To Thrombotic Microangiopathy Research Articles

A Modified Busulfan/Cyclophosphamide Preconditioning Regimen Incorporating Selinexor for Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Hematologic Malignancies

Objective: To investigate the safety and efficacy of a modified busulfan (Bu)/cyclophosphamide (Cy) conditioning regimen incorporating Selinexor for allogeneic hematopoietic stem cell transplantation in relapsed/refractory hematologic malignancies. Methods: We retrospectively evaluated the clinical outcomes of patients with hematologic malignancies who had received allo-HSCT with conditioning incorporating Selinexor at the Institute of Hematology and Blood Disease Hospital. Results: Between September 2022 and June 2023, 13 adult patients with high-risk hematologic malignancies were enrolled including 6 males and 7 females with a median age of 49 (13-58) years. There were 7 patients with acute myeloid leukemia (AML), 4 with myelodysplastic syndromes (MDS)/AML, 1 with multiple myeloma (MM) and 1 with extramedullary plasmacytoma. Six patients were in complete remission (CR), four in CR1, two in ≥CR2, five in non-remission (NR), and two patients were in a progressive disease status (PD) prior to conditioning. Three patients received matched-sibling donors transplant, while ten received related haploid hematopoietic stem cell transplantation. All patients had received myeloablative conditioning regimen incorporating Selinexor. Eleven patients received the conditioning: Bu (3.2mg/kg/d*2d); Melphalan (Mel, 60mg/m 2/d*2d), Fludarabine(Flu 30mg/m 2/d*3d) or CLA (5mg/m 2/d*3d), Cy (40mg/kg/d*2d), Selinexor 60mg/d*2d. The other 2 patients received the conditioning: Decitabine (DAC, 20mg/m 2/d*5d), Bu (3.2mg/kg/d*3d), Cy (40mg/kg/d *2d), Flu 30mg/m2/d*3d, Selinexor 60mg/d*2d. The median amount of infused mononuclear cell and CD34 + stem cell were 11.72×10 8/kg(range, 9.66 to 14) and 2.92×10 6/kg(range, 2.35 to 9.61), respectively. All the 13 patients achieved neutrophil engraftment with a median time of 12 (range, 9 to 18) days and 9 patients achieved platelet engraftment with a median time of 13 (range, 11 to 30) days. Four patients were still experiencing prolonged isolated thrombocytopenia. All patients achieved complete donor chimerism and minimal residual disease (MRD) negative at 30 days post-transplantation.The cumulative incidence of cytomegalovirus (CMV) reactivation was 15.4%, while Epstein-Barr virus (EBV) reactivation was not observed. Six patients (46.2%) experienced mucosal barrier injury, comprising three cases of oral mucosal ulcer, one case of digestive tract hemorrhage, and two cases of hemorrhagic cystitis. The cumulative incidence of II-IV and III-IV acute GVHD was 23.1% and 15.4%. The median follow-up for all the participants was 93 (40-316) days after transplantation. Only one patient was dead due to Thrombotic Microangiopathy (TMA) 78 days after transplant. One patient experienced molecular relapse 156 days after transplant, and another patient experienced hematology relapse 20 days after transplant. The two relapsed patients had received donor lymphocyte infusions after chemotherapy. The other 10 patients were still in CR with complete donor chimerism and MRD negative. The cumulative transplant-related mortality (TRM) and relapse rates are 7.7% (1 case) and 15.4% (2 cases), respectively. Conclusions: Incorporating Selinexor into the modified BU/CY conditioning regimen for allogeneic HSCT in patients with relapsed/refractory hematologic malignancies demonstrated a favorable safety profile. Ongoing prospective trials will provide valuable insights into the potential benefits of Selinexor in patients undergoing HSCT.

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Heme as Possible Contributing Factor in the Evolvement of Shiga-Toxin Escherichia coli Induced Hemolytic-Uremic Syndrome.

