Renal Thrombotic Microangiopathy Research Articles

Ocular ischemic changes in thrombotic microangiopathy associated with malignant arterial hypertension (case study)

The article presents a clinical observation of visual organ damage as an extrarenal manifestation of thrombotic microangiopathy in malignant arterial hypertension with an analysis of structural and functional changes in the eye by modern examination methods. The presence of renal thrombotic microangiopathy was verified by kidney biopsy. Optical coherence tomography was used to determine structural changes in the inner and outer layers of the retina in the form of their disorganization, areas of thickening of the nerve fiber layer, intraretinal inclusions and cysts, alterations of the ellipsoid zone and retinal pigment epithelium. Optical coherence tomography angiography revealed areas of vascular pattern attenuation in the deep and superficial retinal plexuses corresponding to OCT-detected foci of disorganization of the inner retinal layers. Color Doppler imaging showed absence of the diastolic component of the Doppler spectrum with an increase in the peripheral resistance index RI up to 1.0 in the central retinal artery and posterior short ciliary arteries in both eyes. Functional changes observed with multifocal electroretinography and microperimetry corresponded to the structural changes. Taking into account the similarity of microcirculation in the kidneys and the eyes, the probable pathogenetic mechanism underlying the detected structural and functional symptoms of ischemic damage to the visual organ in malignant arterial hypertension is chronic thrombotic microangiopathy. An interdisciplinary approach to studying thrombotic microangiopathy, including those associated with malignant arterial hypertension, using high-tech examination methods can be useful for timely diagnosis and treatment of this pathology.

Clinico-Histological Features of Thrombotic Microangiopathy in Renal Biopsies: A Retrospective Study.

Thrombotic microangiopathy (TMA) is often first detected on a renal biopsy performed for renal manifestations. Apart from hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura, there are various secondary conditions associated with TMA. This study analyzes the clinico-pathological spectrum, etiological factors and renal outcome of TMA diagnosed on renal biopsy. A retrospective evaluation of renal biopsies for TMA over 5.5 years was performed. Clinical and laboratory data was collected from patient records. A total of 40 biopsies from 39 patients showed TMA comprising 33 native and 7 transplant biopsies. Malignant hypertension (n=13) was the most common etiology in native biopsies followed by postpartum TMA (n=7), atypical HUS (aHUS) (n=7), and lupus nephritis (n=6). TMA in transplant biopsies was due to acute rejection (n=4) and CNI toxicity (n=3). Serum creatinine was high in most patients (mean 5.6 + 2.5 mg/ dl). aHUS showed the highest mean LDH levels and the lowest average platelet counts. Renal biopsies in malignant hypertension and postpartum TMA showed isolated arterial changes while aHUS and lupus nephritis showed both glomerular and arterial involvement. Postpartum TMA and aHUS had poor renal outcome requiring renal replacement therapy. Most postpartum TMA and aHUS had systemic features of TMA while malignant hypertension and lupus nephritis showed 'isolated renal TMA'. This emphasizes the importance of careful evaluation of renal biopsies even in the absence of systemic features of TMA.

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.

Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.

COVID-19 Manifesting as Renal Allograft Dysfunction, Acute Pancreatitis, and Thrombotic Microangiopathy: A Case Report

Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis.

Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare plasma and urine complement activation products between patients with active lupus nephritis (aLN) and those with acute TMA plus concomitant active LN (aTMA+aLN). Plasma and urine samples were obtained from 20 patients with aTMA+aLN, 20 patients with aLN matched by the histological activity index, 5 patients with chronic TMA, 20 patients with inactive LN, and 10 kidney donors. Complement fragments C3a, C4a, C4d, Ba, C5a, C5bC9, and factor H were determined by ELISA; and kidney C4d deposition was detected by immunohistochemistry. Patients were followed for > 12 months and complement activation products re-measured after treatment in 10 aTMA+aLN patients. Both aTMA+aLN and aLN groups had increased circulating C3a, Ba, and C5bC9; and decreased circulating C3, C4, C4a, C4d, and factor H. Urinary C3a, C5a, Ba, and C5bC9 were higher in patients with aTMA+aLN than in aLN. After treatment, levels of circulating C3, C4, and factor H increased; while levels of urinary C3a, C5a, Ba, and C5bC9 decreased in patients with aTMA+aLN. These changes were observed at each aTMA episode in two patients studied during repeated TMA episodes. There was no difference in C4d deposition in glomerular capillaries, tubular basement membrane, peritubular capillaries, and arterioles between patients with aLN and those aTMA+aLN. Circulating and urine complement activation products suggest that thrombotic microangiopathy associated with LN is mediated through activation of the alternative complement pathway. Key Points • Immune-complex kidney disease in systemic lupus erythematosus (SLE) is associated with activation of the classical, lectin, and alternative complement pathways • Indirect evidence from measurement of circulating and urinary complement pathway activation products suggests that renal acute thrombotic microangiopathy in SLE is mediated by activation of the alternative complement pathway • C4d kidney immunohistochemistry may be positive in both immune complex nephritis and thrombotic microangiopathy. Therefore, it is not a specific marker of renal thrombotic microangiopathy in SLE.

