiopathy (n = 5), antiphospholipid syndrome (n = 6), diabetic nephropathy (n = 5), minimal change disease with cyclosporine toxicity (n = 5), or nephroangiosclerosis (n = 5). Kidney biopsies from all systemic sclerosis patients presented specific lesions: glomerular lesions with thickened capillary walls (n = 6, 42.8%), mesangiolysis (n = 3, 21.4%), fibrin thrombi (n = 3, 21.4%), hypertrophy of juxtaglomerular apparatus (n = 5, 35.7%), arteriolar lesions showing mucinous intimal thickening and lumen mucoid occlusions (n = 13, 92.8%), proliferation of intimal cells (ie, “onion-skin” lesions; n = 13, 92.8%), fibrinoid necrosis (n = 3, 21.4%), and fibrin thrombosis (n = 4, 28.6%). Chronic lesions in large arteries showed modifications such as fibrous intimal thickening (n = 13, 92.8%). The pattern of endothelial staining for endothelin-1 in both glomeruli and arteriolar lesions appears to be specific for scleroderma renal crisis. Glomerular endothelin-1 staining without arteriolar staining was seen in hemolytic uremic syndrome; and isolated arteriolar staining (without glomerular staining) was seen in a number of conditions including antiphospholipid nephropathy, cyclosporine toxicity, and diabetic nephropathy. Endothelin-1 is overexpressed in glomeruli and arterioles of patients with scleroderma renal crisis, which suggests that endothelin-1 might be a therapeutic target in this condition.
Objective The objective of the study was to determine the value of maternal serum Down syndrome screening in patients affected by renal disease. Study Design A study group of 54 pregnant women with ...renal diseases defined before pregnancy, was compared with a control group of 108 patients matched for maternal age, maternal weight, smoking status, and gestational age. Maternal serum markers (free β-human chorionic gonadotropin hCG, total hCG, alpha-fetoprotein) expressed in multiple of median and maternal renal function markers (creatinine, β2-microglobulin, α1-microglobulin) were assayed. Results The percentage of patients in the Down syndrome at-risk group (>1:250) using free β-hCG was significantly higher ( P < .02) in the renal disease group (48%) than in the control group (12%). No significant difference was observed for total hCG (25% vs 15%). Conclusion Down syndrome screening using free β-hCG is not applicable in patients with renal disease whatever the maternal serum creatinine and can be used with caution when total hCG is used.
Alagille syndrome (AGS; Online Mendelian Inheritance in Man no. 118450) is a multisystem autosomal dominant disorder with highly variable expression characterized by chronic cholestasis caused by a ...paucity of interlobular bile ducts, skeletal abnormalities, peculiar facies, ocular abnormalities, and cardiovascular disorders. AGS is diagnosed almost exclusively in children in the setting of predominant liver manifestations or, more rarely, in their adult relatives. We report 2 patients in whom AGS was diagnosed in adulthood during the workup of renal disease in the absence of a well-defined familial history. Renal disease caused by AGS probably is underdiagnosed in adult patients.
Pauci-immune renal vasculitis is associated strongly with antineutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin G (IgG) class, which are detected in 80% to 90% of affected patients. IgA ...ANCAs have been reported in association with various conditions, but never in the setting of pauci-immune vasculitis. A 28-year-old man with unexplained polyclonal hyper-IgA1 diagnosed in childhood presented with decreased kidney function, nephrotic syndrome, and microscopic hematuria. Kidney biopsy showed pauci-immune crescentic glomerulonephritis. Serum test results were negative for IgG ANCA by means of both indirect immunofluorescence and enzyme-linked immunosorbent assay techniques. Conversely, indirect immunofluorescence performed using anti-IgA antibody was strongly positive with a cytoplasmic ANCA pattern, and an enzyme-linked immunosorbent assay test had positive results for both antimyeloperoxidase and anti–proteinase 3 IgA. IgA ANCAs were not detected in 2 control serum samples from 1 patient with polyclonal hyper-IgA and 1 patient with monoclonal hyper-IgA. The patient received corticosteroids and 4 weekly perfusions of rituximab (375 mg/m2 ). After a 6-month follow-up, decreased kidney function and nephrotic syndrome persisted and IgA ANCA titers were unchanged. However, a control kidney biopsy showed a decrease in vasculitis activity. This first case of pauci-immune vasculitis associated with ANCA of the IgA class suggests the potential pathogenetic role of these peculiar antibodies. Additional studies are needed to determine whether IgA ANCAs, which are not routinely screened for, can be detected in patients with pauci-immune vasculitis either alone or in association with IgG ANCA.
Lupus nephritis (LN) is a severe and frequent complication of systemic lupus erythematosus. For decades, cyclophosphamide-based regimens have been the gold standard in treating patients with LN. ...However, cyclophosphamide use is associated with increased morbidity and mortality, and thus alternative treatments are needed. We report 3 cases of severe class IV LN successfully treated with rituximab as an induction, as well as a long-term maintenance, treatment. Complete remission of LN, documented by means of a control kidney biopsy, occurred in all patients and was maintained during follow-up using rituximab as sole maintenance treatment. No severe infectious complications were observed during treatment with rituximab. Our data suggest that rituximab may prove to be an optimal maintenance treatment in patients with severe LN.
Plasma Exchange for Disseminated Cryptococcosis Bollée, Guillaume, MD; Touzot, Maxime, MD; Mechai, Fredéric, MD ...
American journal of kidney diseases,
04/2009, Volume:
53, Issue:
4
Journal Article
Peer reviewed
Acute renal failure is frequent in HIV–infected patients and may be related to HIV–associated nephropathy, drugs, or opportunistic infections. We report a peculiar case of disseminated cryptococcosis ...complicated by acute renal failure associated with obstruction of intrarenal capillaries by Cryptococus neoformans dead bodies and successfully treated with plasma exchanges.
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