Shiga-toxin (Stx)-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) is one of the most common causes of acute kidney injury in children. Stx-mediated endothelial injury initiates the cascade leading to thrombotic microangiopathy (TMA), still the exact pathogenesis remains elusive. Interestingly, there is wide variability in clinical presentation and outcome. One explanation for this could be the enhancement of TMA through other factors. We hypothesize that heme, as released during extensive hemolysis, contributes to the etiology of TMA. Plasma levels of heme and its scavenger hemopexin and degrading enzyme heme-oxygenase-1 (HO-1) were measured in 48 STEC-HUS patients. Subsequently, the effect of these disease-specific heme concentrations, in combination with Stx, was assessed on primary human glomerular microvascular endothelial cells (HGMVECs). Significantly elevated plasma heme levels up to 21.2 µM were found in STEC-HUS patients compared to controls and were inversely correlated with low or depleted plasma hemopexin levels (R2 −0.74). Plasma levels of HO-1 are significantly elevated compared to controls. Interestingly, especially patients with high heme levels (n = 12, heme levels above 75 quartile range) had high plasma HO-1 levels with median of 332.5 (86–720) ng/ml (p = 0.008). Furthermore, heme is internalized leading to a significant increase in reactive oxygen species production and stimulated both nuclear translocation of NF-κB and increased levels of its target gene (tissue factor). In conclusion, we are the first to show elevated heme levels in patients with STEC-HUS. These increased heme levels mediate endothelial injury by promoting oxidative stress and a pro-inflammatory and pro-thrombotic state. Hence, heme may be a contributing and driving factor in the pathogenesis of STEC-HUS and could potentially amplify the cascade leading to TMA.

Hemolytic Uremic Syndrome

The emergence of specific treatment of atypical hemolytic uremic syndrome (aHUS) using eculizumab has allowed renal function recovery and safe kidney transplantation (KT). Early and precise recognition of complement-mediated (CM) atypical HUS (aHUS) is challenging and differs between children and adults. Our aim is to facilitate a decision-making process on HUS management. Hemolytic uremic syndrome (HUS) represents a heterogeneous group of diseases characterized by systemic endothelial cell injury, most often involving kidney, and which leads to thrombotic microangiopathy (TMA). Many inherited factors and environmental triggers cause HUS, but in children and the young, 90% are related to Shiga toxin-producing-Escherichia coli (STEC). Most non-STEC-HUS present primary complement (C) dysregulation and defective protection against C injury at the endothelial surface. Before eculizumab, CM-aHUS mortality was 60%, and progression to end stage kidney disease the rule, with frequent relapses after KT. Worldwide, the most common questions are who could benefit the most from C blockade, the most appropriate monitoring strategy for these individuals, and optimal duration of treatment with eculizumab. HUS is a life-threatening disease with poor outcome if untreated. Early and clear distinction between aHUS from other primary TMA (thrombotic thrombocytopenic-purpura, STEC-HUS), rare non-CM-aHUS, and secondary TMA is required as clinical features overlap. The current approach is terminology consensus, classification based on disease pathogenic mechanisms, and patient risk stratification.

Carfilzomib, Elotuzumab and Dexamethasone for Relapsed or Refractory Myeloma Patients

Carfilzomib, Elotuzumab and Dexamethasone for Relapsed or Refractory Myeloma Patients

Short Course of Eculizumab May Be Effective in Dialysis-Dependent Transplantation-Associated Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplantation: A Case Report