Does Therapeutic Plasma Exchange Improve Kidney Function in Renal Transplant-Associated Thrombotic Microangiopathy?

Does Therapeutic Plasma Exchange Improve Kidney Function in Renal Transplant-Associated Thrombotic Microangiopathy?

Podocyte Involvement in Renal Thrombotic Microangiopathy: A Clinicopathological Study

Background: The current study aimed to evaluate the associations between podocyte injury and clinicopathological features in renal thrombotic microangiopathy (TMA) based on a Chinese cohort, which might be underscored in this disease. Methods: The clinical, laboratory, and renal histopathological data of patients with renal biopsy-proven TMA from 2000 to 2015 in our institute were collected. Foot process effacement (FPE) was quantified by foot process width (FPW) by electron microscopy. Podocytes in the renal specimens were also detected by stainings for podocyte-specific markers, including Wilms tumor 1 (WT-1), synaptopodin, and podocalyxin. The associations between FPW and clinico-histopathological data were further analyzed. A composite end-point was defined by all-cause death or end-stage renal disease to address the predictive value of FPW. Results: Sixty-three patients with renal biopsy-proven TMA were enrolled. The FPW of renal TMA patients was 1,090 ± 637 nm (range, 572–4,748 nm), which was significantly higher than the normal range in our center (p = 0.005). By immunohistochemistry and immunofluorescence assays, we found decreased expressions of synaptopodin, podocalyxin, and WT-1 and continued stainings of WT-1 in some podocytes without detectable synaptopodin stainings in the areas of sclerotic tufts and cellular crescents. The FPW value was correlated with the serum albumin concentration (r_s = −0.281, p = 0.026), proteinuria amount (r_s = 0.255, p = 0.047), serum creatinine levels (r_s = 0.339, p = 0.007), and eGFR (r_s = −0.335, p = 0.007). According to ROC curve analysis, the optimal cutoff level of FPW for predicting the composite end-point was 869 nm. In patients with FPW ≥ 869 nm, FPW levels were further correlated with the severity of mesangiolysis (r_s = 0.351, p = 0.033) and glomerulosclerosis (r_s = 0.369, p = 0.025) in pathological evaluations. Patients without clinical remission also had higher FPW than those with remission (1,240 ± 793 vs. 925 ± 344 nm, p = 0.013). The multivariate Cox hazard model showed that FPW ≥ 869 nm was an independent risk factor for the composite end-point (hazard ratio: 3.64, 95% CI: 1.37–9.66, p = 0.009). Conclusion: The podocyte injury was prevalent and the FPW levels were closely associated with clinicopathological features, especially prognosis, in renal TMA patients.

Complement and Renal Thrombotic Microangiopathy Associated With Hypertension and Scleroderma.

Thrombotic microangiopathy is characterized by the presence of thrombocytopenia and microangiopathic hemolytic anemia and can occur in up to 50% of patients with hypertensive emergency and 10-15% with scleroderma. This review discusses the emerging role of complement in these 2 clinical entities. Specifically, we evaluate the evidence linking complement dysregulation with the manifestation of thrombotic microangiopathy and its clinical course in these settings. We also explore the rationale for complement blockade in these complex clinical scenarios that often have poor outcomes.

Сase of neonatal lupus in one of two children of dichorial diamniotic pregnancy in a woman with unrecognized systemic lupus erythematosus and lupus nephritis

The ability to realize the reproductive function for both patients with systemic lupus erythematosus and patients with a different cause of chronic kidney disease is rightfully considered as one of the most important achievements of modern medicine. The work describes the pregnancy case of the patient with systemic lupus erythematosus and secondary antiphospholipid syndrome. Renal damage with the development of renal thrombotic microangiopathy came to the fore in the clinical picture, which was regarded as nephritis and complicated the diagnosis of systemic lupus erythematosus. A positive pregnancy outcome was achieved with the development of neonatal lupus erythematosus in one twin child. The options for the prevention and treatment of thrombotic complications as well as methods for minimizing gestational complications (including preeclampsia, which the patient had in history) are discussed, inter alia, with the purposed of low-molecular-weight heparins and acetylsalicylic acid preparations. Treatment options are also described to improve the outcome of such pregnancies and to decrease the symptoms of neonatal lupus erythematosus using hydroxychloroquine. The article summarizes current management approaches for these patients with special attention to the interdisciplinary approach.

Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series

BackgroundCancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent.Cases presentationWe describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor.ConclusionsCR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients’ evolution, the persistence of TMA may reflect an uncontrolled malignancy.

Renal Complications after Hematopoietic Stem Cell Transplantation: Role of Graft-Versus-Host Disease in Renal Thrombotic Microangiopathy.

Hematopoietic stem cell transplantation (HSCT) is a widely accepted treatment for mainly hematopoietic disorders. Recent advances in transplantation techniques have increased the number of long-time survivors with chronic kidney disease (CKD). The presence of CKD affects outcomes and is associated with high mortality rates. Therefore, physicians treating transplant survivors should consider renal complications and optimize management of patients with CKD after HSCT. The pathology of CKD after HSCT is affected by many factors, and the causes of renal thrombotic microangiopathy (TMA) are diverse and complicated. We have treated patients who underwent allogeneic HSCT and developed late-stage renal TMA possibly associated with graft-versus-host disease (GVHD). Administration of immunosuppressive drugs, such as calcineurin inhibitors, is typically reduced in patients with TMA. However, if renal TMA is caused by renal GVHD, the use of immunosuppressive drugs should be increased, contradicting conventional thinking. On the basis of previous findings and our own observations, we review the pathology of renal complications after HSCT and focus on the role of GVHD in the development of renal TMA.

Renal thrombotic microangiopathy in an ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA) disease remains a diagnostic challenge due to the heterogeneity of possible clinical presentations. We present the case of a 63-year-old white male with a known history of ANCA-associated vasculitis (AAV) with anti-myeloperoxidase antibodies (MPO) – mainly with respiratory manifestations – treated with corticosteroids and cyclophosphamide, resulting in partial improvement. Six months later he was referred to the nephrology department for rapidly progressive renal failure and a kidney biopsy was performed, which showed several glomeruli globally sclerosed and others presenting fibrous crescents. Vascular involvement was also noted with several small arteries revealing endothelial swelling and entrapped erythrocytes within a fibrin thrombus. Immunofluorescence was negative. A high percentage of parenchymal fibrosis and no evidence of active extra-renal manifestations dictated no specific treatment. The patient is currently monitored in a low clearance nephrology consultation. Evidence of thrombotic microangiopathy (TMA) is an uncommon histological finding in kidney biopsies of patients with AAV, being associated with worst prognosis.

Renal and pulmonary thrombotic microangiopathy triggered by proteasome-inhibitor therapy in patient with smoldering myeloma

Rationale:Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common. A more recently described association is with monoclonal gammopathy. Lung involvement by TMA is infrequent, but has been described in Cobalamin C deficiency and post stem-cell transplantation TMA.Patient concerns:This is the case of a patient with smoldering myeloma who received proteasome-inhibitor therapy due to retinopathy and developed acute renal failure within one week of therapy initiation.Diagnoses:A renal biopsy showed thrombotic microangiopathy. At the time, mild pulmonary hypertension was also noted and presumed to be idiopathic.Interventions:Given the known association of proteasome-inhibitor therapy with thrombotic microangiopathy, Bortezomib was discontinued and dialysis was initiated.Outcomes:Drug withdrawal failed to prevent disease progression and development of end-stage renal disease, as well as severe pulmonary hypertension that eventually lead to the patient's death.Lessons:To our knowledge, this is the first reported case of pulmonary involvement by TMA associated with monoclonal gammopathy which appears to have been triggered by proteasome-inhibitor therapy. Clinicians should be aware of this possibility to allow for more prompt recognition of pulmonary hypertension as a potential manifestation of monoclonal gammopathy-associated TMA, especially in patients also receiving proteasome-inhibitors, so that treatment aiming to slow disease progression can be instituted.

Association of vascular endothelial growth factor and renal thrombotic microangiopathy-like lesions in patients with Castleman's disease.