BackgroundAllogeneic hematopoietic stem cell transplantation (alloHSCT) could induce several complications. The most frequent viral infections and graft-vs-host disease (GvHD) sometimes lead to thrombotic microangiopathy (TMA). It is associated with significant morbidity and mortality with the risk of death reaching 90%. Effective prevention and treatment are not available to date. Recent attempts at using antibody against C5 have been made. Case reportA 19-year-old girl with acute myeloid leukemia twice underwent alloHSCTs from her 10/10 HLA-matched sister. After the second HSCT severe acute steroid-resistant grade 4 GvHD occurred. Despite treatment with high doses of steroids, mycophenolate mofetil, biological therapy, and extracorporeal photopheresis, the patient developed TMA with acute kidney injury and the need for renal replacement therapy. The concentration of complement component 3 and activity of ADAMTS 13 were normal, and infection with Escherichia coli (E. coli) 0157H7 was excluded. Due to failure of all ordered therapies and severity of the condition, an attempt was taken to use eculizumab. Two 900-mg doses of eculizumab (Soliris) were administered at an interval of 2 weeks, which resulted in the improvement of renal function and amelioration of hemolysis and thrombocytopenia. Dialysis therapy was finished after 5 weeks, and then a third dose of the drug was administered. Eighteen months later, the patient is alive and well, with limited chronic GvHD. eGFR remains stable at 40 to 46 mL/min/1.73 m2, and mild hypertension requires treatment with angiotensin converting enzyme inhibitors and furosemide. ConclusionEven a short course of eculizumab can be sufficient in controlling the TMA after HSCT, provided that the TMA-triggering factors are well controlled.

Hemolytic uremic syndrome associated with pregnancy

Atypical hemolytic uremic syndrome (aHUS) in 12-31% of cases is associated with pregnancy or childbirth and can determine the prognosis of both the mother and the child. In recent years more attention in obstetric practice has been paid to thrombotic microangiopathy (TMA) as one of the most serious complications of pregnancy. Despite the fact that during pregnancy TMA rarely develops (TMA in obstetrics accounts for 8-18% in the structure of all forms of TMA), high risk of pre-eclampsia, maternal and perinatal mortality, unfavorable "renal prognosis" associated with this pathology, determine the relevance of studying this problem.

Observations from the First 1,000 Suspected aHUS Patients, Tested By a Rapid aHUS Genetic (NGS) Panel: Causative Genes Identified in a Subpopulation of Our Database

Atypical Hemolytic Uremic Syndrome (aHUS) is a life-threatening, progressive genetic disease. aHUS results from uncontrolled activation of the complement system, which then targets endothelial cells, leading to thrombotic microangiopathy (TMA). The disease commonly progresses to kidney failure and death. Currently, aHUS is diagnosed by ruling out other diseases which cause TMA. Treatment is often performed with eculizumab, a terminal inhibitor of complement, which is expensive. Due to the severity of aHUS and the expense of treatment, rapid diagnosis of the disease is desirable. With a genetic sequencing assay for aHUS with a turnaround time of two days, we have gained comprehensive genetic understanding of a population of patients displaying acute clinical presentation of aHUS. The genes sequenced for the assay are CFH, MCP (CD46), CFI, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, THBD, PLG, and DGKE, alongside deletion/duplication analysis for CFHR1-3 and CFHR1-4. Currently, over 1000 patients have been tested using this panel. We reviewed de-identified aggregate results for a subset of patients tested using this panel (416 patients). We tabulated the frequency of clear-cut causative genetic variants in each of the genes among the patients tested positive for aHUS. The most common variant among the positives tabulated is the large deletion in CFHR1, at 23%. 23% of positives have a variant in MCP, 15% in CFH, 10% in THBD, 9% in CFI, 6% in C3, 6% in PLG, 5% in CFB, 3% in CFHR5, and 1% in DGKE. Furthermore, we report the frequency of positive, equivocal and negative results, breakdown of rare variant types per gene, frequency of patients with multiple rare variants, frequency of novel variants in the genes sequenced, frequency of deletion-duplication events in CFHR1-3 and CFHR1-4, and the CFH and MCP/CD46 risk polymorphisms. These data may provide the largest overview to date of genetic variants in risk-factor genes in patients where an aHUS diagnosis is suspected. DisclosuresNo relevant conflicts of interest to declare.

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

IntroductionCobalamin C (cblC) deficiency is the most common inborn error of vitamin B12 metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.MethodsWe performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.ResultsThe histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.ConclusionThis study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.

Hemolytic uremic syndrome with dual caution in an infant: cobalamin C defect and complement dysregulation successfully treated with eculizumab.

Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury. Atypical hemolytic uremic syndrome (aHUS) is a devastating disease with significant mortality and high risk of progression to end-stage kidney disease. It is mostly caused by dysregulation of the alternative complement pathway. Cobalamin C (Cbl C) defect is a genetic disorder of cobalamin metabolism and is a rare cause of HUS. We present a 6-month-old male infant who was admitted to the pediatric intensive care unit (PICU) due to restlessness, severe hypertension, anemia, respiratory distress, and acute kidney injury. Metabolic screening revealed elevated plasma homocysteine levels, low methionine levels, and methylmalonic aciduria, and the patient was diagnosed as having HUS secondary to Cbl C defect. Additionally, complement factor H (CFH) and complement C3 levels were decreased. The infant was treated with betaine, hydroxycobalamin, and folic acid. After treatment, the homocysteine and methylmalonic acid levels were normalized but hemolysis and acute kidney failure persisted. He required continued renal replacement treatment (CRRT) and plasma exchange due to thrombotic microangiopathy (TMA). Therefore, we considered a second mechanism in the pathogenesis as complement dysregulation and gave eculizumab to the patient. After eculizumab treatment, the renal and hematologic indices improved and he was free of dialysis. To the best of our knowledge, our patient is the first to have Cbl C defect-HUS accompanied by complement dysregulation, who responded well to eculizumab therapy.

Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy

IntroductionInterferon (IFN)-α and IFN-β approved for treatment of chronic hepatitis C viral infection and multiple sclerosis respectively have been linked to thrombotic microangiopathy (TMA) affecting renal function. Since the molecular mechanisms underlying this severe complication remain largely unclear, we aimed to investigate whether IFN affects directly in vitro endothelial cell functions associated with angiogenesis and blood haemostasis, as well as endothelial cell-derived vasodilators of nitric oxide (NO) and prostacyclin. MethodsProliferation and survival of human umbilical vein endothelial cells (HUVECs) were measured by BrdU incorporation and alamarBlue assays. Angiogenesis was evaluated in co-cultures of HUVECs and human dermal fibroblasts. Fibrinolysis molecules were measured with ELISA. NO and prostacyclin were measured using a fluorescent NO-specific probe and a competitive enzyme immunoassay, respectively. ResultsHUVEC proliferation was dose-dependently inhibited by IFN-β1a and IFN-β1b, but not by IFN-α2a and IFN-α2b. Consistently, IFN-β1a and IFN-β1b also reduced survival of HUVECs, but this again was not observed with IFN-α. However, both IFN subtypes inhibited VEGF-induced development of capillary-like structures, but the effect of IFN-α was less potent than IFN-β. In addition, both IFN subtypes upregulated interferon inducible protein 10 production from treated co-cultures while suppressing angiogenesis. Furthermore, intracellular NO generation was reduced by IFN-α2a and IFN-β1a, whereas prostacyclin release from HUVECs was not affected by IFN. Importantly, both IFN-β1a- and IFN-β1b-treated HUVECs showed a marked reduction in urokinase-type plasminogen activator release and a much greater secretion of plasminogen activator inhibitor-1 than tissue-type plasminogen activator compared with untreated cells, suggesting decreased fibrinolytic activity. IFN-α, however was less effective in modulating the fibrinolysis system. ConclusionsWe demonstrate the detrimental effects of IFN on endothelial cell functions mediated with angiogenesis and fibrinolysis, which could potentially cause the loss of physiological endothelium thromboresistance and facilitate the development of vascular complications in a clinical setting. Mechanistically, our findings have implications for understanding how IFN therapy can foster the development of TMA.

Renal-limited thrombotic microangiopathy and acute interstitial nephritis with a single dose of quinine.