Renal thrombotic microangiopathy (TMA) is a common pathological manifestation of Castleman's disease (CD)-associated renal lesions. Increased level of plasma vascular endothelial growth factor (VEGF) has been shown in single-case reports. We aimed to investigate the dysregulation of VEGF in the pathogenesis of CD-associated TMA-like lesions (CD-TMA) in a larger cohort. Nineteen patients with clinico-pathologically diagnosed CD with renal involvement were enrolled. Ten patients with pregnancy TMA or TMA of unknown reasons were enrolled as TMA control group. The plasma levels of VEGF, soluble Flt-1 and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay kits. The expression of VEGF in the kidney biopsied tissue sections and the lymph node specimens were detected by immunostaining. The plasma levels of VEGF and IL-6 levels were the highest in CD-TMA group compared to TMA control group and healthy controls. The levels of plasma VEGF was positively correlated with that of IL-6, and increased expression of VEGF and IL-6 was also observed in the lymph nodes from CD-TMA patients. However, the expression of VEGF in the glomerular podocytes was significantly decreased in CD-TMA group as well as in the TMA control. Our findings suggest that renal VEGF expression might be important in the pathogenetic mechanism of CD-associated TMA-like lesions.

MON-224 DIAGNOSING RENAL THROMBOTIC MICROANGIOPATHY BASED ON HISTOPATHOLOGY IN RAPIDLY PROGRESSIVE RENAL FAILURE

Appart from glomerular and tubulointerstitial lesion of rapidly progressive renal failure (RPRF), renal vascular lesion is a critical prognostic finding in which renal thrombotic microangiopathy (TMA) present with severe clinical manifestation and have a high morality. The aim of this study were to describe (1) the histopatological features of TMA, (2) its classification and (3) the associated lesions in RPRF. We observed 133 kidney biopsies performed in patients presented with RPRF from 2013 to March 2018 by by using light microscopy. Renal TMA was classified as acute TMA, defined by luminal thrombi including fibrin and fragments of red blood cells and associated with ischemic capillaries, mesangiolysis and edematous and mucinous intimal thickening, often infiltrated with foam cells. Chronic TMA was characterized by onion-skin fibrointimal sclerosis. Chronic active TMA showed both acute and chronic changes. There were 38 cases of TMA diagnosed histopathologically including 31/38 (81.6%) lupus nephritis (LN) with 26/31 classIV, 1/31 class V, 1/31 class III-V, 2/31class IV-V; 6/38 (15.8%) IgA nephropathy (IgAN) and 1/38 (2.6%) focal segmental sclerosis (FSGS). All 45% acute TMA were LN. 23% chronic TMA included 13% LN, 8% IgAN and 2% FSGS. 32% Chronic active TMA were 24% LN and 8% IgAN. Only one LN (2.6%) showed thrombus in artery. 34.2% cases with capillary occlusion were LN. The associated arteriolar lesions including thrombi (55.3%), edematous and mucinous intimal thickening (73.7%), fibrointimal sclerosis (34.2%) and immunofluorescence staining of thrombi with fibrin (44.7%) presented both in LN and IgAN. 55% had ischemic glomeruli. The FSGS solely showed arteriolar fibrointimal sclerosis and ischemic loops suggested for chronic TMA. The mesangiolysis, endothelial swelling and subendothelial expansion were not recognised in our observation probably due to the limitation of the quality of the microscopic slides as well as the lack of electromicroscopic equipment. The duplication of the basement membrane features was not applied for defining chronic TMA in capillaries especially in LN because of its frequent presence in many chronic conditions. Pathological features of renal thrombotic microangiopathy can varies considerably and can be seen frequently in many different severe kidney conditions.

Renal Thrombotic Microangiopathy Associated with Carfilozomib Use in Treatment of Multiple Myeloma

Abstract Carfilzomib is a newer class of selective proteasome inhibitor approved by FDA in 2012. It is used for the treatment of refractory multiple myeloma in patients who have received two prior therapies. We report a case of drug induced thrombotic microangiopathy associated with carfilzomib in a patient with refractory multiple myeloma. <span style=mso-bidi-font-size: 10.0pt;font-family: times= new= roman,serif;color:black;mso-themecolor:text1=>Keywords: Carfilzomib; Proteasome inhibitor; Thrombotic microangiopathy; Refractory <span style=font-size:11.0pt; mso-bidi-font-size:10.0pt;line-height:107%;font-family: times= new= roman,serif;= mso-fareast-font-family:calibri;mso-fareast-theme-font:minor-latin;color:black;= mso-themecolor:text1;mso-ansi-language:en-us;mso-fareast-language:en-us;= mso-bidi-language:ar-sa=>Abbreviations: <span style=font-size:10.0pt; line-height:107%;font-family: times= new= roman,serif;mso-fareast-font-family:= calibri;mso-fareast-theme-font:minor-latin;color:black;mso-themecolor:text1;= mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa=> AKI: Acute Kidney Injury; TMA: Thrombotic Microangiopathy; LDH: Lactate Dehydrogenase; CKD: Chronic Kidney Disease; RA: Rheumatoid Arthritis; TTP: Thrombotic Thrombocytopenic Purpura; HUS: Hemolytic Uremic Syndrome

Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

The role of the terminal complement pathway as the cause of atypical hemolytic uremic syndrome (aHUS) is widely recognized, but the relative contribution of the effectors C5a/C5aR1 and C5b-9 to disease pathogenesis has not been defined. Using FHR/R mice carrying a factor H mutation that causes cell surface complement alternative pathway dysregulation, Ueda documented that in FHR/R mice, C5b-9 causes renal thrombotic microangiopathy (TMA) whereas C5a/C5aR drives macrovascular thrombosis. This commentary addresses the implications and limitations of this study.

Atteintes rénales au cours du déficit en cobalamine C

Cobalamin C deficiency (cblC) is the most common inborn error of vitamin B12 metabolism. This autosomal recessive disease is due to mutations in MMACHC gene, encoding a cyanocobalamin decyanase. It leads to hyperhomocysteinemia associated with hypomethioninemia and methylmalonic aciduria. Two distinct phenotypes have been described : early-onset forms occur before the age of one year and are characterized by a severe multisystem disease associating failure to thrive to neurological and ophthalmological manifestations. They are opposed to late-onset forms, less severe and heterogeneous. CblC deficiency-associated kidney lesions remain poorly defined. Thirty-eight cases have been described. Age at initial presentation varied from a few days to 28 years. Most of the patients presented renal thrombotic microangiopathy (TMA) associated with acute renal failure, and 21 patients presented typical lesions of renal thrombotic microangiopathy on kidney biopsy. Prognosis was poor, leading to death in the absence of treatment, and related to the severity of renal lesions in the early-onset forms. Late-onset disease had better prognosis and most of patients were weaned off dialysis after treatment initiation. We suggest that all the patients with renal TMA be screened for cobalamin metabolism disorder, regardless of age and even in the absence of neurological symptoms, to rapidly initiate the appropriate treatment.

Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study

BackgroundThere are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab.MethodsPatients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events.ResultsAmong 93 patients (0–80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported.ConclusionsThe current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes.Trial registrationClinicalTrials.govNCT01522170, January 31, 2012.

Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy.

Renal thrombotic microangiopathy (TMA) is an uncommon pathological finding in lupus nephritis (LN), and its clinical significance remains to be defined. Twenty-four patients with lupus nephritis (LN) and renal TMA were selected from a retrospective review of 677 biopsy-proven LN patients, and compared with 48 LN controls without TMA (1:2 ratio) matched according to demographics and treatments. Renal TMA was noted in 3.5% of kidney biopsies of LN. TMA was associated with a higher prevalence of anti-Ro (45.8% vs 18.8%; p = 0.016), higher Systemic Lupus Erythematosus Disease Activity Index scores (21.4 ± 8.5 vs 10.8 ± 2.3; p < 0.001), lower estimated glomerular filtration rate (eGFR; 16.8 ± 11.7 ml/min vs 77.8 ± 28.6 ml/min; p < 0.001), and a higher percentage of patients who required dialysis (37.5% vs 2.1%; p < 0.001) at the time of kidney biopsy. Activity and chronicity indices [median (range)] were higher in the TMA group [11 (2-19) and 3 (1-8), respectively, compared with 7 (0-15) and 1 (0-3) in controls; p = 0.004 and p < 0.001; respectively]. Patients with TMA showed inferior 5-year renal survival and higher incidence of chronic kidney disease at last followup (70% and 66.6%, respectively, compared with 95% and 29.2% in controls; p = 0.023 and 0.002, respectively). The TMA group also showed lower median eGFR compared with controls [50.1 (IQR 7-132) ml/min vs 85.0 (IQR 12-147) ml/min; p = 0.003]. Five-year patient survival rate was similar between the 2 groups (87% and 98% in TMA and control group, respectively; p = 0.127). TMA in kidney biopsy was associated with more severe clinical and histological activity, and significantly inferior longterm renal outcome in LN.