Quinine has been reported to cause acute kidney injury by various mechanisms. The response to quinine can result in a spectrum of problems ranging from isolated thrombocytopenia to thrombotic microangiopathy (TMA) to disseminated intravascular coagulation. Quinine has also been reported to cause acute interstitial nephritis (AIN). We report an unusual presentation where both of these entities of renal-limited TMA and AIN were precipitated by a single dose of quinine.

Hemolytic uremic syndrome associated with Clostridium difficile infection

We report 3 cases of Clostridium difficile-associated hemolytic uremic syndrome (HUS) with biopsy proven renal thrombotic microangiopathy. Two patients with acute renal failure were kidney transplants recipients whereas the third patient developed renal failure in the native kidneys. The presentation was preceded by acute diarrhea and stool. Clostridium difficile toxin was detected in all the 3 patients. Stool studies were negative for Escherichia coli, Shigella dysenteriae and other enteric pathogens. The diagnosis of Clostridium difficile-associated hemolytic uremic syndrome was suspected due to presence of thrombocytopenia, microangiopathic hemolytic anemia and biopsy proven renal thrombotic microangiopathy without another clinically apparent cause. This case series suggest that Clostridium difficile infection may cause renal failure due to thrombotic microangiopathy (TMA) and should be considered in the differential diagnosis of diarrhea-associated HUS.

Uremia and Thrombotic Microangiopathy: Conditions That May Havethe Same Manifestation

In this article, we present the case of a man with uremia. Laboratory testing revealed thrombocytopenia, erythrocyte fragmentation, elevated lactate dehydrogenase, and malignant hypertension, manifestations that are similar to thrombotic microangiopathy (TMA). Thromboasthenia, manifested as a decrease in the platelet aggregation rate, was also noted. Regular hemodialysis (3 times per week) improved the patient’s thrombocytopenia and thromboasthenia. This case supports the conclusion that uremic toxin, which can be removed by hemodialysis, inhibits the quantity and quality of platelets. We believe that the platelet aggregation rate can be a useful tool in distinguishing uremia from TMA.

Eculizumab (ECU) Safety and Efficacy in Atypical Hemolytic Uremic Syndrome (aHUS) Patients with Long Disease Duration and Chronic Kidney Disease (CKD): 2-Year Results

AbstractAbstract 985 Introduction:aHUS is a rare, life-threatening genetic disease of chronic, uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA) and vital organ damage. After the first clinical manifestation, 33%–40% of aHUS patients (pts) will progress to end-stage renal disease (ESRD) or die. Long-term dialysis and high graft rejection rates complicate aHUS management. We previously reported a statistically significant suppression of TMA in a phase 2 trial of the terminal complement inhibitor ECU in pts with persistent aHUS, CKD, and previous chronic plasma exchange/infusion (PE/PI). Here we report 2-year (y) results. Methods:aHUS pts ≥12 y (N=20) treated with chronic PE/PI enrolled in an open-label, phase 2 trial. After 8 weeks (wk) of observation, pts stopped PE/PI and initiated ECU for 26 wk, followed by a long-term ECU treatment extension. Results:Twenty pts received ECU through wk 26, and 19 pts continued ECU in the extension phase. Data analysis was performed in the intention to treat population (n=19). Median time from diagnosis to screening was 48 months (mo) (range 0.66–286). 50% of pts had baseline (BL) estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, and 2 of these pts were on chronic dialysis; 8 pts had prior renal transplants. Pts received PE/PI for a median of 10 mo (range 2.4–47) prior to ECU. Median ECU treatment duration was 114 wk (range 2–145). TMA event-free statusa was achieved by 19 pts (95%) for an average duration of 698 days (d). Hematologic normalizationb was achieved or maintained in 18 pts (90%) by wk 26, and sustained to data cutoff. eGFR improved significantly from BL to data cutoff (P=0.05). The proportion of pts with improved renal function (eGFR ≥15 mL/min/1.73 m2) increased from 26 wk (5%) to 1 y (15%) and to 2 y (40%). A flat slope of eGFR change from d −42 to 0, followed by rapid eGFR improvement from d 0 to 28 (P=0.0066) that was maintained through d 860 was demonstrated by a 3-piece linear model. Earlier ECU treatment was associated with greater eGFR improvement (P=0.0013), but pts showed clinical benefit regardless of when ECU was initiated. The proportion of pts with decreases in proteinuria ≥1 grade increased from 26 wk (50%) to 2 y (83%). No pt received PE/PI or progressed to ESRD/dialysis. In a pt subgroup able to show an accepted clinically important difference (n=11), 82% attained significant and sustained improvements in quality of life (QOL). Outcomes were similar in pts with or without an identified complement regulatory factor mutation. Long-term ECU was well tolerated. Most common adverse events (AEs): diarrhea, hypertension and upper respiratory tract infection. Three serious AEs were related to ECU (all resolved with no change in ECU dosing). There were no meningococcal infections. There was 1 pt death due to gastrointestinal bleed after 1.9 y of ECU treatment that was deemed unrelated to drug. Conclusions:In aHUS pts with substantial renal damage despite prior chronic PE/PI, those expected to reach ESRD and those with renal transplant, long-term ECU treatment was associated with sustained TMA inhibition and continued significant improvements in eGFR and proteinuria. Earlier intervention with ECU resulted in greater improvement in eGFR. All pts eliminated PE/PI and no pt required new dialysis. Long-term ECU treatment was well tolerated and led to significant improvements in QOL in pts with chronic aHUS disease.TableOutcomes of ECU treatment (N=20)ParameterWk 26Median 114 WkTMA event-free status, n (%) (primary)16 (80)19 (95)eGFR increase of ≥15 mL/min/1.73 m2, n (%)1 (5)8 (40)CKD improvement of ≥1 stage, n (%)7 (35)12 (60)≥25% serum creatinine reduction, n (%)3 (15)11 (55)Mean eGFR change, mL/min/1.73 m2 (95% CI)6.1 (3.3, 8.7)7.1 (−0.03, 14)cP<0.0001P=0.05 (wk 96)Proteinuria decrease ≥1 grade,d n/N8/1612/15Mean health-related QOL change, EuroQOL 5D scoree (95% CI)0.12 (0.07, 0.17)0.14 (0.10, 0.18)P<0.0001P<0.0001 (wk 96)CI=confidence interval.ECU dose: 900 mg/wk for 4 wk, 1200 mg at wk 5, and 1200 mg q2 wk thereafter. Repeated measures model for significance.a≥12 consecutive wk of no platelet count decrease >25%, no PE/PI and no new dialysis.bNormal platelet and lactate dehydrogenase levels, ≥2 consecutive measurements, ≥4 wk apart.cOne pt on dialysis received transplant on d 217; pt renal data were censored on d 217 with continued ECU.dEvaluable pts.eClinically meaningful threshold ≥0.6. Disclosures:Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals: Sat on advisory board of Alexion Pharmaceuticals. Other. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Herthelius:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other. Goodship:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.

Thrombotic microangiopathic nephropathy, pulmonary hypertension and nephromegaly: case report of a patient treated with endothelin receptor antagonist

The coexistence of thrombotic microangiopathic nephropathy and pulmonary hypertension has only been described in association with malignancy and its treatment. Here we describe a 14-year-old boy with no prior medical history who presented with hypertension, proteinuria and nephromegaly, and then developed progressive pulmonary hypertension. Renal histology showed lesions consistent with glomerulopathy due to thrombotic microangiopathy (TMA). Pulmonary hypertension was controlled by the use of an oral endothelin receptor antagonist (bosentan). Although renal function deteriorated at the onset of pulmonary hypertension, an improvement was observed after the bosentan treatment. Nephromegaly persisted, but current creatinine clearance values are within the normal range. While this case exemplifies how thrombotic microangiopathic nephropathy may be associated with pulmonary hypertension, a therapeutic role of endothelin antagonists is suggested, not only for pulmonary hypertension but also for microangiopathic nephropathy.

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Resistant to Plasma Exchange/Infusion (PE/PI): Results of An Extension Study

Abstract 193▪FN2▪This icon denotes a clinically relevant abstract INTRODUCTION:aHUS is a genetic, systemic disease with a devastating prognosis caused by chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA), progressive organ damage and premature mortality. In a 26-wk phase II trial, pts receiving ECU, a terminal complement inhibitor, had a highly significant increase in platelet count (a measure of TMA improvement) (primary endpoint: 73×109/L increase; p=0.0001). 13/15 pts with low platelet count at baseline (BL) (ITT) had platelet normalization at Wk 26. 15/17 pts (88%) achieved TMA event-free status (≥12 wks of stable platelet count, no PE/PI and no new dialysis). 13/13 pts treated with ECU for 26 wks had platelet normalization at Wk 26 and 15/15 treated with ECU for 26 wks achieved TMA event-free status. Median TMA intervention rate was 0 (no. of PE/PI and new dialysis events/pt/day). Importantly, 4/5 pts on dialysis with PE/PI discontinued dialysis with ECU. ECU was well tolerated (Legendre. ASN 2010). We report longer follow-up data from the extension phase of this ongoing trial. METHODS:Pts ≥12 yrs with aHUS and persistent TMA despite ≥4 PE/PI sessions 1 wk before screening were enrolled in a 26-wk, controlled, open-label, single-arm phase II trial and continued into an extension trial. ECU dosage: 900mg/wk for 4 wks, 1200mg at Wk 5, 1200mg q2 wks. All pts received a meningococcal vaccine and prophylactic antibiotics ≥14 days after vaccination. Efficacy analyses were based on ITT population. RESULTS:17 pts enrolled (2 discontinued at Wks 1 and 6; systemic lupus erythematosus [protocol violation] and an adverse event unrelated to ECU, respectively). Median time from diagnosis to screening=10mo (0.3–236). Median duration from overt clinical manifestations of aHUS to screening=0.75mo (0.2–4). Median number of PE/PI sessions per pt during aHUS current clinical presentation=17 (2–37). 5 patients (29%) required dialysis at baseline. Median age=28 yrs. 4 pts (24%) had no identified complement regulatory factor mutations (CRFM). ECU mean (SD) duration=58 (29) wks at data cut-off. Mean change (SD) in platelet count from BL was maintained (97×109/L [81] at Wk 26 vs 98×109/L [60] at 1 yr). All 13 pts who had platelet normalization at Wk 26 continued to maintain normal levels at data cut-off. The same 15/17 (88%) pts achieved TMA event-free status at data cut-off. All pts receiving sustained ECU treatment throughout the study achieved TMA event-free status at data cut-off. Renal function was maintained and continued to further improve in pts with ongoing ECU: improvement ≥1 CKD stage from BL: from 10 (59%) pts at Wk 26 to 11 (65%) pts at data cut-off and ≥25% decrease in creatinine from BL: from 11 (65%) pts at Wk 26 to 13 (77%) pts at data cut-off. With sustained ECU therapy, only 1 of the 5 pts at baseline continued on to require dialysis and no patient newly required dialysis (as of data cut off). Long-term chronic ECU was similarly effective in pts with/without identified CRFM. ECU was generally well tolerated; adverse events deemed related to ECU were reported in 12 pts (mostly mild to moderate, 1 severe). The extension trial continues. CONCLUSIONS:In aHUS, despite PE/PI, >50% of pts either die, require dialysis, or have permanent renal damage within the first year of diagnosis. In contrast, all pts treated with ECU for a mean duration of >1 yr remain alive, 4 out of 5 pts became dialysis free, and no pt newly required dialysis. This demonstrates that continued ECU treatment significantly transformed the clinical course of aHUS in this pt population. In addition, long-term ECU therapy suppressed TMA and dramatically improved renal function. These long-term follow-up data further strengthen the evidence for ECU as the new standard of care for aHUS. Disclosures:Greenbaum:Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Eculizumab for the treatment of atypical hemolytic syndrome as part of clinical trials. Babu:Alexion: Research Funding. Furman:Alexion: Research Funding. Sheerin:Alexion: Research Funding. Cohen:Alexion: Research Funding. Gaber:Alexion: Research Funding. Delmas:Alexion: Research Funding. Loirat:Alexion: Research Funding. Bedrosian:Alexion: Employment. Legendre:Alexion: Research Funding.

Inhibition of tyrosine kinases by sunitinib associated with focal segmental glomerulosclerosis lesion in addition to thrombotic microangiopathy

Sunitinib is an orally administered inhibitor of tyrosine kinases and has become the standard of care for many patients with metastatic renal cell carcinoma. Its use has been associated with renal toxicity in some patients. We report a patient with a metastatic clear-cell renal carcinoma who showed arterial hypertension, nephrotic syndrome and azotaemia 10 months after treatment with sunitinib. The renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in addition to thrombotic microangiopathy (TMA), and the complete syndrome disappeared 6 months after sunitinib withdrawal. To our knowledge, this is the first case of FSGS associated to TMA secondary to sunitinib treatment. We discuss the possible glomerular pathomechanism.

Thrombotic Thrombocytopenic Purpura: The Masquerader

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder with a mortality rate of up to 90% if left untreated, and is characterized by microvascular thrombi, mainly in small arteries and capillaries, thrombocytopenia, hemolysis, and neurological abnormalities. Malignant hypertension (HTN) is a clinical syndrome characterized by severe hypertension associated with end-organ damage; including encephalopathy, renal dysfunction, and retinal hemorrhage due to platelet aggregation in the microcirculation leading to thrombotic microangiopathy (TMA). These are similar to TTP. Malignant hypertension can cause endothelial injury and fibrinoid necrosis in the vessel wall which results in its clinical manifestations. Therefore, it is difficult to differentiate malignant hypertension from TTP. However, it is critical to differentiate these two entities, as early initiation of plasmapheresis in TTP can be life saving. TTP is considered a masquerader as it can present with few clinical features and, if the index of suspicion is not very high, lead to mortality.

Thrombotic microangiopathy in a sirolimus-treated renal transplant patient receiving gemcitabine for lung cancer

Many etiologies lead to thrombotic microangiopathy (TMA), amongst which are antineoplastic chemotherapies. Gemcitabine, a nucleoside analogue, has been approved for the treatment ofbladder and advanced non-small cell lung carcinomas (NSCLC). The reported incidence of gemcitabine-associated TMA in the literature is low, ranging from 0.015-0.31%. Herein, we describe the first reported case of gemcitabine-induced TMA in a renal transplant patient. This occurred in a 54-year-old male transplant recipient undergoing sirolimus-based immunosuppression. In February 2005, he was diagnosed to have NSCLC, for which he received dual chemotherapy, including carboplatin and gemcitabine. After the third cycle he developed TMA. On admission, he presented with weakness, edema, normal blood pressure, leucopenia (2440/mm3), thrombopenia (11,000/mm3), hemolytic anemia with hemoglobin at 8 g/dl, schistocytes between 18-33% per hundred, increase in lactate dehydrogenase at 600 IU/l (N <380), and decreased haptoglobin at 0.29 g/l. Renal function was stable: serum creatinine was 1.3 mg/dl, albuminemia 30 g/l, proteinuria was present at 3 g/l in association with microscopic hematuria, and sirolimus trough level was 6.4 ng/ml. Treatment included infusions of fresh frozen plasma, withdrawal of sirolimus, which was replaced by mycophenolate mofetil, and suspension of chemotherapy. He fully recovered from TMA within 4 weeks. The concomitant use of sirolimus, which inhibits vascular endothelial growth factor, plus gemcitabine may have resulted in TMA.